Pathogens

41 pages, 1952 KiB

Open AccessEditor’s ChoiceReview

Fungal-Bacterial Interactions in Health and Disease

by Wibke Krüger, Sarah Vielreicher, Mario Kapitan, Ilse D. Jacobsen and Maria Joanna Niemiec

Pathogens 2019, 8(2), 70; https://doi.org/10.3390/pathogens8020070 - 21 May 2019

Cited by 136 | Viewed by 17509

Fungi and bacteria encounter each other in various niches of the human body. There, they interact directly with one another or indirectly via the host response. In both cases, interactions can affect host health and disease. In the present review, we summarized current [...] Read more.

Fungi and bacteria encounter each other in various niches of the human body. There, they interact directly with one another or indirectly via the host response. In both cases, interactions can affect host health and disease. In the present review, we summarized current knowledge on fungal-bacterial interactions during their commensal and pathogenic lifestyle. We focus on distinct mucosal niches: the oral cavity, lung, gut, and vagina. In addition, we describe interactions during bloodstream and wound infections and the possible consequences for the human host. Full article

(This article belongs to the Special Issue Immunology of Fungal Infections)

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13 pages, 1404 KiB

Open AccessEditor’s ChoiceArticle

Putative Periodontal Pathogens, Filifactor alocis and Peptoanaerobacter stomatis, Induce Differential Cytokine and Chemokine Production by Human Neutrophils

by Aruna Vashishta, Emeri Jimenez-Flores, Christopher K. Klaes, Shifu Tian, Irina Miralda, Richard J. Lamont and Silvia M. Uriarte

Pathogens 2019, 8(2), 59; https://doi.org/10.3390/pathogens8020059 - 1 May 2019

Cited by 24 | Viewed by 4343

Abstract

Periodontitis is a highly prevalent infectious disease that affects ~ 50% of the adults in the USA alone. Two Gram-positive anaerobic oral bacteria, Filifactor alocis and Peptoanaerobacter stomatis, have emerged as important periodontal pathogens. Neutrophils are a major component of the innate [...] Read more.

Periodontitis is a highly prevalent infectious disease that affects ~ 50% of the adults in the USA alone. Two Gram-positive anaerobic oral bacteria, Filifactor alocis and Peptoanaerobacter stomatis, have emerged as important periodontal pathogens. Neutrophils are a major component of the innate host response in the gingival tissue, and the contribution of neutrophil-derived cytokines and chemokines plays a central role in disease progression. The pattern of cytokines and chemokines released by human neutrophils upon stimulation with newly appreciated periodontal bacteria compared to the keystone oral pathogen Porphyromonas gingivalis was investigated. Our results showed that both F. alocis and P. stomatis triggered TLR2/6 activation. F. alocis induced significant changes in gene expression of cytokines and chemokines in human neutrophils compared to unstimulated cells. However, except for IL-1ra, neutrophils released lower levels of cytokines and chemokines in response to F. alocis compared to P. stomatis. Furthermore, bacteria-free conditioned supernatant collected from neutrophils challenged with P. stomatis, but not from P. gingivalis or F. alocis, was chemotactic towards both neutrophils and monocytes. Elucidating stimuli-specific modulation of human neutrophil effector functions in the context of dysbiotic microbial community constituents provides valuable information for understanding the pathogenesis of periodontal diseases. Full article

(This article belongs to the Section Immunological Responses and Immune Defense Mechanisms)

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13 pages, 4201 KiB

Open AccessEditor’s ChoiceArticle

Inhibition of Pseudomonas aeruginosa Biofilm Formation with Surface Modified Polymeric Nanoparticles

by Tyler R. Flockton, Logan Schnorbus, Agustin Araujo, Jill Adams, Maryjane Hammel and Lark J. Perez

Pathogens 2019, 8(2), 55; https://doi.org/10.3390/pathogens8020055 - 24 Apr 2019

Cited by 30 | Viewed by 5566

Abstract

The gram-negative bacterial pathogen Pseudomonas aeruginosa represents a prominent clinical concern. Due to the observed high levels of antibiotic resistance, copious biofilm formation, and wide array of virulence factors produced by these bacteria, new treatment technologies are required. Here, we present the development [...] Read more.

The gram-negative bacterial pathogen Pseudomonas aeruginosa represents a prominent clinical concern. Due to the observed high levels of antibiotic resistance, copious biofilm formation, and wide array of virulence factors produced by these bacteria, new treatment technologies are required. Here, we present the development of a series of P. aeruginosa LecA-targeted polymeric nanoparticles and demonstrate the anti-adhesion and biofilm inhibitory properties of these constructs. Full article

(This article belongs to the Special Issue Signaling Systems in Pseudomonas aeruginosa Biofilm)

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23 pages, 1440 KiB

Open AccessEditor’s ChoiceReview

Candida albicans Interactions with Mucosal Surfaces during Health and Disease

by Spyridoula-Angeliki Nikou, Nessim Kichik, Rhys Brown, Nicole O. Ponde, Jemima Ho, Julian R. Naglik and Jonathan P. Richardson

Pathogens 2019, 8(2), 53; https://doi.org/10.3390/pathogens8020053 - 22 Apr 2019

Cited by 57 | Viewed by 17334

Abstract

Flexible adaptation to the host environment is a critical trait that underpins the success of numerous microbes. The polymorphic fungus Candida albicans has evolved to persist in the numerous challenging niches of the human body. The interaction of C. albicans with a mucosal [...] Read more.

Flexible adaptation to the host environment is a critical trait that underpins the success of numerous microbes. The polymorphic fungus Candida albicans has evolved to persist in the numerous challenging niches of the human body. The interaction of C. albicans with a mucosal surface is an essential prerequisite for fungal colonisation and epitomises the complex interface between microbe and host. C. albicans exhibits numerous adaptations to a healthy host that permit commensal colonisation of mucosal surfaces without provoking an overt immune response that may lead to clearance. Conversely, fungal adaptation to impaired immune fitness at mucosal surfaces enables pathogenic infiltration into underlying tissues, often with devastating consequences. This review will summarise our current understanding of the complex interactions that occur between C. albicans and the mucosal surfaces of the human body. Full article

(This article belongs to the Special Issue Immunology of Fungal Infections)

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11 pages, 256 KiB

Open AccessEditor’s ChoiceReview

Interleukin-17 in Antifungal Immunity

by Florian Sparber and Salomé LeibundGut-Landmann

Pathogens 2019, 8(2), 54; https://doi.org/10.3390/pathogens8020054 - 22 Apr 2019

Cited by 59 | Viewed by 5303

Abstract

The field of IL-17 biology has received much attention over the last decade owing to the pathogenic role of this cytokine in psoriasis and other autoinflammatory disorders and the successful implementation of IL-17-targeting therapies in patients suffering from these diseases. IL-17-mediated pathologies are [...] Read more.

The field of IL-17 biology has received much attention over the last decade owing to the pathogenic role of this cytokine in psoriasis and other autoinflammatory disorders and the successful implementation of IL-17-targeting therapies in patients suffering from these diseases. IL-17-mediated pathologies are contrasted by the important host beneficial effects of this cytokine. IL-17 is essential for regulating microbial colonization in barrier tissues. Rare congenital defects in the IL-17 pathway exemplify the relevance of IL-17 in protective immunity against the opportunistic fungal pathogen C. albicans. However, more recently, evidence is accumulating that IL-17 can also provide protection against fungi other than C. albicans. Importantly, protective IL-17 responses directed against commensal fungi can, under certain conditions, promote inflammation with detrimental consequences for the host, thereby assigning fungi a new role as disease-promoting factors apart from their role as potential infectious agents. Full article

(This article belongs to the Special Issue Immunology of Fungal Infections)

24 pages, 1002 KiB

Open AccessEditor’s ChoiceReview

ApiAP2 Transcription Factors in Apicomplexan Parasites

by Myriam D. Jeninga, Jennifer E. Quinn and Michaela Petter

Pathogens 2019, 8(2), 47; https://doi.org/10.3390/pathogens8020047 - 7 Apr 2019

Cited by 65 | Viewed by 10159

Abstract

Apicomplexan parasites are protozoan organisms that are characterised by complex life cycles and they include medically important species, such as the malaria parasite Plasmodium and the causative agents of toxoplasmosis (Toxoplasma gondii) and cryptosporidiosis (Cryptosporidium spp.). Apicomplexan parasites can infect [...] Read more.

Apicomplexan parasites are protozoan organisms that are characterised by complex life cycles and they include medically important species, such as the malaria parasite Plasmodium and the causative agents of toxoplasmosis (Toxoplasma gondii) and cryptosporidiosis (Cryptosporidium spp.). Apicomplexan parasites can infect one or more hosts, in which they differentiate into several morphologically and metabolically distinct life cycle stages. These developmental transitions rely on changes in gene expression. In the last few years, the important roles of different members of the ApiAP2 transcription factor family in regulating life cycle transitions and other aspects of parasite biology have become apparent. Here, we review recent progress in our understanding of the different members of the ApiAP2 transcription factor family in apicomplexan parasites. Full article

(This article belongs to the Section Human Pathogens)

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11 pages, 747 KiB

Open AccessEditor’s ChoiceReview

The Hidden Cost of Modern Medical Interventions: How Medical Advances Have Shaped the Prevalence of Human Fungal Disease

by Callum Clark and Rebecca A. Drummond

Pathogens 2019, 8(2), 45; https://doi.org/10.3390/pathogens8020045 - 4 Apr 2019

Cited by 34 | Viewed by 7255

Abstract

Life expectancy in the West is the highest it has ever been, due to the introduction of better hygiene practices and sophisticated medical interventions for cancer, autoimmunity and infectious disease. With these modern advances, a rise in the prevalence of opportunistic infections has [...] Read more.

Life expectancy in the West is the highest it has ever been, due to the introduction of better hygiene practices and sophisticated medical interventions for cancer, autoimmunity and infectious disease. With these modern advances, a rise in the prevalence of opportunistic infections has also been observed. These include several fungal infections, which present a particular clinical challenge due to the lack of fungal vaccines, limited diagnostics and increasing antifungal drug resistance. This mini-review outlines how modern-day clinical practices have shaped the recent increase in fungal diseases observed in the last few decades. We discuss new research that has implicated the use of immune-modulating drugs in the enhanced susceptibility of vulnerable patients to life-threatening fungal infections. Full article

(This article belongs to the Special Issue Immunology of Fungal Infections)

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16 pages, 2129 KiB

Open AccessEditor’s ChoiceArticle

Epidemiology of Tick-Borne Encephalitis (TBE) in Germany, 2001–2018

by Wiebke Hellenbrand, Teresa Kreusch, Merle M. Böhmer, Christiane Wagner-Wiening, Gerhard Dobler, Ole Wichmann and Doris Altmann

Pathogens 2019, 8(2), 42; https://doi.org/10.3390/pathogens8020042 - 29 Mar 2019

Cited by 58 | Viewed by 9151

Abstract

We reviewed tick-borne encephalitis (TBE) surveillance and epidemiology in Germany, as these underlie public health recommendations, foremost vaccination. We performed descriptive analyses of notification data (2001–2018, n = 6063) according to region, demographics and clinical manifestations and calculated incidence trends using negative binomial [...] Read more.

We reviewed tick-borne encephalitis (TBE) surveillance and epidemiology in Germany, as these underlie public health recommendations, foremost vaccination. We performed descriptive analyses of notification data (2001–2018, n = 6063) according to region, demographics and clinical manifestations and calculated incidence trends using negative binomial regression. Risk areas were defined based on incidence in administrative districts. Most cases (89%) occurred in the federal states of Baden-Wurttemberg and Bavaria, where annual TBE incidence fluctuated markedly between 0.7–2.0 cases/100,000 inhabitants. A slight but significantly increasing temporal trend was observed from 2001–2018 (age-adjusted incidence rate ratio (IRR) 1.02 (95% confidence interval (CI): 1.01–1.04)), primarily driven by high case numbers in 2017–2018. Mean incidence was highest in 40–69-year-olds and in males. More males (23.7%) than females (18.0%, p = 0.02) had severe disease (encephalitis or myelitis), which increased with age, as did case-fatality (0.4% overall; 2.1% among ≥70-year-olds). Risk areas increased from 129 districts in 2007 to 161 in 2019. Expansion occurred mainly within existent southern endemic areas, with slower contiguous north-eastern and patchy north-western spread. Median vaccination coverage at school entry in risk areas in 2016–2017 ranged from 20%–41% in 4 states. Increasing TBE vaccine uptake is an urgent priority, particularly in high-incidence risk areas. Full article

(This article belongs to the Special Issue Ticks and Tick Borne Diseases Surveillance)

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14 pages, 256 KiB

Open AccessEditor’s ChoiceReview

Candida albicans at Host Barrier Sites: Pattern Recognition Receptors and Beyond

by Marc Swidergall

Pathogens 2019, 8(1), 40; https://doi.org/10.3390/pathogens8010040 - 25 Mar 2019

Cited by 32 | Viewed by 5523

Abstract

Over the last decades, fungal infections have emerged as a growing threat to human health. Although the human body is at potential risk, various body sites host several commensal fungal species, including Candida albicans. In healthy individuals, C. albicans colonizes different mucosal [...] Read more.

Over the last decades, fungal infections have emerged as a growing threat to human health. Although the human body is at potential risk, various body sites host several commensal fungal species, including Candida albicans. In healthy individuals, C. albicans colonizes different mucosal surfaces without causing harm, while under diverse circumstances the fungus can proliferate and cause disease. In this context, the understanding of host–C. albicans interactions in health and during infection may lead to novel therapeutic approaches. Importantly, host cells express pattern recognition receptors (PRRs), which sense conserved fungal structures and orchestrate innate immune responses. Herein, important findings on the topic of the recognition of C. albicans at host barrier sites are discussed. This review briefly summarizes the importance and functions of myeloid PRRs, reviews the fungal recognition and biology of stromal cells, and highlights important C. albicans virulence attributes during site-specific proliferation and invasion. Full article

(This article belongs to the Special Issue Immunology of Fungal Infections)

12 pages, 838 KiB

Open AccessEditor’s ChoiceArticle

Intra-Species and Inter-Species Differences in Cytokine Production by Porcine Antigen-Presenting Cells Stimulated by Mycoplasma hyopneumoniae, M. hyorhinis, and M. flocculare

by Sarah Fourour, Corinne Marois-Créhan, Léa Martelet, Christelle Fablet, Isabelle Kempf, Marcelo Gottschalk and Mariela Segura

Pathogens 2019, 8(1), 34; https://doi.org/10.3390/pathogens8010034 - 16 Mar 2019

Cited by 23 | Viewed by 4014

Abstract

Mycoplasma hyorhinis and M. flocculare are commonly co-isolated with M. hyopneumoniae (primary agent of swine enzootic pneumonia) in gross pneumonia-like lesions, but their involvement in the disease process remains unknown. T cells play an immuno-pathological role during mycoplasmal infections. Dendritic cells (DCs) are [...] Read more.

Mycoplasma hyorhinis and M. flocculare are commonly co-isolated with M. hyopneumoniae (primary agent of swine enzootic pneumonia) in gross pneumonia-like lesions, but their involvement in the disease process remains unknown. T cells play an immuno-pathological role during mycoplasmal infections. Dendritic cells (DCs) are major antigen-presenting cells involved in T cell activation and differentiation. In this study, we investigated cytokine (IL-6, IL-8, IL-10, IL-12, and TNF-α) production by porcine bone-marrow-derived DCs (BM-DCs) stimulated by M. hyopneumoniae, M. hyorhinis, and/or M. flocculare. Results showed that cytokine production levels were relatively homogenous for all evaluated M. hyopneumoniae strains in contrast to M. hyorhinis and M. flocculare strains. The most noteworthy inter-species differences were the overall (i) lower IL-12 production capacity of M. hyopneumoniae, and (ii) higher TNF-α production capacity of M. flocculare. Co-stimulation of BM-DCs showed that M. hyorhinis dominated the IL-12 production independently of its association with M. hyopneumoniae or M. flocculare. In addition, a decreased BM-DC production of TNF-α was generally observed in the presence of mycoplasma associations. Lastly, M. flocculare association with M. hyopneumoniae increased BM-DC ability to secrete IL-10. A higher cytotoxicity level in BM-DCs stimulated by M. hyorhinis was also observed. Overall, this study demonstrated that the combination of M. hyorhinis or M. flocculare with M. hyopneumoniae may participate to the modulation of the immune response that might affect the final disease outcome. Full article

(This article belongs to the Section Immunological Responses and Immune Defense Mechanisms)

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16 pages, 3582 KiB

Open AccessEditor’s ChoiceArticle

HIV Replication in Humanized IL-3/GM-CSF-Transgenic NOG Mice

by Federico Perdomo-Celis, Sandra Medina-Moreno, Harry Davis, Joseph Bryant and Juan C. Zapata

Pathogens 2019, 8(1), 33; https://doi.org/10.3390/pathogens8010033 - 12 Mar 2019

Cited by 15 | Viewed by 5838

Abstract

The development of mouse models that mimic the kinetics of Human Immunodeficiency Virus (HIV) infection is critical for the understanding of the pathogenesis of disease and for the design of novel therapeutic strategies. Here, we describe the dynamics of HIV infection in humanized [...] Read more.

The development of mouse models that mimic the kinetics of Human Immunodeficiency Virus (HIV) infection is critical for the understanding of the pathogenesis of disease and for the design of novel therapeutic strategies. Here, we describe the dynamics of HIV infection in humanized NOD/Shi-scid-IL2rγ^null (NOG) mice bearing the human genes for interleukin (IL)-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) (NOG-EXL mice). The kinetics of viral load, as well as the frequencies of T-cells, B-cells, Natural killer cells (NK), monocytes, and dendritic cells in blood and secondary lymphoid organs were evaluated throughout the time of infection. In comparison with a non-transgenic humanized mouse (NSG) strain, lymphoid and myeloid populations were more efficiently engrafted in humanized NOG-EXL mice, both in peripheral blood and lymphoid tissues. In addition, HIV actively replicated in humanized NOG-EXL mice, and infection induced a decrease in the percentage of CD4⁺ T-cells, inversion of the CD4:CD8 ratio, and changes in some cell populations, such as monocytes and dendritic cells, that recapitulated those found in human natural infection. Thus, the humanized IL-3/GM-CSF-transgenic NOG mouse model is suitable for the study of the dynamics of HIV infection and provides a tool for basic and preclinical studies. Full article

(This article belongs to the Section Human Pathogens)

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16 pages, 2068 KiB

Open AccessEditor’s ChoiceArticle

Characteristics of Listeria Monocytogenes Strains Persisting in a Meat Processing Facility over a 4-Year Period

by Andrea Stoller, Marc J. A. Stevens, Roger Stephan and Claudia Guldimann

Pathogens 2019, 8(1), 32; https://doi.org/10.3390/pathogens8010032 - 7 Mar 2019

Cited by 58 | Viewed by 6299

Abstract

Listeria monocytogenes can persist in food production facilities, resulting in serious threats to consumers due to the high mortality associated with listeriosis, especially in the very young, old and pregnant. We subtyped 124 strains of L. monocytogenes isolated from a meat processing facility [...] Read more.

Listeria monocytogenes can persist in food production facilities, resulting in serious threats to consumers due to the high mortality associated with listeriosis, especially in the very young, old and pregnant. We subtyped 124 strains of L. monocytogenes isolated from a meat processing facility in Switzerland by serotyping, multi locus sequence typing (MLST) typing and whole genome sequencing. We then analyzed their ability to form biofilms and their resistance to the disinfectants benzalkonium chloride (BC) and peracetic acid (PAA). The genotyping results of the strains showed that several clonal populations of L. monocytogenes belonging to CC9, CC204 and CC121 had persisted in this meat processing facility for at least four years. All of the strains showed biofilm forming capacity comparable to a known high biofilm forming strain. Known efflux pumps for BC were present in CC204, CC9 (brcABC) and CC121 (qacH) strains, while strains from other CC showed very low minimal inhibitory concentrations (MICs) for BC. For PAA, minimal bactericidal concentrations of 1.2–1.6% for 20 min and minimal inhibitory concentrations between 0.1 and 0.2% were observed. These values were close to or above the recommended concentration for use (0.5–1%), suggesting that PAA might be ineffective at controlling L. monocytogenes in this and potentially other meat processing facilities. Full article

(This article belongs to the Section Human Pathogens)

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11 pages, 1915 KiB

Open AccessEditor’s ChoiceArticle

Molecular Epidemiology and Genetic Diversity of Zika Virus from Field-Caught Mosquitoes in Various Regions of Thailand

by Atchara Phumee, Rome Buathong, Rungfar Boonserm, Proawpilart Intayot, Nucharat Aungsananta, Akanitt Jittmittraphap, Yutthana Joyjinda, Supaporn Wacharapluesadee and Padet Siriyasatien

Pathogens 2019, 8(1), 30; https://doi.org/10.3390/pathogens8010030 - 6 Mar 2019

Cited by 29 | Viewed by 8748

Abstract

Zika virus (ZIKV) infection is an emerging and re-emerging arbovirus disease that is transmitted to humans through the bite of infected mosquitoes. ZIKV infections were first described in Thailand in 1954 from the sera of indigenous residents and several travelers returning from Thailand [...] Read more.

Zika virus (ZIKV) infection is an emerging and re-emerging arbovirus disease that is transmitted to humans through the bite of infected mosquitoes. ZIKV infections were first described in Thailand in 1954 from the sera of indigenous residents and several travelers returning from Thailand in 2014. However, reported cases in Thailand have been increasing since 2015 and 2016, and epidemiological information about the vectors of ZIKV is unclear. We investigated the molecular epidemiology and genetic diversity of ZIKV from mosquitoes collected from different geographic regions experiencing ZIKV outbreaks in Thailand. Polymerase chain reaction was used to amplify the non-structural protein (NS5) gene of ZIKV, which was then sequenced. A total of 1026 mosquito samples (626 females, 367 males, and 33 larvae) were collected from active ZIKV patients’ houses. ZIKV was detected in 79 samples (7.7%), including Aedes aegypti (2.24% female, 1.27% male, and 0.19% larvae), Culex quinquefasciatus (1.85% female, 1.66% male, and 0.29% larvae), and Armigeres subalbatus (0.1% female and 0.1% male), whereas no ZIKV was detected in Aedes albopictus. Phylogenetic analysis of the 79 positive samples were classified into two clades: Those closely related to a previous report in Thailand, and those related to ZIKV found in the Americas. This is the first report of the detection of ZIKV in Ae. aegypti, Cx. quinquefasciatus, and Ar. subalbatus mosquitoes, and genetic variations of ZIKV in the mosquitoes collected from several geographic regions of Thailand were examined. Detection of ZIKV in male and larval mosquitoes suggests that vertical transmission of ZIKV occurred in these mosquito species. This study provides a more in-depth understanding of the patterns and epidemiologic data of ZIKV in Thailand; the data could be used for future development of more effective prevention and control strategies of ZIKV in Thailand. Full article

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19 pages, 1541 KiB

Open AccessEditor’s ChoiceArticle

The 3′ Untranslated Region of a Plant Viral RNA Directs Efficient Cap-Independent Translation in Plant and Mammalian Systems

by Jelena J. Kraft, Mariko S. Peterson, Sung Ki Cho, Zhaohui Wang, Alice Hui, Aurélie M. Rakotondrafara, Krzysztof Treder, Cathy L. Miller and W. Allen Miller

Pathogens 2019, 8(1), 28; https://doi.org/10.3390/pathogens8010028 - 28 Feb 2019

Cited by 11 | Viewed by 5589

Abstract

Many plant viral RNA genomes lack a 5′ cap, and instead are translated via a cap-independent translation element (CITE) in the 3′ untranslated region (UTR). The panicum mosaic virus-like CITE (PTE), found in many plant viral RNAs, binds and requires the cap-binding translation [...] Read more.

Many plant viral RNA genomes lack a 5′ cap, and instead are translated via a cap-independent translation element (CITE) in the 3′ untranslated region (UTR). The panicum mosaic virus-like CITE (PTE), found in many plant viral RNAs, binds and requires the cap-binding translation initiation factor eIF4E to facilitate translation. eIF4E is structurally conserved between plants and animals, so we tested cap-independent translation efficiency of PTEs of nine plant viruses in plant and mammalian systems. The PTE from thin paspalum asymptomatic virus (TPAV) facilitated efficient cap-independent translation in wheat germ extract, rabbit reticulocyte lysate, HeLa cell lysate, and in oat and mammalian (BHK) cells. Human eIF4E bound the TPAV PTE but not a PTE that did not stimulate cap-independent translation in mammalian extracts or cells. Selective 2′-hydroxyl acylation analyzed by primer extension (SHAPE) footprinting revealed that both human and wheat eIF4E protected the conserved guanosine (G)-rich domain in the TPAV PTE pseudoknot. The central G plays a key role, as it was found to be required for translation and protection from SHAPE modification by eIF4E. These results provide insight on how plant viruses gain access to the host’s translational machinery, an essential step in infection, and raise the possibility that similar PTE-like mechanisms may exist in mRNAs of mammals or their viruses. Full article

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15 pages, 288 KiB

Open AccessEditor’s ChoiceOpinion

Maternal and Congenital Toxoplasmosis: Diagnosis and Treatment Recommendations of a French Multidisciplinary Working Group

by François Peyron, Coralie L’ollivier, Laurent Mandelbrot, Martine Wallon, Renaud Piarroux, François Kieffer, Eve Hadjadj, Luc Paris and Patricia Garcia –Meric

Pathogens 2019, 8(1), 24; https://doi.org/10.3390/pathogens8010024 - 18 Feb 2019

Cited by 104 | Viewed by 14877

Abstract

Women infected with toxoplasmosis during pregnancy do not present symptoms in most cases, but the consequences of the congenital infection may be severe for the unborn child. Fetal damage can range from asymptomatic to severe neurological alterations to retinal lesions prone to potential [...] Read more.

Women infected with toxoplasmosis during pregnancy do not present symptoms in most cases, but the consequences of the congenital infection may be severe for the unborn child. Fetal damage can range from asymptomatic to severe neurological alterations to retinal lesions prone to potential flare up and relapses lifelong. Despite the possible severity of outcome, congenital toxoplasmosis (CT) is a neglected disease. There is no consensus regarding screening during pregnancy, prenatal/postnatal treatment or short or medium term follow-up. Since 1992, France has offered systematic serological testing to non-immune pregnant women, monthly until delivery. Any maternal infection is thus detected; moreover, diagnosis of congenital infection can be made at birth and follow-up can be provided. “Guidelines” drawn up by a multidisciplinary group are presented here, concerning treatment, before and after birth. The recommendations are based on the regular analysis of the literature and the results of the working group. The evaluation of the recommendations takes into account the robustness of the recommendation and the quality of the evidence. Full article

(This article belongs to the Section Human Pathogens)

14 pages, 2198 KiB

Open AccessEditor’s ChoiceArticle

In silico Identification of Novel Toxin Homologs and Associated Mobile Genetic Elements in Clostridium perfringens

by Jake A. Lacey, Priscilla A. Johanesen, Dena Lyras and Robert J. Moore

Pathogens 2019, 8(1), 16; https://doi.org/10.3390/pathogens8010016 - 29 Jan 2019

Cited by 14 | Viewed by 4994

Abstract

Clostridium perfringens causes a wide range of diseases in a variety of hosts, due to the production of a diverse set of toxins and extracellular enzymes. The C. perfringens toxins play an important role in pathogenesis, such that the presence and absence of [...] Read more.

Clostridium perfringens causes a wide range of diseases in a variety of hosts, due to the production of a diverse set of toxins and extracellular enzymes. The C. perfringens toxins play an important role in pathogenesis, such that the presence and absence of the toxins is used as a typing scheme for the species. In recent years, several new toxins have been discovered that have been shown to be essential or highly correlated to diseases; these include binary enterotoxin (BecAB), NetB and NetF. In the current study, genome sequence analysis of C. perfringens isolates from diverse sources revealed several putative novel toxin homologs, some of which appeared to be associated with potential mobile genetic elements, including transposons and plasmids. Four novel toxin homologs encoding proteins related to the pore-forming Leukocidin/Hemolysin family were found in type A and G isolates. Two novel toxin homologs encoding proteins related to the epsilon aerolysin-like toxin family were identified in Type A and F isolates from humans, contaminated food and turkeys. A novel set of proteins related to clostridial binary toxins was also identified. While phenotypic characterisation is required before any of these homologs can be established as functional toxins, the in silico identification of these novel homologs on mobile genetic elements suggests the potential toxin reservoir of C. perfringens may be much larger than previously thought. Full article

(This article belongs to the Section Animal Pathogens)

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10 pages, 1196 KiB

Open AccessEditor’s ChoiceCase Report

Disease Manifestation and Viral Sequences in a Bonobo More Than 30 Years after Papillomavirus Infection

by Markus Hoffmann, Enrika Schütze, Andreas Bernhard, Lennart Schlaphoff, Artur Kaul, Sandra Schöniger and Stefan Pöhlmann

Pathogens 2019, 8(1), 13; https://doi.org/10.3390/pathogens8010013 - 26 Jan 2019

Cited by 6 | Viewed by 3827

Abstract

Pan paniscus Papillomavirus 1 (PpPV1) causes focal epithelial hyperplasia (FEH) in infected animals. Here, we analyzed the present disease manifestation and PpPV1 genomic sequence of an animal that was afflicted by an FEH epizootic outbreak in 1987 for which the sequence of the [...] Read more.

Pan paniscus Papillomavirus 1 (PpPV1) causes focal epithelial hyperplasia (FEH) in infected animals. Here, we analyzed the present disease manifestation and PpPV1 genomic sequence of an animal that was afflicted by an FEH epizootic outbreak in 1987 for which the sequence of the responsible PpPV1 was determined. The animal displayed FEH more than 30 years after the initial diagnosis, indicating persistence or recurrence of the disease, and evidence for active PpPV1 infection was obtained. Moreover, the sequences of the viral genomes present in the late 1980s and in 2018 differed at 23 nucleotide positions, resulting in 11 amino acid exchanges within coding regions. These findings suggest that PpPV1-induced FEH might not undergo complete and/or permanent remission in a subset of afflicted animals. Full article

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21 pages, 4563 KiB

Open AccessEditor’s ChoiceArticle

Molecular Characterisation of Equine Herpesvirus 1 Isolates from Cases of Abortion, Respiratory and Neurological Disease in Ireland between 1990 and 2017

by Marie Garvey, Rachel Lyons, Ralph D Hector, Cathal Walsh, Sean Arkins and Ann Cullinane

Pathogens 2019, 8(1), 7; https://doi.org/10.3390/pathogens8010007 - 15 Jan 2019

Cited by 28 | Viewed by 4113

Abstract

Multiple locus typing based on sequencing heterologous regions in 26 open reading frames (ORFs) of equine herpesvirus 1 (EHV-1) strains Ab4 and V592 was used to characterise 272 EHV-1 isolates from 238 outbreaks of abortion, respiratory or neurological disease over a 28-year period. [...] Read more.

Multiple locus typing based on sequencing heterologous regions in 26 open reading frames (ORFs) of equine herpesvirus 1 (EHV-1) strains Ab4 and V592 was used to characterise 272 EHV-1 isolates from 238 outbreaks of abortion, respiratory or neurological disease over a 28-year period. The analysis grouped the 272 viruses into at least 10 of the 13 unique long region (U_L) clades previously recognised. Viruses from the same outbreak had identical multi-locus profiles. Sequencing of the ORF68 region of EHV-1 isolates from 222 outbreaks established a divergence into seven groups and network analysis demonstrated that Irish genotypes were not geographically restricted but clustered with viruses from all over the world. Multi-locus analysis proved a more comprehensive method of strain typing than ORF68 sequencing. It was demonstrated that when interpreted in combination with epidemiological data, this type of analysis has a potential role in tracking virus between premises and therefore in the implementation of targeted control measures. Viruses from 31 of 238 outbreaks analysed had the proposed ORF30 G2254/D752 neuropathogenic marker. There was a statistically significant association between viruses of the G2254/D752 genotype and both neurological disease and hypervirulence as defined by outbreaks involving multiple abortion or neurological cases. The association of neurological disease in those with the G2254/D752 genotype was estimated as 27 times greater than in those with the A2254/N752 genotype. Full article

(This article belongs to the Section Animal Pathogens)

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17 pages, 8731 KiB

Open AccessEditor’s ChoiceArticle

Attenuated Replication of Lassa Virus Vaccine Candidate ML29 in STAT-1^-/- Mice

by Dylan M. Johnson, Jenny D. Jokinen and Igor S. Lukashevich

Pathogens 2019, 8(1), 9; https://doi.org/10.3390/pathogens8010009 - 15 Jan 2019

Cited by 12 | Viewed by 4998

Abstract

Lassa virus (LASV), a highly prevalent mammalian arenavirus endemic in West Africa, can cause Lassa fever (LF), which is responsible for thousands of deaths annually. LASV is transmitted to humans from naturally infected rodents. At present, there is not an effective vaccine nor [...] Read more.

Lassa virus (LASV), a highly prevalent mammalian arenavirus endemic in West Africa, can cause Lassa fever (LF), which is responsible for thousands of deaths annually. LASV is transmitted to humans from naturally infected rodents. At present, there is not an effective vaccine nor treatment. The genetic diversity of LASV is the greatest challenge for vaccine development. The reassortant ML29 carrying the L segment from the nonpathogenic Mopeia virus (MOPV) and the S segment from LASV is a vaccine candidate under current development. ML29 demonstrated complete protection in validated animal models against a Nigerian strain from clade II, which was responsible for the worst outbreak on record in 2018. This study demonstrated that ML29 was more attenuated than MOPV in STAT1^-/- mice, a small animal model of human LF and its sequelae. ML29 infection of these mice resulted in more than a thousand-fold reduction in viremia and viral load in tissues and strong LASV-specific adaptive T cell responses compared to MOPV-infected mice. Persistent infection of Vero cells with ML29 resulted in generation of interfering particles (IPs), which strongly interfered with the replication of LASV, MOPV and LCMV, the prototype of the Arenaviridae. ML29 IPs induced potent cell-mediated immunity and were fully attenuated in STAT1^-/- mice. Formulation of ML29 with IPs will improve the breadth of the host’s immune responses and further contribute to development of a pan-LASV vaccine with full coverage meeting the WHO requirements. Full article

(This article belongs to the Special Issue Lassa Fever: Viral Replication, Disease Pathogenesis, and Host Immune Modulations)

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17 pages, 6695 KiB

Open AccessEditor’s ChoiceArticle

Staphylococcus aureus Superantigen-Like Protein SSL1: A Toxic Protease

by Aihua Tang, Armando R. Caballero, Michael A. Bierdeman, Mary E. Marquart, Timothy J. Foster, Ian R. Monk and Richard J. O’Callaghan

Pathogens 2019, 8(1), 2; https://doi.org/10.3390/pathogens8010002 - 1 Jan 2019

Cited by 11 | Viewed by 4953

Abstract

Staphylococcus aureus is a major cause of corneal infections that can cause reduced vision, even blindness. Secreted toxins cause tissue damage and inflammation resulting in scars that lead to vision loss. Identifying tissue damaging proteins is a prerequisite to limiting these harmful reactions. [...] Read more.

Staphylococcus aureus is a major cause of corneal infections that can cause reduced vision, even blindness. Secreted toxins cause tissue damage and inflammation resulting in scars that lead to vision loss. Identifying tissue damaging proteins is a prerequisite to limiting these harmful reactions. The present study characterized a previously unrecognized S. aureus toxin. This secreted toxin was purified from strain Newman ΔhlaΔhlg, the N-terminal sequence determined, the gene cloned, and the purified recombinant protein was tested in the rabbit cornea. The virulence of a toxin deletion mutant was compared to its parent and the mutant after gene restoration (rescue strain). The toxin (23 kDa) had an N-terminal sequence matching the Newman superantigen-like protein SSL1. An SSL1 homodimer (46 kDa) had proteolytic activity as demonstrated by zymography and cleavage of a synthetic substrate, collagens, and cytokines (IL-17A, IFN-γ, and IL-8); the protease was susceptible to serine protease inhibitors. As compared to the parent and rescue strains, the ssl1 mutant had significantly reduced virulence, but not reduced bacterial growth, in vivo. The ocular isolates tested had the ssl1 gene, with allele type 2 being the predominant type. SSL1 is a protease with corneal virulence and activity on host defense and structural proteins. Full article

(This article belongs to the Section Human Pathogens)

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13 pages, 2152 KiB

Open AccessEditor’s ChoiceArticle

Identification of Residues in Lassa Virus Glycoprotein Subunit 2 That Are Critical for Protein Function

by Katherine A. Willard, Jacob T. Alston, Marissa Acciani and Melinda A. Brindley

Pathogens 2019, 8(1), 1; https://doi.org/10.3390/pathogens8010001 - 26 Dec 2018

Cited by 15 | Viewed by 5354

Abstract

Lassa virus (LASV) is an Old World arenavirus, endemic to West Africa, capable of causing hemorrhagic fever. Currently, there are no approved vaccines or effective antivirals for LASV. However, thorough understanding of the LASV glycoprotein and entry into host cells could accelerate therapeutic [...] Read more.

Lassa virus (LASV) is an Old World arenavirus, endemic to West Africa, capable of causing hemorrhagic fever. Currently, there are no approved vaccines or effective antivirals for LASV. However, thorough understanding of the LASV glycoprotein and entry into host cells could accelerate therapeutic design. LASV entry is a two-step process involving the viral glycoprotein (GP). First, the GP subunit 1 (GP1) binds to the cell surface receptor and the viral particle is engulfed into an endosome. Next, the drop in pH triggers GP rearrangements, which ultimately leads to the GP subunit 2 (GP2) forming a six-helix-bundle (6HB). The process of GP2 forming 6HB fuses the lysosomal membrane with the LASV envelope, allowing the LASV genome to enter the host cell. The aim of this study was to identify residues in GP2 that are crucial for LASV entry. To achieve this, we performed alanine scanning mutagenesis on GP2 residues. We tested these mutant GPs for efficient GP1-GP2 cleavage, cell-to-cell membrane fusion, and transduction into cells expressing α-dystroglycan and secondary LASV receptors. In total, we identified seven GP2 mutants that were cleaved efficiently but were unable to effectively transduce cells: GP-L280A, GP-L285A/I286A, GP-I323A, GP-L394A, GP-I403A, GP-L415A, and GP-R422A. Therefore, the data suggest these residues are critical for GP2 function in LASV entry. Full article

(This article belongs to the Special Issue Lassa Fever: Viral Replication, Disease Pathogenesis, and Host Immune Modulations)

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14 pages, 2423 KiB

Open AccessEditor’s ChoiceCommunication

Host-Driven Phosphorylation Appears to Regulate the Budding Activity of the Lassa Virus Matrix Protein

by Christopher M. Ziegler, Philip Eisenhauer, Inessa Manuelyan, Marion E. Weir, Emily A. Bruce, Bryan A. Ballif and Jason Botten

Pathogens 2018, 7(4), 97; https://doi.org/10.3390/pathogens7040097 - 9 Dec 2018

Cited by 6 | Viewed by 4274

Abstract

Lassa mammarenavirus (LASV) is an enveloped RNA virus that can cause Lassa fever, an acute hemorrhagic fever syndrome associated with significant morbidity and high rates of fatality in endemic regions of western Africa. The arenavirus matrix protein Z has several functions during the [...] Read more.

Lassa mammarenavirus (LASV) is an enveloped RNA virus that can cause Lassa fever, an acute hemorrhagic fever syndrome associated with significant morbidity and high rates of fatality in endemic regions of western Africa. The arenavirus matrix protein Z has several functions during the virus life cycle, including coordinating viral assembly, driving the release of new virus particles, regulating viral polymerase activity, and antagonizing the host antiviral response. There is limited knowledge regarding how the various functions of Z are regulated. To investigate possible means of regulation, mass spectrometry was used to identify potential sites of phosphorylation in the LASV Z protein. This analysis revealed that two serines (S18, S98) and one tyrosine (Y97) are phosphorylated in the flexible N- and C-terminal regions of the protein. Notably, two of these sites, Y97 and S98, are located in (Y97) or directly adjacent to (S98) the PPXY late domain, an important motif for virus release. Studies with non-phosphorylatable and phosphomimetic Z proteins revealed that these sites are important regulators of the release of LASV particles and that host-driven, reversible phosphorylation may play an important role in the regulation of LASV Z protein function. Full article

(This article belongs to the Special Issue Lassa Fever: Viral Replication, Disease Pathogenesis, and Host Immune Modulations)

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14 pages, 1918 KiB

Open AccessEditor’s ChoiceArticle

Stimulating Respiratory Activity Primes Anaerobically Grown Listeria monocytogenes for Subsequent Intracellular Infections

by Nathan Wallace, Erica Rinehart and Yvonne Sun

Pathogens 2018, 7(4), 96; https://doi.org/10.3390/pathogens7040096 - 8 Dec 2018

Cited by 2 | Viewed by 2963

Abstract

Listeria monocytogenes (L. monocytogenes) is a Gram-positive, enteric pathogen and the causative agent of listeriosis. During transition through the gastrointestinal tract, L. monocytogenes routinely encounters suboxic conditions. However, how the exposure to the low oxygen environment affects subsequent pathogenesis is not completely understood. [...] Read more.

Listeria monocytogenes (L. monocytogenes) is a Gram-positive, enteric pathogen and the causative agent of listeriosis. During transition through the gastrointestinal tract, L. monocytogenes routinely encounters suboxic conditions. However, how the exposure to the low oxygen environment affects subsequent pathogenesis is not completely understood. Our lab previously reported that anaerobically grown L. monocytogenes exhibited an intracellular growth defect in macrophages even though the infection took place under aerobic conditions. This phenotype suggests that prior growth conditions have a prolonged effect on the outcome of subsequent intracellular infection. In this study, to further investigate the mechanisms that contribute to the compromised intracellular growth after anaerobic exposure, we hypothesized that the lack of respiratory activity under anaerobic conditions prevented anaerobically grown L. monocytogenes to establish subsequent intracellular growth under aerobic conditions. To test this hypothesis, respiratory activity in anaerobically grown L. monocytogenes was stimulated by exogenous fumarate and subsequent intracellular pathogenesis was assessed. The results showed that fumarate supplementation significantly increased the respiratory activity of anaerobically grown L. monocytogenes and rescued the subsequent intracellular growth defect, likely through promoting the production of listeriolysin O, phagosomal escape, and cell-cell spread. This study highlights the importance of respiratory activity in L. monocytogenes in modulating the outcome of subsequent intracellular infections. Full article

(This article belongs to the Section Human Pathogens)

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14 pages, 8238 KiB

Open AccessEditor’s ChoiceArticle

Epigallocatechin Gallate Remodelling of Hfq Amyloid-Like Region Affects Escherichia coli Survival

by David Partouche, Florian Turbant, Omar El Hamoui, Camille Campidelli, Marianne Bombled, Sylvain Trépout, Frank Wien and Véronique Arluison

Pathogens 2018, 7(4), 95; https://doi.org/10.3390/pathogens7040095 - 1 Dec 2018

Cited by 12 | Viewed by 3708

Abstract

Hfq is a pleiotropic regulator that has key roles in the control of genetic expression. The protein noticeably regulates translation efficiency and RNA decay in Gram-negative bacteria, due to the Hfq-mediated interaction between small regulatory noncoding RNA and mRNA. This property is of [...] Read more.

Hfq is a pleiotropic regulator that has key roles in the control of genetic expression. The protein noticeably regulates translation efficiency and RNA decay in Gram-negative bacteria, due to the Hfq-mediated interaction between small regulatory noncoding RNA and mRNA. This property is of primary importance for bacterial adaptation and virulence. We have previously shown that the Hfq E. coli protein, and more precisely its C-terminal region (CTR), self-assembles into an amyloid-like structure. In the present work, we demonstrate that epigallocatechin gallate (EGCG), a major green tea polyphenol compound, targets the Hfq amyloid region and can be used as a potential antibacterial agent. We analysed the effect of this compound on Hfq amyloid fibril stability and show that EGCG both disrupts Hfq-CTR fibrils and inhibits their formation. We show that, even if EGCG affects other bacterial amyloids, it also specifically targets Hfq-CTR in vivo. Our results provide an alternative approach for the utilisation of EGCG that may be used synergistically with conventional antibiotics to block bacterial adaptation and treat infections. Full article

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15 pages, 324 KiB

Open AccessEditor’s ChoiceReview

Fusarium, an Entomopathogen—A Myth or Reality?

by Lav Sharma and Guilhermina Marques

Pathogens 2018, 7(4), 93; https://doi.org/10.3390/pathogens7040093 - 28 Nov 2018

Cited by 46 | Viewed by 6881

Abstract

The Fusarium species has diverse ecological functions ranging from saprophytes, endophytes, and animal and plant pathogens. Occasionally, they are isolated from dead and alive insects. However, research on fusaria-insect associations is very limited as fusaria are generalized as opportunistic insect-pathogens. Additionally, their phytopathogenicity [...] Read more.

The Fusarium species has diverse ecological functions ranging from saprophytes, endophytes, and animal and plant pathogens. Occasionally, they are isolated from dead and alive insects. However, research on fusaria-insect associations is very limited as fusaria are generalized as opportunistic insect-pathogens. Additionally, their phytopathogenicity raises concerns in their use as commercial biopesticides. Insect biocontrol potential of Fusarium is favored by their excellent soil survivability as saprophytes, and sometimes, insect-pathogenic strains do not exhibit phytopathogenicity. In addition, a small group of fusaria, those belonging to the Fusarium solani species complex, act as insect mutualists assisting in host growth and fecundity. In this review, we summarize mutualism and pathogenicity among fusaria and insects. Furthermore, we assert on Fusarium entomopathogenicity by analyzing previous studies clearly demonstrating their natural insect-pathogenicity in fields, and their presence in soils. We also review the presence and/or production of a well-known insecticidal metabolite beauvericin by different Fusarium species. Lastly, some proof-of-concept studies are also summarized, which demonstrate the histological as well as immunological changes that a larva undergoes during Fusarium oxysporum pathogenesis. These reports highlight the insecticidal properties of some Fusarium spp., and emphasize the need of robust techniques, which can distinguish phytopathogenic, mutualistic and entomopathogenic fusaria. Full article

(This article belongs to the Special Issue Fusarium)

15 pages, 2297 KiB

Open AccessEditor’s ChoiceArticle

Relation between Biofilm and Virulence in Vibrio tapetis: A Transcriptomic Study

by Sophie Rodrigues, Christine Paillard, Sabine Van Dillen, Ali Tahrioui, Jean-Marc Berjeaud, Alain Dufour and Alexis Bazire

Pathogens 2018, 7(4), 92; https://doi.org/10.3390/pathogens7040092 - 26 Nov 2018

Cited by 15 | Viewed by 4540

Abstract

Marine pathogenic bacteria are able to form biofilms on many surfaces, such as mollusc shells, and they can wait for the appropriate opportunity to induce their virulence. Vibrio tapetis can develop such biofilms on the inner surface of shells of the Ruditapes philippinarum [...] Read more.

Marine pathogenic bacteria are able to form biofilms on many surfaces, such as mollusc shells, and they can wait for the appropriate opportunity to induce their virulence. Vibrio tapetis can develop such biofilms on the inner surface of shells of the Ruditapes philippinarum clam, leading to the formation of a brown conchiolin deposit in the form of a ring, hence the name of the disease: Brown Ring Disease. The virulence of V. tapetis is presumed to be related to its capacity to form biofilms, but the link has never been clearly established at the physiological or genetic level. In the present study, we used RNA-seq analysis to identify biofilm- and virulence-related genes displaying altered expression in biofilms compared to the planktonic condition. A flow cell system was employed to grow biofilms to obtain both structural and transcriptomic views of the biofilms. We found that 3615 genes were differentially expressed, confirming that biofilm and planktonic lifestyles are very different. As expected, the differentially expressed genes included those involved in biofilm formation, such as motility- and polysaccharide synthesis-related genes. The data show that quorum sensing is probably mediated by the AI-2/LuxO system in V. tapetis biofilms. The expression of genes encoding the Type VI Secretion System and associated exported proteins are strongly induced, suggesting that V. tapetis activates this virulence factor when living in biofilm. Full article

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16 pages, 2611 KiB

Open AccessEditor’s ChoiceArticle

Kupffer Cells Survive Plasmodium berghei Sporozoite Exposure and Respond with a Rapid Cytokine Release

by Rebecca E. Tweedell, Le Qi, Zhaoli Sun and Rhoel R. Dinglasan

Pathogens 2018, 7(4), 91; https://doi.org/10.3390/pathogens7040091 - 24 Nov 2018

Cited by 12 | Viewed by 4257

Abstract

The liver stage of the Plasmodium life cycle features sporozoite traversal of the liver sinusoidal barrier through Kupffer cells (KCs) followed by invasion of hepatocytes. Little is known about the interaction of Plasmodium sporozoites with KCs, the liver-resident macrophages. Previous reports suggest KCs [...] Read more.

The liver stage of the Plasmodium life cycle features sporozoite traversal of the liver sinusoidal barrier through Kupffer cells (KCs) followed by invasion of hepatocytes. Little is known about the interaction of Plasmodium sporozoites with KCs, the liver-resident macrophages. Previous reports suggest KCs do not mount a pro-inflammatory response and undergo cell death following this interaction. Our work explores this interaction using primary rat KCs (PRKCs) and Plasmodium berghei sporozoites. We analyzed PRKC culture supernatants for markers of an immunological response through cytokine arrays. Additionally, cell wounding and death were assessed by monitoring lactate dehydrogenase (LDH) levels in these supernatants and by live/dead cell imaging. We found that PRKCs mount an immunological response to P. berghei sporozoites by releasing a diverse set of both pro- and anti-inflammatory cytokines, including IFNγ, IL-12p70, Mip-3α, IL-2, RANTES, IL-1α, IL-4, IL-5, IL-13, EPO, VEGF, IL-7, and IL-17α. We also observed no difference in LDH level or live/dead staining upon sporozoite exposure, suggesting that the KCs are not deeply wounded or dying. Overall, our data suggest that sporozoites may be actively modulating the KC’s reaction to their presence and altering the way the innate immune system is triggered by KCs. Full article

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16 pages, 1401 KiB

Open AccessEditor’s ChoiceReview

Modelling a Silent Epidemic: A Review of the In Vitro Models of Latent Tuberculosis

by Savannah E.R. Gibson, James Harrison and Jonathan A.G. Cox

Pathogens 2018, 7(4), 88; https://doi.org/10.3390/pathogens7040088 - 15 Nov 2018

Cited by 34 | Viewed by 6802

Abstract

Tuberculosis (TB) is the primary cause of death by a single infectious agent; responsible for around two million deaths in 2016. A major virulence factor of TB is the ability to enter a latent or Non-Replicating Persistent (NRP) state which is presumed untreatable. [...] Read more.

Tuberculosis (TB) is the primary cause of death by a single infectious agent; responsible for around two million deaths in 2016. A major virulence factor of TB is the ability to enter a latent or Non-Replicating Persistent (NRP) state which is presumed untreatable. Approximately 1.7 billion people are latently infected with TB and on reactivation many of these infections are drug resistant. As the current treatment is ineffective and diagnosis remains poor, millions of people have the potential to reactivate into active TB disease. The immune system seeks to control the TB infection by containing the bacteria in a granuloma, where it is exposed to stressful anaerobic and nutrient deprived conditions. It is thought to be these environmental conditions that trigger the NRP state. A number of in vitro models have been developed that mimic conditions within the granuloma to a lesser or greater extent. These different models have all been utilised for the research of different characteristics of NRP Mycobacterium tuberculosis, however their disparity in approach and physiological relevance often results in inconsistencies and a lack of consensus between studies. This review provides a summation of the different NRP models and a critical analysis of their respective advantages and disadvantages relating to their physiological relevance. Full article

(This article belongs to the Section Human Pathogens)

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9 pages, 1138 KiB

Open AccessEditor’s ChoiceArticle

Hsp90 Interacts with the Bacterial Effector NleH1

by Miaomiao Wu and Philip R. Hardwidge

Pathogens 2018, 7(4), 87; https://doi.org/10.3390/pathogens7040087 - 13 Nov 2018

Cited by 4 | Viewed by 3796

Abstract

Enterohemorrhagic Escherichia coli (EHEC) utilizes a type III secretion system (T3SS) to inject effector proteins into host cells. The EHEC NleH1 effector inhibits the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway by reducing the nuclear translocation of the ribosomal protein S3 [...] Read more.

Enterohemorrhagic Escherichia coli (EHEC) utilizes a type III secretion system (T3SS) to inject effector proteins into host cells. The EHEC NleH1 effector inhibits the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway by reducing the nuclear translocation of the ribosomal protein S3 (RPS3). NleH1 prevents RPS3 phosphorylation by the IκB kinase-β (IKKβ). IKKβ is a central kinase in the NF-κB pathway, yet NleH1 only restricts the phosphorylation of a subset of the IKKβ substrates. We hypothesized that a protein cofactor might dictate this inhibitory specificity. We determined that heat shock protein 90 (Hsp90) interacts with both IKKβ and NleH1 and that inhibiting Hsp90 activity reduces RPS3 nuclear translocation. Full article

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12 pages, 2535 KiB

Open AccessEditor’s ChoiceArticle

SseL Deubiquitinates RPS3 to Inhibit Its Nuclear Translocation

by Miaomiao Wu, Samir El Qaidi and Philip R. Hardwidge

Pathogens 2018, 7(4), 86; https://doi.org/10.3390/pathogens7040086 - 7 Nov 2018

Cited by 8 | Viewed by 4114

Abstract

Many Gram-negative bacterial pathogens use type III secretion systems to deliver virulence proteins (effectors) into host cells to counteract innate immunity. The ribosomal protein S3 (RPS3) guides NF-κB subunits to specific κB sites and plays an important role in the innate response to [...] Read more.

Many Gram-negative bacterial pathogens use type III secretion systems to deliver virulence proteins (effectors) into host cells to counteract innate immunity. The ribosomal protein S3 (RPS3) guides NF-κB subunits to specific κB sites and plays an important role in the innate response to bacterial infection. Two E. coli effectors inhibit RPS3 nuclear translocation. NleH1 inhibits RPS3 phosphorylation by IKK-β, an essential aspect of the RPS3 nuclear translocation process. NleC proteolysis of p65 generates an N-terminal p65 fragment that competes for full-length p65 binding to RPS3, thus also inhibiting RPS3 nuclear translocation. Thus, E. coli has multiple mechanisms by which to block RPS3-mediated transcriptional activation. With this in mind, we considered whether other enteric pathogens also encode T3SS effectors that impact this important host regulatory pathway. Here we report that the Salmonella Secreted Effector L (SseL), which was previously shown to function as a deubiquitinase and inhibit NF-κB signaling, also inhibits RPS3 nuclear translocation by deubiquitinating this important host transcriptional co-factor. RPS3 deubiquitination by SseL was restricted to K63-linkages and mutating the active-site cysteine of SseL abolished its ability to deubiquitinate and subsequently inhibit RPS3 nuclear translocation. Thus, Salmonella also encodes at least one T3SS effector that alters RPS3 activities in the host nucleus. Full article

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18 pages, 1111 KiB

Open AccessEditor’s ChoiceReview

Improving the Breadth of the Host’s Immune Response to Lassa Virus

by Juan Carlos Zapata, Sandra Medina-Moreno, Camila Guzmán-Cardozo and Maria S. Salvato

Pathogens 2018, 7(4), 84; https://doi.org/10.3390/pathogens7040084 - 28 Oct 2018

Cited by 16 | Viewed by 6660

Abstract

In 2017, the global Coalition for Epidemic Preparedness (CEPI) declared Lassa virus disease to be one of the world’s foremost biothreats. In January 2018, World Health Organization experts met to address the Lassa biothreat. It was commonly recognized that the diversity of Lassa [...] Read more.

In 2017, the global Coalition for Epidemic Preparedness (CEPI) declared Lassa virus disease to be one of the world’s foremost biothreats. In January 2018, World Health Organization experts met to address the Lassa biothreat. It was commonly recognized that the diversity of Lassa virus (LASV) isolated from West African patient samples was far greater than that of the Ebola isolates from the West African epidemic of 2013–2016. Thus, vaccines produced against Lassa virus disease face the added challenge that they must be broadly-protective against a wide variety of LASV. In this review, we discuss what is known about the immune response to Lassa infection. We also discuss the approaches used to make broadly-protective influenza vaccines and how they could be applied to developing broad vaccine coverage against LASV disease. Recent advances in AIDS research are also potentially applicable to the design of broadly-protective medical countermeasures against LASV disease. Full article

(This article belongs to the Special Issue Lassa Fever: Viral Replication, Disease Pathogenesis, and Host Immune Modulations)

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18 pages, 2474 KiB

Open AccessEditor’s ChoiceReview

Armillaria Root-Rot Pathogens: Species Boundaries and Global Distribution

by Martin P.A. Coetzee, Brenda D. Wingfield and Michael J. Wingfield

Pathogens 2018, 7(4), 83; https://doi.org/10.3390/pathogens7040083 - 24 Oct 2018

Cited by 37 | Viewed by 7209

Abstract

This review considers current knowledge surrounding species boundaries of the Armillaria root-rot pathogens and their distribution. In addition, a phylogenetic tree using translation elongation factor subunit 1-alpha (tef-1α) from isolates across the globe are used to present a global phylogenetic framework [...] Read more.

This review considers current knowledge surrounding species boundaries of the Armillaria root-rot pathogens and their distribution. In addition, a phylogenetic tree using translation elongation factor subunit 1-alpha (tef-1α) from isolates across the globe are used to present a global phylogenetic framework for the genus. Defining species boundaries based on DNA sequence-inferred phylogenies has been a central focus of contemporary mycology. The results of such studies have in many cases resolved the biogeographic history of species, mechanisms involved in dispersal, the taxonomy of species and how certain phenotypic characteristics have evolved throughout lineage diversification. Such advances have also occurred in the case of Armillaria spp. that include important causal agents of tree root rots. This commenced with the first phylogeny for Armillaria that was based on IGS-1 (intergenic spacer region one) DNA sequence data, published in 1992. Since then phylogenies were produced using alternative loci, either as single gene phylogenies or based on concatenated data. Collectively these phylogenies revealed species clusters in Armillaria linked to their geographic distributions and importantly species complexes that warrant further research. Full article

(This article belongs to the Special Issue Fungal Pathogens of Forest Trees)

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16 pages, 785 KiB

Open AccessEditor’s ChoiceReview

Fungal Pathogens of Maize Gaining Free Passage Along the Silk Road

by Michelle E. H. Thompson and Manish N. Raizada

Pathogens 2018, 7(4), 81; https://doi.org/10.3390/pathogens7040081 - 11 Oct 2018

Cited by 48 | Viewed by 9590

Abstract

Silks are the long threads at the tips of maize ears onto which pollen land and sperm nuclei travel long distances to fertilize egg cells, giving rise to embryos and seeds; however fungal pathogens also use this route to invade developing grain, causing [...] Read more.

Silks are the long threads at the tips of maize ears onto which pollen land and sperm nuclei travel long distances to fertilize egg cells, giving rise to embryos and seeds; however fungal pathogens also use this route to invade developing grain, causing damaging ear rots with dangerous mycotoxins. This review highlights the importance of silks as the direct highways by which globally important fungal pathogens enter maize kernels. First, the most important silk-entering fungal pathogens in maize are reviewed, including Fusarium graminearum, Fusarium verticillioides, and Aspergillus flavus, and their mycotoxins. Next, we compare the different modes used by each fungal pathogen to invade the silks, including susceptible time intervals and the effects of pollination. Innate silk defences and current strategies to protect silks from ear rot pathogens are reviewed, and future protective strategies and silk-based research are proposed. There is a particular gap in knowledge of how to improve silk health and defences around the time of pollination, and a need for protective silk sprays or other technologies. It is hoped that this review will stimulate innovations in breeding, inputs, and techniques to help growers protect silks, which are expected to become more vulnerable to pathogens due to climate change. Full article

(This article belongs to the Special Issue Fusarium)

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14 pages, 940 KiB

Open AccessEditor’s ChoiceReview

New Insights on the Pathogenesis of Takayasu Arteritis: Revisiting the Microbial Theory

by J. Luis Espinoza, Suzue Ai and Itaru Matsumura

Pathogens 2018, 7(3), 73; https://doi.org/10.3390/pathogens7030073 - 6 Sep 2018

Cited by 41 | Viewed by 8526

Abstract

Takayasu arteritis (TAK) is a chronic vasculitis that mainly affects the aorta, its major branches, and the pulmonary arteries. Since the description of the first case by Mikito Takayasu in 1908, several aspects of this rare disease, including the epidemiology, diagnosis, and the [...] Read more.

Takayasu arteritis (TAK) is a chronic vasculitis that mainly affects the aorta, its major branches, and the pulmonary arteries. Since the description of the first case by Mikito Takayasu in 1908, several aspects of this rare disease, including the epidemiology, diagnosis, and the appropriate clinical assessment, have been substantially defined. Nevertheless, while it is well-known that TAK is associated with a profound inflammatory process, possibly rooted to an autoimmune disorder, its precise etiology has remained largely unknown. Efforts to identify the antigen(s) that trigger autoimmunity in this disease have been unsuccessful, however, it is likely that viruses or bacteria, by a molecular mimicry mechanism, initiate or propagate the auto-immune process in this disease. In this article, we summarize recent advances in the understanding of TAK, with emphasis on new insights related to the pathogenesis of this entity that may contribute to the design of novel therapeutic approaches. Full article

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12 pages, 1941 KiB

Open AccessEditor’s ChoiceArticle

Preliminary Studies on Immune Response and Viral Pathogenesis of Zika Virus in Rhesus Macaques

by Shawna M. Woollard, Omalla A. Olwenyi, Debashis Dutta, Rajnish S. Dave, Saumi Mathews, Santhi Gorantla, Noel Johnson, Luis Giavedoni, Robert B. Norgren Jr. and Siddappa N. Byrareddy

Pathogens 2018, 7(3), 70; https://doi.org/10.3390/pathogens7030070 - 20 Aug 2018

Cited by 14 | Viewed by 4706

Abstract

Zika Virus (ZIKV) is primarily transmitted through mosquito bites. It can also be transmitted during sexual intercourse and in utero from mother to fetus. To gain preliminary insight into ZIKV pathology and immune responses on route of transmission, rhesus macaques (RMs) were inoculated [...] Read more.

Zika Virus (ZIKV) is primarily transmitted through mosquito bites. It can also be transmitted during sexual intercourse and in utero from mother to fetus. To gain preliminary insight into ZIKV pathology and immune responses on route of transmission, rhesus macaques (RMs) were inoculated with ZIKV (PRVABC59) via intravaginal (IVAG) (n = 3) or subcutaneous (sub Q) (n = 2) routes. Systemic ZIKV infection was observed in all RMs, regardless of the route of inoculation. After 9 days postinfection (dpi), ZIKV was not detected in the plasma of IVAG- and sub-Q-inoculated RMs. Importantly, RMs harbored ZIKV up to 60 dpi in various anatomical locations. Of note, ZIKV was also present in several regions of the brain, including the caudate nucleus, parietal lobe, cortex, and amygdala. These observations appear to indicate that ZIKV infection may be systemic and persistent regardless of route of inoculation. In addition, we observed changes in key immune cell populations in response to ZIKV infection. Importantly, IVAG ZIKV infection of RMs is associated with increased depletion of CD11C hi myeloid cells, reduced PD-1 expression in NK cells, and elevated frequencies of Ki67⁺ CD8⁺ central memory cells as compared to sub Q ZIKV-infected RMs. These results need to interpreted with caution due to the small number of animals utilized in this study. Future studies involving large groups of animals that have been inoculated through both routes of transmission are needed to confirm our findings. Full article

(This article belongs to the Special Issue Virus-Host Interactions of Zika Virus)

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13 pages, 1462 KiB

Open AccessEditor’s ChoiceReview

A Window to Toxoplasma gondii Egress

by Lucio Ayres Caldas and Wanderley De Souza

Pathogens 2018, 7(3), 69; https://doi.org/10.3390/pathogens7030069 - 14 Aug 2018

Cited by 7 | Viewed by 6166

Abstract

The Toxoplasma gondii cellular cycle has been widely studied in many lifecycle stages; however, the egress event still is poorly understood even though different types of molecules were shown to be involved. Assuming that there is no purpose or intentionality in biological phenomena, [...] Read more.

The Toxoplasma gondii cellular cycle has been widely studied in many lifecycle stages; however, the egress event still is poorly understood even though different types of molecules were shown to be involved. Assuming that there is no purpose or intentionality in biological phenomena, there is no such question as “Why does the parasite leaves the host cell”, but “Under what conditions and how?”. In this review we aimed to summarize current knowledge concerning T. gondii egress physiology (signalling pathways), structures, and route. Full article

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38 pages, 3103 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Early Events in Japanese Encephalitis Virus Infection: Viral Entry

by Sang-Im Yun and Young-Min Lee

Pathogens 2018, 7(3), 68; https://doi.org/10.3390/pathogens7030068 - 13 Aug 2018

Cited by 40 | Viewed by 12088

Abstract

Japanese encephalitis virus (JEV), a mosquito-borne zoonotic flavivirus, is an enveloped positive-strand RNA virus that can cause a spectrum of clinical manifestations, ranging from mild febrile illness to severe neuroinvasive disease. Today, several killed and live vaccines are available in different parts of [...] Read more.

Japanese encephalitis virus (JEV), a mosquito-borne zoonotic flavivirus, is an enveloped positive-strand RNA virus that can cause a spectrum of clinical manifestations, ranging from mild febrile illness to severe neuroinvasive disease. Today, several killed and live vaccines are available in different parts of the globe for use in humans to prevent JEV-induced diseases, yet no antivirals are available to treat JEV-associated diseases. Despite the progress made in vaccine research and development, JEV is still a major public health problem in southern, eastern, and southeastern Asia, as well as northern Oceania, with the potential to become an emerging global pathogen. In viral replication, the entry of JEV into the cell is the first step in a cascade of complex interactions between the virus and target cells that is required for the initiation, dissemination, and maintenance of infection. Because this step determines cell/tissue tropism and pathogenesis, it is a promising target for antiviral therapy. JEV entry is mediated by the viral glycoprotein E, which binds virions to the cell surface (attachment), delivers them to endosomes (endocytosis), and catalyzes the fusion between the viral and endosomal membranes (membrane fusion), followed by the release of the viral genome into the cytoplasm (uncoating). In this multistep process, a collection of host factors are involved. In this review, we summarize the current knowledge on the viral and cellular components involved in JEV entry into host cells, with an emphasis on the initial virus-host cell interactions on the cell surface. Full article

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9 pages, 375 KiB

Open AccessEditor’s ChoiceArticle

Impact of Mosquito Age and Insecticide Exposure on Susceptibility of Aedes albopictus (Diptera: Culicidae) to Infection with Zika Virus

by Heidi Knecht, Stephanie L. Richards, Jo Anne G. Balanay and Avian V. White

Pathogens 2018, 7(3), 67; https://doi.org/10.3390/pathogens7030067 - 12 Aug 2018

Cited by 18 | Viewed by 4533

Abstract

Zika virus (ZIKV) is primarily transmitted to humans by Aedes aegypti and Ae. albopictus. Vector–virus interactions influencing vector competence vary and depend on biological and environmental factors. A mosquito’s chronological age may impact its immune response against virus infection. Insecticides, source reduction, [...] Read more.

Zika virus (ZIKV) is primarily transmitted to humans by Aedes aegypti and Ae. albopictus. Vector–virus interactions influencing vector competence vary and depend on biological and environmental factors. A mosquito’s chronological age may impact its immune response against virus infection. Insecticides, source reduction, and/or public education are currently the best defense against mosquitoes that transmit ZIKV. This study assessed the effects of a mosquito’s chronological age at time of infection on its response to ZIKV infection. We exposed young (6–7 d post-emergence) and old (11–12 d post-emergence) Ae. albopictus to a sublethal dose of bifenthrin prior to oral exposure to blood meals containing ZIKV (7-day incubation period). Old mosquitoes experienced a significantly (p < 0.01) higher rate of mortality than young mosquitoes. Significantly higher ZIKV body titers (p < 0.01) were observed in the old control group compared to the young control group. Significantly higher (p < 0.01) ZIKV dissemination rates and leg titers (p < 0.01) were observed in old bifenthrin-exposed mosquitoes compared to old control mosquitoes or young bifenthrin-exposed or control mosquitoes. Hence, bifenthrin exposure may increase the potential for virus transmission; however, the degree of these impacts varies with mosquito age. Impacts of insecticides should be considered in risk assessments of potential vector populations. Full article

(This article belongs to the Special Issue Virus-Host Interactions of Zika Virus)

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14 pages, 1390 KiB

Open AccessEditor’s ChoiceReview

An Update on Sexual Transmission of Zika Virus

by Hercules Sakkas, Petros Bozidis, Xenofon Giannakopoulos, Nikolaos Sofikitis and Chrissanthy Papadopoulou

Pathogens 2018, 7(3), 66; https://doi.org/10.3390/pathogens7030066 - 3 Aug 2018

Cited by 36 | Viewed by 6417

Abstract

Zika virus (ZIKV) is a single-stranded RNA virus belonging to the arthropod-borne flaviviruses (arboviruses) which are mainly transmitted by blood-sucking mosquitoes of the genus Aedes. ZIKV infection has been known to be rather asymptomatic or presented as febrile self-limited disease; however, during the [...] Read more.

Zika virus (ZIKV) is a single-stranded RNA virus belonging to the arthropod-borne flaviviruses (arboviruses) which are mainly transmitted by blood-sucking mosquitoes of the genus Aedes. ZIKV infection has been known to be rather asymptomatic or presented as febrile self-limited disease; however, during the last decade the manifestation of ZIKV infection has been associated with a variety of neuroimmunological disorders including Guillain–Barré syndrome, microcephaly and other central nervous system abnormalities. More recently, there is accumulating evidence about sexual transmission of ZIKV, a trait that has never been observed in any other mosquito-borne flavivirus before. This article reviews the latest information regarding the latter and emerging role of ZIKV, focusing on the consequences of ZIKV infection on the male reproductive system and the epidemiology of human-to-human sexual transmission. Full article

(This article belongs to the Special Issue Virus-Host Interactions of Zika Virus)

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31 pages, 1001 KiB

Open AccessEditor’s ChoiceReview

Solid Organ Transplant and Parasitic Diseases: A Review of the Clinical Cases in the Last Two Decades

by Silvia Fabiani, Simona Fortunato and Fabrizio Bruschi

Pathogens 2018, 7(3), 65; https://doi.org/10.3390/pathogens7030065 - 31 Jul 2018

Cited by 41 | Viewed by 6003

Abstract

The aim of this study was to evaluate the occurrence of parasitic infections in solid organ transplant (SOT) recipients. We conducted a systematic review of literature records on post-transplant parasitic infections, published from 1996 to 2016 and available on PubMed database, focusing only [...] Read more.

The aim of this study was to evaluate the occurrence of parasitic infections in solid organ transplant (SOT) recipients. We conducted a systematic review of literature records on post-transplant parasitic infections, published from 1996 to 2016 and available on PubMed database, focusing only on parasitic infections acquired after SOT. The methods and findings of the present review have been presented based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist. From data published in the literature, the real burden of parasitic infections among SOT recipients cannot really be estimated. Nevertheless, publications on the matter are on the increase, probably due to more than one reason: (i) the increasing number of patients transplanted and then treated with immunosuppressive agents; (ii) the “population shift” resulting from immigration and travels to endemic areas, and (iii) the increased attention directed to diagnosis/notification/publication of cases. Considering parasitic infections as emerging and potentially serious in their evolution, additional strategies for the prevention, careful screening and follow-up, with a high level of awareness, identification, and pre-emptive therapy are needed in transplant recipients. Full article

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17 pages, 2037 KiB

Open AccessEditor’s ChoiceArticle

Staphylococcus aureus Lipoprotein Induces Skin Inflammation, Accompanied with IFN-γ-Producing T Cell Accumulation through Dermal Dendritic Cells

by Suguru Saito and Ali F. Quadery

Pathogens 2018, 7(3), 64; https://doi.org/10.3390/pathogens7030064 - 29 Jul 2018

Cited by 12 | Viewed by 4645

Abstract

Staphylococcus aureus (S. aureus) is a commensal bacteria on the human skin, which causes serious skin inflammation. Several immune cells, especially effector T cells (Teff), have been identified as key players in S. aureus-derived skin inflammation. However, the bacterial component [...] Read more.

Staphylococcus aureus (S. aureus) is a commensal bacteria on the human skin, which causes serious skin inflammation. Several immune cells, especially effector T cells (Teff), have been identified as key players in S. aureus-derived skin inflammation. However, the bacterial component that induces dramatic host immune responses on the skin has not been well characterized. Here, we report that S. aureus lipoprotein (SA-LP) was recognized by the host immune system as a strong antigen, so this response induced severe skin inflammation. SA-LP activated dendritic cells (DCs), and this activation led to Teff accumulation on the inflamed skin in the murine intradermal (ID) injection model. The skin-accumulated Teff pool was established by IFN-ɤ-producing CD4⁺ and CD8⁺T (Th1 and Tc1). SA-LP activated dermal DC (DDC) in a dominant manner, so that these DCs were presumed to possess the strong responsibility of SA-LP-specific Teff generation in the skin-draining lymph nodes (dLN). SA-LP activated DC transfer into the mice ear, which showed similar inflammation, accompanied with Th1 and Tc1 accumulation on the skin. Thus, we revealed that SA-LP has a strong potential ability to establish skin inflammation through the DC-Teff axis. This finding provides novel insights not only for therapy, but also for the prevention of S. aureus-derived skin inflammation. Full article

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11 pages, 420 KiB

Open AccessEditor’s ChoiceReview

Epstein-Barr Virus-Induced Epigenetic Pathogenesis of Viral-Associated Lymphoepithelioma-Like Carcinomas and Natural Killer/T-Cell Lymphomas

by Lili Li, Brigette B. Y. Ma, Anthony T. C. Chan, Francis K. L. Chan, Paul Murray and Qian Tao

Pathogens 2018, 7(3), 63; https://doi.org/10.3390/pathogens7030063 - 18 Jul 2018

Cited by 21 | Viewed by 9317

Abstract

Cancer genome studies of Epstein-Barr virus (EBV)-associated tumors, including lymphoepithelioma-like carcinomas (LELC) of nasopharyngeal (NPC), gastric (EBVaGC) and lung tissues, and natural killer (NK)/T-cell lymphoma (NKTCL), reveal a unique feature of genomic alterations with fewer gene mutations detected than other common cancers. It [...] Read more.

Cancer genome studies of Epstein-Barr virus (EBV)-associated tumors, including lymphoepithelioma-like carcinomas (LELC) of nasopharyngeal (NPC), gastric (EBVaGC) and lung tissues, and natural killer (NK)/T-cell lymphoma (NKTCL), reveal a unique feature of genomic alterations with fewer gene mutations detected than other common cancers. It is known now that epigenetic alterations play a critical role in the pathogenesis of EBV-associated tumors. As an oncogenic virus, EBV establishes its latent and lytic infections in B-lymphoid and epithelial cells, utilizing hijacked cellular epigenetic machinery. EBV-encoded oncoproteins modulate cellular epigenetic machinery to reprogram viral and host epigenomes, especially in the early stage of infection, using host epigenetic regulators. The genome-wide epigenetic alterations further inactivate a series of tumor suppressor genes (TSG) and disrupt key cellular signaling pathways, contributing to EBV-associated cancer initiation and progression. Profiling of genome-wide CpG methylation changes (CpG methylome) have revealed a unique epigenotype of global high-grade methylation of TSGs in EBV-associated tumors. Here, we have summarized recent advances of epigenetic alterations in EBV-associated tumors (LELCs and NKTCL), highlighting the importance of epigenetic etiology in EBV-associated tumorigenesis. Epigenetic study of these EBV-associated tumors will discover valuable biomarkers for their early detection and prognosis prediction, and also develop effective epigenetic therapeutics for these cancers. Full article

(This article belongs to the Special Issue Emerging Topics in Epstein-Barr virus-Associated Diseases)

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12 pages, 2224 KiB

Open AccessEditor’s ChoiceArticle

Preparation of Poly (dl-Lactide-co-Glycolide) Nanoparticles Encapsulated with Periglaucine A and Betulinic Acid for In Vitro Anti-Acanthamoeba and Cytotoxicity Activities

by Tooba Mahboob, Muhammad Nawaz, Tan Tian-Chye, Chandramathi Samudi, Christophe Wiart and Veeranoot Nissapatorn

Pathogens 2018, 7(3), 62; https://doi.org/10.3390/pathogens7030062 - 16 Jul 2018

Cited by 19 | Viewed by 4748

Abstract

Poly (dl-lactide-co-glycolide) (PLGA) microspheres were synthesized as delivery system for the natural anti-parasitic compounds, Periglaucine A (PGA) and Betulinic acid (BA). Periglaucine A and Betulinic acid were encapsulated in PLGA nanoparticles by single emulsion method with an average particle size of [...] Read more.

Poly (dl-lactide-co-glycolide) (PLGA) microspheres were synthesized as delivery system for the natural anti-parasitic compounds, Periglaucine A (PGA) and Betulinic acid (BA). Periglaucine A and Betulinic acid were encapsulated in PLGA nanoparticles by single emulsion method with an average particle size of approximately 100–500 nm. Periglaucine A and Betulinic acid encapsulation efficiency was observed to be 90% and 35% respectively. Anti-Acanthamoeba property of Periglaucine A and Betulinic acid remained intact after encapsulation. PGA-PLGA and BA-PLGA nanoparticles demonstrated inhibition in viability of Acanthamoeba triangularis trophozoites by 74.9%, 59.9%, 49.9% and 71.2%, 52.2%, 88% respectively at concentration of 100 µg/mL, 50 µg/mL and 25 µg/mL. Cytotoxicity of PGA-PLGA and BA-PLGA nanoparticles has been evaluated against lung epithelial cell line and showed dose dependent cytotoxicity value of IC₅₀ 2 µg/mL and 20 µg/mL respectively. Futher, increased viability was observed in lung epithelial cell line in higher doses of synthesized polymeric nanoparticles. Results indicate that poly (dl-lactide-co-glycolide) (PLGA) nanoparticles could be exploratory delivery systems for natural products to improve their therapeutic efficacy. Full article

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17 pages, 680 KiB

Open AccessEditor’s ChoiceReview

Contribution of Epstein–Barr Virus Latent Proteins to the Pathogenesis of Classical Hodgkin Lymphoma

by Katerina Vrzalikova, Taofik Sunmonu, Gary Reynolds and Paul Murray

Pathogens 2018, 7(3), 59; https://doi.org/10.3390/pathogens7030059 - 27 Jun 2018

Cited by 21 | Viewed by 5378

Abstract

Pathogenic viruses have evolved to manipulate the host cell utilising a variety of strategies including expression of viral proteins to hijack or mimic the activity of cellular functions. DNA tumour viruses often establish latent infection in which no new virions are produced, characterized [...] Read more.

Pathogenic viruses have evolved to manipulate the host cell utilising a variety of strategies including expression of viral proteins to hijack or mimic the activity of cellular functions. DNA tumour viruses often establish latent infection in which no new virions are produced, characterized by the expression of a restricted repertoire of so-called latent viral genes. These latent genes serve to remodel cellular functions to ensure survival of the virus within host cells, often for the lifetime of the infected individual. However, under certain circumstances, virus infection may contribute to transformation of the host cell; this event is not a usual outcome of infection. Here, we review how the Epstein–Barr virus (EBV), the prototypic oncogenic human virus, modulates host cell functions, with a focus on the role of the EBV latent genes in classical Hodgkin lymphoma. Full article

(This article belongs to the Special Issue Emerging Topics in Epstein-Barr virus-Associated Diseases)

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27 pages, 4013 KiB

Open AccessEditor’s ChoiceArticle

A Quantitative Proteomics View on the Function of Qfhb1, a Major QTL for Fusarium Head Blight Resistance in Wheat

by Moustafa Eldakak, Aayudh Das, Yongbin Zhuang, Jai S. Rohila, Karl Glover and Yang Yen

Pathogens 2018, 7(3), 58; https://doi.org/10.3390/pathogens7030058 - 22 Jun 2018

Cited by 13 | Viewed by 7178

Abstract

Fusarium head blight (FHB) is a highly detrimental disease of wheat. A quantitative trait locus for FHB resistance, Qfhb1, is the most utilized source of resistance in wheat-breeding programs, but very little is known about its resistance mechanism. In this study, we [...] Read more.

Fusarium head blight (FHB) is a highly detrimental disease of wheat. A quantitative trait locus for FHB resistance, Qfhb1, is the most utilized source of resistance in wheat-breeding programs, but very little is known about its resistance mechanism. In this study, we elucidated a prospective FHB resistance mechanism by investigating the proteomic signatures of Qfhb1 in a pair of contrasting wheat near-isogenic lines (NIL) after 24 h of inoculation of wheat florets by Fusarium graminearum. Statistical comparisons of the abundances of protein spots on the 2D-DIGE gels of contrasting NILs (fhb1+ NIL = Qfhb1 present; fhb1- NIL = Qfhb1 absent) enabled us to select 80 high-ranking differentially accumulated protein (DAP) spots. An additional evaluation confirmed that the DAP spots were specific to the spikelet from fhb1- NIL (50 spots), and fhb1+ NIL (seven spots). The proteomic data also suggest that the absence of Qfhb1 makes the fhb1- NIL vulnerable to Fusarium attack by constitutively impairing several mechanisms including sucrose homeostasis by enhancing starch synthesis from sucrose. In the absence of Qfhb1, Fusarium inoculations severely damaged photosynthetic machinery; altered the metabolism of carbohydrates, nitrogen and phenylpropanoids; disrupted the balance of proton gradients across relevant membranes; disturbed the homeostasis of many important signaling molecules induced the mobility of cellular repair; and reduced translational activities. These changes in the fhb1- NIL led to strong defense responses centered on the hypersensitive response (HSR), resulting in infected cells suicide and the consequent initiation of FHB development. Therefore, the results of this study suggest that Qfhb1 largely functions to either alleviate HSR or to manipulate the host cells to not respond to Fusarium infection. Full article

(This article belongs to the Special Issue Wheat Diseases)

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13 pages, 1342 KiB

Open AccessEditor’s ChoiceReview

The Mammalian Intestinal Microbiome: Composition, Interaction with the Immune System, Significance for Vaccine Efficacy, and Potential for Disease Therapy

by Ulrich Desselberger

Pathogens 2018, 7(3), 57; https://doi.org/10.3390/pathogens7030057 - 21 Jun 2018

Cited by 40 | Viewed by 6466

Abstract

The mammalian gut is colonized by a large variety of microbes, collectively termed ‘the microbiome’. The gut microbiome undergoes rapid changes during the first few years of life and is highly variable in adulthood depending on various factors. With the gut being the [...] Read more.

The mammalian gut is colonized by a large variety of microbes, collectively termed ‘the microbiome’. The gut microbiome undergoes rapid changes during the first few years of life and is highly variable in adulthood depending on various factors. With the gut being the largest organ of immune responses, the composition of the microbiome of the gut has been found to be correlated with qualitative and quantitative differences of mucosal and systemic immune responses. Animal models have been very useful to unravel the relationship between gut microbiome and immune responses and for the understanding of variations of immune responses to vaccination in different childhood populations. However, the molecular mechanisms underlying optimal immune responses to infection or vaccination are not fully understood. The gut virome and gut bacteria can interact, with bacteria facilitating viral infectivity by different mechanisms. Some gut bacteria, which have a beneficial effect on increasing immune responses or by overgrowing intestinal pathogens, are considered to act as probiotics and can be used for therapeutic purposes (as in the case of fecal microbiome transplantation). Full article

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22 pages, 657 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Listeria Monocytogenes: A Model Pathogen Continues to Refine Our Knowledge of the CD8 T Cell Response

by Zhijuan Qiu, Camille Khairallah and Brian S. Sheridan

Pathogens 2018, 7(2), 55; https://doi.org/10.3390/pathogens7020055 - 16 Jun 2018

Cited by 29 | Viewed by 7850

Abstract

Listeria monocytogenes (Lm) infection induces robust CD8 T cell responses, which play a critical role in resolving Lm during primary infection and provide protective immunity to re-infections. Comprehensive studies have been conducted to delineate the CD8 T cell response after Lm [...] Read more.

Listeria monocytogenes (Lm) infection induces robust CD8 T cell responses, which play a critical role in resolving Lm during primary infection and provide protective immunity to re-infections. Comprehensive studies have been conducted to delineate the CD8 T cell response after Lm infection. In this review, the generation of the CD8 T cell response to Lm infection will be discussed. The role of dendritic cell subsets in acquiring and presenting Lm antigens to CD8 T cells and the events that occur during T cell priming and activation will be addressed. CD8 T cell expansion, differentiation and contraction as well as the signals that regulate these processes during Lm infection will be explored. Finally, the formation of memory CD8 T cell subsets in the circulation and in the intestine will be analyzed. Recently, the study of CD8 T cell responses to Lm infection has begun to shift focus from the intravenous infection model to a natural oral infection model as the humanized mouse and murinized Lm have become readily available. Recent findings in the generation of CD8 T cell responses to oral infection using murinized Lm will be explored throughout the review. Finally, CD8 T cell-mediated protective immunity against Lm infection and the use of Lm as a vaccine vector for cancer immunotherapy will be highlighted. Overall, this review will provide detailed knowledge on the biology of CD8 T cell responses after Lm infection that may shed light on improving rational vaccine design. Full article

(This article belongs to the Special Issue Listeria monocytogenes and Its Interactions with the Host)

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23 pages, 2245 KiB

Open AccessEditor’s ChoiceReview

Manipulation of Innate and Adaptive Immunity by Staphylococcal Superantigens

by Stephen W. Tuffs, S. M. Mansour Haeryfar and John K. McCormick

Pathogens 2018, 7(2), 53; https://doi.org/10.3390/pathogens7020053 - 29 May 2018

Cited by 78 | Viewed by 10292

Abstract

Staphylococcal superantigens (SAgs) constitute a family of potent exotoxins secreted by Staphylococcus aureus and other select staphylococcal species. SAgs function to cross-link major histocompatibility complex (MHC) class II molecules with T cell receptors (TCRs) to stimulate the uncontrolled activation of T lymphocytes, potentially [...] Read more.

Staphylococcal superantigens (SAgs) constitute a family of potent exotoxins secreted by Staphylococcus aureus and other select staphylococcal species. SAgs function to cross-link major histocompatibility complex (MHC) class II molecules with T cell receptors (TCRs) to stimulate the uncontrolled activation of T lymphocytes, potentially leading to severe human illnesses such as toxic shock syndrome. The ubiquity of SAgs in clinical S. aureus isolates suggests that they likely make an important contribution to the evolutionary fitness of S. aureus. Although the apparent redundancy of SAgs in S. aureus has not been explained, the high level of sequence diversity within this toxin family may allow for SAgs to recognize an assorted range of TCR and MHC class II molecules, as well as aid in the avoidance of humoral immunity. Herein, we outline the major diseases associated with the staphylococcal SAgs and how a dysregulated immune system may contribute to pathology. We then highlight recent research that considers the importance of SAgs in the pathogenesis of S. aureus infections, demonstrating that SAgs are more than simply an immunological diversion. We suggest that SAgs can act as targeted modulators that drive the immune response away from an effective response, and thus aid in S. aureus persistence. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Staphylococcal Infections)

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14 pages, 2498 KiB

Open AccessEditor’s ChoiceReview

Vertical Transmission of Listeria monocytogenes: Probing the Balance between Protection from Pathogens and Fetal Tolerance

by Nicole M. Lamond and Nancy E. Freitag

Pathogens 2018, 7(2), 52; https://doi.org/10.3390/pathogens7020052 - 25 May 2018

Cited by 29 | Viewed by 7312

Abstract

Protection of the developing fetus from pathogens is one of the many critical roles of the placenta. Listeria monocytogenes is one of a select number of pathogens that can cross the placental barrier and cause significant harm to the fetus, leading to spontaneous [...] Read more.

Protection of the developing fetus from pathogens is one of the many critical roles of the placenta. Listeria monocytogenes is one of a select number of pathogens that can cross the placental barrier and cause significant harm to the fetus, leading to spontaneous abortion, stillbirth, preterm labor, and disseminated neonate infection despite antibiotic treatment. Such severe outcomes serve to highlight the importance of understanding how L. monocytogenes mediates infiltration of the placental barrier. Here, we review what is currently known regarding vertical transmission of L. monocytogenes as a result of cell culture and animal models of infection. In vitro cell culture and organ models have been useful for the identification of L. monocytogenes virulence factors that contribute to placental invasion. Examples include members of the Internalin family of bacterial surface proteins such as Interalin (Inl)A, InlB, and InlP that promote invasion of cells at the maternal-fetal interface. A number of animal models have been used to interrogate L. monocytogenes vertical transmission, including mice, guinea pigs, gerbils, and non-human primates; each of these models has advantages while still not providing a comprehensive understanding of L. monocytogenes invasion of the human placenta and/or fetus. These models do, however, allow for the molecular investigation of the balance between fetal tolerance and immune protection from L. monocytogenes during pregnancy. Full article

(This article belongs to the Special Issue Listeria monocytogenes and Its Interactions with the Host)

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19 pages, 776 KiB

Open AccessEditor’s ChoiceReview

Zika Virus Trafficking and Interactions in the Human Male Reproductive Tract

by Lucia Regina Cangussu Da Silva

Pathogens 2018, 7(2), 51; https://doi.org/10.3390/pathogens7020051 - 11 May 2018

Cited by 10 | Viewed by 18464

Abstract

Sexual transmission of Zika virus (ZIKV) is a matter of great concern. Infectious viral particles can be shed in semen for as long as six months after infection and can be transferred to male and female sexual partners during unprotected sexual intercourse. The [...] Read more.

Sexual transmission of Zika virus (ZIKV) is a matter of great concern. Infectious viral particles can be shed in semen for as long as six months after infection and can be transferred to male and female sexual partners during unprotected sexual intercourse. The virus can be found inside spermatozoa and could be directly transferred to the oocyte during fertilization. Sexual transmission of ZIKV can contribute to the rise in number of infected individuals in endemic areas as well as in countries where the mosquito vector does not thrive. There is also the possibility, as has been demonstrated in mouse models, that the vaginal deposition of ZIKV particles present in semen could lead to congenital syndrome. In this paper, we review the current literature to understand ZIKV trafficking from the bloodstream to the human male reproductive tract and viral interactions with host cells in interstitial spaces, tubule walls, annexed glands and semen. We hope to highlight gaps to be filled by future research and potential routes for vaccine and antiviral development. Full article

(This article belongs to the Special Issue Virus-Host Interactions of Zika Virus)

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