Editorial

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Open AccessEditorial

by Adilia Warris

J. Fungi 2018, 4(1), 7; https://doi.org/10.3390/jof4010007 - 02 Jan 2018

Cited by 1 | Viewed by 3088

The clinical presentation of fungal disease is strongly determined by the underlying immune defect present [...]
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(This article belongs to the Special Issue Host–Fungus Interactions)

Research

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4594 KiB

Open AccessArticle

Conserved Inhibition of Neutrophil Extracellular Trap Release by Clinical Candida albicans Biofilms

by John F. Kernien, Chad J. Johnson and Jeniel E. Nett

J. Fungi 2017, 3(3), 49; https://doi.org/10.3390/jof3030049 - 06 Sep 2017

Cited by 26 | Viewed by 4771

Abstract

Candida albicans biofilms are difficult to eradicate due to their resistance to host defenses and antifungal drugs. Although neutrophils are the primary responder to C. albicans during invasive candidiasis, biofilms resist killing by neutrophils. Prior investigation, with the commonly used laboratory strain SC5314, [...] Read more.

Candida albicans biofilms are difficult to eradicate due to their resistance to host defenses and antifungal drugs. Although neutrophils are the primary responder to C. albicans during invasive candidiasis, biofilms resist killing by neutrophils. Prior investigation, with the commonly used laboratory strain SC5314, linked this phenotype to the impaired release of neutrophil extracellular traps (NETs), which are structures of DNA, histones, and antimicrobial proteins involved in extracellular microbial killing. Considering the diversity of C. albicans biofilms, we examined the neutrophil response to a subset of clinical isolates forming biofilms with varying depths and architectures. Using fluorescent staining of DNA and scanning electron microscopy, we found that inhibition of NET release was conserved across the clinical isolates. However, the dampening of the production of reactive oxygen species (ROS) by neutrophils was strain-dependent, suggesting an uncoupling of ROS and NET inhibition. Our findings show that biofilms formed by clinical C. albicans isolates uniformly impair the release of NETs. Further investigation of this pathway may reveal novel approaches to augment immunity to C. albicans biofilm infections. Full article

(This article belongs to the Special Issue Host–Fungus Interactions)

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3976 KiB

Open AccessArticle

Macrophage Migration Is Impaired within Candida albicans Biofilms

by Maria F. Alonso, Neil A. R. Gow, Lars P. Erwig and Judith M. Bain

J. Fungi 2017, 3(3), 31; https://doi.org/10.3390/jof3030031 - 22 Jun 2017

Cited by 23 | Viewed by 5956

Abstract

Candida albicans is an opportunistic fungal pathogen that infects immunocompromised patients. Infection control requires phagocytosis by innate immune cells, including macrophages. Migration towards, and subsequent recognition of, C. albicans fungal cell wall components by macrophages is critical for phagocytosis. Using live-cell imaging of [...] Read more.

Candida albicans is an opportunistic fungal pathogen that infects immunocompromised patients. Infection control requires phagocytosis by innate immune cells, including macrophages. Migration towards, and subsequent recognition of, C. albicans fungal cell wall components by macrophages is critical for phagocytosis. Using live-cell imaging of phagocytosis, the macrophage cell line J774.1 showed enhanced movement in response to C. albicans cell wall mutants, particularly during the first 30 min, irrespective of the infection ratio. However, phagocyte migration was reduced up to 2-fold within a C. albicans biofilm compared to planktonic fungal cells. Biofilms formed from C. albicans glycosylation mutant cells also inhibited macrophage migration to a similar extent as wildtype Candida biofilms, suggesting that the physical structure of the biofilm, rather than polysaccharide matrix composition, may hamper phagocyte migration. These data illustrate differential macrophage migratory capacities, dependent upon the form of C. albicans encountered. Impaired migration of macrophages within a C. albicans biofilm may contribute to the recalcitrant nature of clinical infections in which biofilm formation occurs. Full article

(This article belongs to the Special Issue Host–Fungus Interactions)

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2893 KiB

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Monocyte Phenotype and IFN-γ-Inducible Cytokine Responses Are Associated with Cryptococcal Immune Reconstitution Inflammatory Syndrome

by David B. Meya, Samuel Okurut, Godfrey Zziwa, Stephen Cose, Paul R. Bohjanen, Harriet Mayanja-Kizza, Moses Joloba, David R. Boulware, Carol Yukari Manabe, Sharon Wahl and Edward N. Janoff

J. Fungi 2017, 3(2), 28; https://doi.org/10.3390/jof3020028 - 02 Jun 2017

Cited by 14 | Viewed by 5749

Abstract

A third of adults with AIDS and cryptococcal meningitis (CM) develop immune reconstitution inflammatory syndrome (IRIS) after initiating antiretroviral therapy (ART), which is thought to result from exaggerated inflammatory antigen-specific T cell responses. The contribution of monocytes to the immunopathogenesis of cryptococcal IRIS [...] Read more.

A third of adults with AIDS and cryptococcal meningitis (CM) develop immune reconstitution inflammatory syndrome (IRIS) after initiating antiretroviral therapy (ART), which is thought to result from exaggerated inflammatory antigen-specific T cell responses. The contribution of monocytes to the immunopathogenesis of cryptococcal IRIS remains unclear. We compared monocyte subset frequencies and immune responses in HIV-infected Ugandans at time of CM diagnosis (IRIS-Baseline) for those who later developed CM-IRIS, controls who did not develop CM-IRIS (Control-Baseline) at CM-IRIS (IRIS-Event), and for controls at a time point matched for ART duration (Control-Event) to understand the association of monocyte distribution and immune responses with cryptococcal IRIS. At baseline, stimulation with IFN-γ ex vivo induced a higher frequency of TNF-α- and IL-6-producing monocytes among those who later developed IRIS. Among participants who developed IRIS, ex vivo IFN-γ stimulation induced higher frequencies of activated monocytes, IL-6⁺, TNF-α⁺ classical, and IL-6⁺ intermediate monocytes compared with controls. In conclusion, we have demonstrated that monocyte subset phenotype and cytokine responses prior to ART are associated with and may be predictive of CM-IRIS. Larger studies to further delineate innate immunological responses and the efficacy of immunomodulatory therapies during cryptococcal IRIS are warranted. Full article

(This article belongs to the Special Issue Host–Fungus Interactions)

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644 KiB

Open AccessArticle

Innate and Adaptive Immune Defects in Chronic Pulmonary Aspergillosis

by Felix Bongomin, Chris Harris, Philip Foden, Chris Kosmidis and David W. Denning

J. Fungi 2017, 3(2), 26; https://doi.org/10.3390/jof3020026 - 29 May 2017

Cited by 449 | Viewed by 6220

Abstract

We evaluated the expression of biomarkers of innate and adaptive immune response in correlation with underlying conditions in 144 patients with chronic pulmonary aspergillosis (CPA). Patients with complete medical and radiological records, white cell counts, and a complete panel of CD3, CD4, CD8, [...] Read more.

We evaluated the expression of biomarkers of innate and adaptive immune response in correlation with underlying conditions in 144 patients with chronic pulmonary aspergillosis (CPA). Patients with complete medical and radiological records, white cell counts, and a complete panel of CD3, CD4, CD8, CD19, and CD56 lymphocyte subsets were included. Eighty-four (58%) patients had lymphopenia. Six (4%) patients had lymphopenia in all five CD variables. There were 62 (43%) patients with low CD56 and 62 (43%) patients with low CD19. Ten (7%) patients had isolated CD19 lymphopenia, 18 (13%) had isolated CD56 lymphopenia, and 15 (10%) had combined CD19 and CD56 lymphopenia only. Forty-eight (33%) patients had low CD3 and 46 (32%) had low CD8 counts. Twenty-five (17%) patients had low CD4, 15 (10%) of whom had absolute CD4 counts <200/μL. Multivariable logistic regression showed associations between: low CD19 and pulmonary sarcoidosis (Odds Ratio (OR), 5.53; 95% Confidence Interval (CI), 1.43–21.33; p = 0.013), and emphysema (OR, 4.58; 95% CI; 1.36–15.38; p = 0.014), low CD56 and no bronchiectasis (OR, 0.27; 95% CI, 0.10–0.77; p = 0.014), low CD3 and both multicavitary CPA disease (OR, 2.95; 95% CI, 1.30–6.72; p = 0.010) and pulmonary sarcoidosis (OR, 4.94; 95% CI, 1.39–17.57; p = 0.014). Several subtle immune defects are found in CPA. Full article

(This article belongs to the Special Issue Host–Fungus Interactions)

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Review

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The Role of IL-17 in Protection against Mucosal Candida Infections

by Bemnet G. Mengesha and Heather R. Conti

J. Fungi 2017, 3(4), 52; https://doi.org/10.3390/jof3040052 - 27 Sep 2017

Cited by 72 | Viewed by 6240

Abstract

Interleukin-17 (IL-17) is a proinflammatory cytokine produced by adaptive CD4+ T helper cells and innate lymphocytes, such as γδ-T cells and TCRβ+ “natural” Th17 cells. IL-17 activates signaling through the IL-17 receptor, which induces other proinflammatory cytokines, antimicrobial peptides and neutrophil chemokines that [...] Read more.

Interleukin-17 (IL-17) is a proinflammatory cytokine produced by adaptive CD4+ T helper cells and innate lymphocytes, such as γδ-T cells and TCRβ+ “natural” Th17 cells. IL-17 activates signaling through the IL-17 receptor, which induces other proinflammatory cytokines, antimicrobial peptides and neutrophil chemokines that are important for antifungal activity. The importance of IL-17 in protective antifungal immunity is evident in mice and humans, where various genetic defects related to the IL-17-signaling pathway render them highly susceptible to forms of candidiasis such oropharyngeal candidiasis (OPC) or more broadly chronic mucocutaneous candidiasis (CMC), both caused mainly by the opportunistic fungal pathogen Candida albicans. OPC is common in infants and the elderly, HIV/AIDS and patients receiving chemotherapy and/or radiotherapy for head and neck cancers. This review focuses on the role of IL-17 in protection against candidiasis, and includes a brief discussion of non-Candida albicans fungal infections, as well as how therapeutic interventions blocking IL-17-related components can affect antifungal immunity. Full article

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Open AccessReview

Fungal Strategies to Evade the Host Immune Recognition

by Marco J. Hernández-Chávez, Luis A. Pérez-García, Gustavo A. Niño-Vega and Héctor M. Mora-Montes

J. Fungi 2017, 3(4), 51; https://doi.org/10.3390/jof3040051 - 23 Sep 2017

Cited by 88 | Viewed by 16063

Abstract

The recognition of fungal cells by the host immune system is key during the establishment of a protective anti-fungal response. Even though the immune system has evolved a vast number of processes to control these organisms, they have developed strategies to fight back, [...] Read more.

The recognition of fungal cells by the host immune system is key during the establishment of a protective anti-fungal response. Even though the immune system has evolved a vast number of processes to control these organisms, they have developed strategies to fight back, avoiding the proper recognition by immune components and thus interfering with the host protective mechanisms. Therefore, the strategies to evade the immune system are as important as the virulence factors and attributes that damage the host tissues and cells. Here, we performed a thorough revision of the main fungal tactics to escape from the host immunosurveillance processes. These include the composition and organization of the cell wall, the fungal capsule, the formation of titan cells, biofilms, and asteroid bodies; the ability to undergo dimorphism; and the escape from nutritional immunity, extracellular traps, phagocytosis, and the action of humoral immune effectors. Full article

(This article belongs to the Special Issue Host–Fungus Interactions)

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1176 KiB

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Immune Recognition of Fungal Polysaccharides

by Brendan D. Snarr, Salman T. Qureshi and Donald C. Sheppard

J. Fungi 2017, 3(3), 47; https://doi.org/10.3390/jof3030047 - 28 Aug 2017

Cited by 63 | Viewed by 10445

Abstract

The incidence of fungal infections has dramatically increased in recent years, in large part due to increased use of immunosuppressive medications, as well as aggressive medical and surgical interventions that compromise natural skin and mucosal barriers. There are relatively few currently licensed antifungal [...] Read more.

The incidence of fungal infections has dramatically increased in recent years, in large part due to increased use of immunosuppressive medications, as well as aggressive medical and surgical interventions that compromise natural skin and mucosal barriers. There are relatively few currently licensed antifungal drugs, and rising resistance to these agents has led to interest in the development of novel preventative and therapeutic strategies targeting these devastating infections. One approach to combat fungal infections is to augment the host immune response towards these organisms. The polysaccharide-rich cell wall is the initial point of contact between fungi and the host immune system, and therefore, represents an important target for immunotherapeutic approaches. This review highlights the advances made in our understanding of the mechanisms by which the immune system recognizes and interacts with exopolysaccharides produced by four of the most common fungal pathogens: Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, and Histoplasma capsulatum. Work to date suggests that inner cell wall polysaccharides that play an important structural role are the most conserved across diverse members of the fungal kingdom, and elicit the strongest innate immune responses. The immune system senses these carbohydrates through receptors, such as lectins and complement proteins. In contrast, a greater diversity of polysaccharides is found within the outer cell walls of pathogenic fungi. These glycans play an important role in immune evasion, and can even induce anti-inflammatory host responses. Further study of the complex interactions between the host immune system and the fungal polysaccharides will be necessary to develop more effective therapeutic strategies, as well as to explore the use of immunosuppressive polysaccharides as therapeutic agents to modulate inflammation. Full article

(This article belongs to the Special Issue Host–Fungus Interactions)

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311 KiB

Open AccessReview

Innate Immune Responses to Cryptococcus

by Lena J. Heung

J. Fungi 2017, 3(3), 35; https://doi.org/10.3390/jof3030035 - 02 Jul 2017

Cited by 23 | Viewed by 5365

Abstract

Cryptococcus species are encapsulated fungi found in the environment that predominantly cause disease in immunocompromised hosts after inhalation into the lungs. Even with contemporary antifungal regimens, patients with cryptococcosis continue to have high morbidity and mortality rates. The development of more effective therapies [...] Read more.

Cryptococcus species are encapsulated fungi found in the environment that predominantly cause disease in immunocompromised hosts after inhalation into the lungs. Even with contemporary antifungal regimens, patients with cryptococcosis continue to have high morbidity and mortality rates. The development of more effective therapies may depend on our understanding of the cellular and molecular mechanisms by which the host promotes sterilizing immunity against the fungus. This review will highlight our current knowledge of how Cryptococcus, primarily the species C. neoformans, is sensed by the mammalian host and how subsequent signaling pathways direct the anti-cryptococcal response by effector cells of the innate immune system. Full article

(This article belongs to the Special Issue Host–Fungus Interactions)

224 KiB

Open AccessReview

NK Cells and Their Role in Invasive Mold Infection

by Stanislaw Schmidt, Annalisa Condorelli, Antonia Koltze and Thomas Lehrnbecher

J. Fungi 2017, 3(2), 25; https://doi.org/10.3390/jof3020025 - 19 May 2017

Cited by 8 | Viewed by 3900

Abstract

There is growing evidence that Natural Killer (NK) cells exhibit in vitro activity against both Aspergillus and non-Aspergillus molds. Cytotoxic molecules such as NK cell-derived perforin seem to play an important role in the antifungal activity. In addition, NK cells release a [...] Read more.

There is growing evidence that Natural Killer (NK) cells exhibit in vitro activity against both Aspergillus and non-Aspergillus molds. Cytotoxic molecules such as NK cell-derived perforin seem to play an important role in the antifungal activity. In addition, NK cells release a number of cytokines upon stimulation by fungi, which modulate both innate and adaptive host immune responses. Whereas the in vitro data of the antifungal activity of NK cells are supported by animal studies, clinical data are scarce to date. Full article

(This article belongs to the Special Issue Host–Fungus Interactions)

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