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Leishmania & Leishmaniasis
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Leishmania & Leishmaniasis

A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Parasitic Pathogens".

Deadline for manuscript submissions: closed (15 June 2022) | Viewed by 63081

Special Issue Editor

Prof. Dr. Kwang Poo Chang

E-Mail Website
Guest Editor
Microbiology and Immunology, Center for Cancer Cell Biology, Immunology, and Infection, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA
Interests: leishmaniasis; host–parasite interactions; pathogenicity; eco-health; biotechnology; molecular science

Special Issue Information

Dear Colleagues,

Leishmania spp. are trypanosomatid protozoa, causing a very widespread disease with a spectrum of clinical manifestations, ranging from self-healing innocuous cutaneous lesions to facial disfiguring mucocutaneous infection and to potentially fatal visceral disease. The disease is a vector-borne zoonosis circulating among animals, e.g., canids, rodents and edentates (S. America). Humans are incidental dead-end hosts. The disease is considered anthroponotic in a few endemic areas where reservoir animals have not been found. For many decades, Leishmania and leishmaniasis have attracted the attention of basic and applied scientists in many disciplinary areas. Medical scientists, epidemiologists, experts of infectious diseases and public health/operational health and medical administrators are dedicated to leishmaniasis for it is designated as a neglected disease targeted by the WHO for elimination. Medical entomologists have developed tools and methodologies for sand fly collection for vector species identification, bloodmeal analysis, laboratory colonization, population dynamics, life cycle development, etc.  Parasitologists are fascinated by Leishmania spp. for their evolution of endoparasitism, alternating between the gut of sand fly vectors and mammalian macrophages. Cell biologists marvel at the ability of Leishmania to take residence in the lysosome–phagosome vacuolar system of macrophages, the archetype of immune cells, which normally kill invading pathogens by phagocytosis. Immunologists use Leishmania infection extensively to study basic immunology in mouse models. Biochemists have put together a Leishmania metabolic pathway map, discovering unique targets for pharmacologists to develop potential anti-leishmanial drugs.  Molecular biologists have described oddities in Leishmania genomic structures/organization, transcriptional and translational mechanisms as well as mitochondrial cryptic genes in circular genomes and the maturation of mRNA via RNA editing. Molecular genetics makes it possible to study gene expression, function and hybrid analysis. In spite of the tremendous progress made, there remain large gaps in our knowledge, leaving many goals unfulfilled, e.g., vaccine and new drug development to control the disease effectively. It is time to seek help from seasoned and emerging colleagues to succinctly summarize their past and current contributions of significance as the foundation to discover the future direction of research for moving forward effectively.

Prof. Dr. Kwang Poo Chang
Guest Editor

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Keywords

  • leishmaniasis
  • host–parasite interactions
  • pathogenicity
  • biotechnology
  • molecular science

Published Papers (18 papers)

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Editorial

Jump to: Research, Review

2 pages, 152 KiB  
Editorial
Leishmania and Leishmaniasis Research: The Past 50 Years and the Future
by Kwang Poo Chang
Pathogens 2023, 12(6), 776; https://doi.org/10.3390/pathogens12060776 - 30 May 2023
Viewed by 1442
Abstract
Leishmaniasis is a widespread disease among impoverished populations with an annual incidence of up to 1 million according to the WHO [...] Full article
(This article belongs to the Special Issue Leishmania & Leishmaniasis)

Research

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11 pages, 1789 KiB  
Article
Morphogenesis Dynamics in Leishmania Differentiation
by Ramu Dandugudumula, Renana Fischer-Weinberger and Dan Zilberstein
Pathogens 2022, 11(9), 952; https://doi.org/10.3390/pathogens11090952 - 23 Aug 2022
Cited by 2 | Viewed by 1607
Abstract
Leishmania, the causative agent of leishmaniasis, is an obligatory intracellular parasite that cycles between phagolysosome of mammalian macrophages, where it resides as round intracellular amastigotes, and the midgut of female sandflies, where it resides as extracellular elongated promastigotes. This protozoan parasite cytoskeleton is [...] Read more.
Leishmania, the causative agent of leishmaniasis, is an obligatory intracellular parasite that cycles between phagolysosome of mammalian macrophages, where it resides as round intracellular amastigotes, and the midgut of female sandflies, where it resides as extracellular elongated promastigotes. This protozoan parasite cytoskeleton is composed of stable and abundant subpellicular microtubules (SPMT). This study aims to determine the kinetics of developmental morphogenesis and assess whether microtubules remodelling is involved in this process. Using image-streaming technology, we observed that rounding of promastigotes during differentiation into amastigotes was initiated promptly after exposure to the differentiation signal. Stabilizing microtubules with taxol sped rounding, but later killed differentiating parasites if taxol was not removed. Microtubule destabilizers such as vinblastine had no effect on the rate of rounding, nor on the viability of differentiating parasites. In the reverse process, elongation is initiated after a delay of 7.5 and completed 72 h after exposure to the amastigote to the promastigote differentiation signal. During the delay, parasites became highly sensitive to treatment with microtubule destabilizers. The addition of vinblastine during the first 7.5 h halted differentiation and killed parasites. Between 8 and 24 h, parasites gradually became resistant to vinblastine and, in parallel, started to elongate. In contrast, taxol had no effect on parasite elongation, nor on the viability of these cells. In a parallel study, we showed that the Leishmania-specific protein kinase A (PKA) holoenzyme containing the LdPKAR3-C3 complex is essential for promastigote elongation. Mutant promastigotes lacking either of these proteins are round, but maintain their flagella. Here, we observed that during differentiation into amastigotes, these mutants round at the same rate as the wild type, but never exceed the WT density of round amastigotes. In the reverse process, these mutants undergo the same initial delay and then elongate at the same rate as the WT. They stop elongating when they reach 20% of elongated cells in mature promastigotes. Our analysis indicates that while promastigote rounding into amastigotes did not require microtubule remodelling, morphogenesis of round amastigotes into elongated promastigotes required microtubule rearrangement before elongation was initiated. This is the first study that investigates the dynamics of microtubules during parasite development. Full article
(This article belongs to the Special Issue Leishmania & Leishmaniasis)
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11 pages, 1164 KiB  
Article
Localization of Epigenetic Markers in Leishmania Chromatin
by Jacquelyn R. McDonald, Bryan C. Jensen, Aakash Sur, Iris L. K. Wong, Stephen M. Beverley and Peter J. Myler
Pathogens 2022, 11(8), 930; https://doi.org/10.3390/pathogens11080930 - 18 Aug 2022
Cited by 3 | Viewed by 1811
Abstract
Eukaryotes use histone variants and post-translation modifications (PTMs), as well as DNA base modifications, to regulate DNA replication/repair, chromosome condensation, and gene expression. Despite the unusual organization of their protein-coding genes into large polycistronic transcription units (PTUs), trypanosomatid parasites also employ a “histone [...] Read more.
Eukaryotes use histone variants and post-translation modifications (PTMs), as well as DNA base modifications, to regulate DNA replication/repair, chromosome condensation, and gene expression. Despite the unusual organization of their protein-coding genes into large polycistronic transcription units (PTUs), trypanosomatid parasites also employ a “histone code” to control these processes, but the details of this epigenetic code are poorly understood. Here, we present the results of experiments designed to elucidate the distribution of histone variants and PTMs over the chromatin landscape of Leishmania tarentolae. These experiments show that two histone variants (H2A.Z and H2B.V) and three histone H3 PTMs (H3K4me3, H3K16ac, and H3K76me3) are enriched at transcription start sites (TSSs); while a histone variant (H3.V) and the trypanosomatid-specific hyper-modified DNA base J are located at transcription termination sites (TTSs). Reduced nucleosome density was observed at all TTSs and TSSs for RNA genes transcribed by RNA polymerases I (RNAPI) or RNAPIII; as well as (to a lesser extent) at TSSs for the PTUs transcribed by RNAPII. Several PTMs (H3K4me3, H3K16ac H3K20me2 and H3K36me3) and base J were enriched at centromeres, while H3K50ac was specifically associated with the periphery of these centromeric sequences. These findings significantly expand our knowledge of the epigenetic markers associated with transcription, DNA replication and/or chromosome segregation in these early diverging eukaryotes and will hopefully lay the groundwork for future studies to elucidate how they control these fundamental processes. Full article
(This article belongs to the Special Issue Leishmania & Leishmaniasis)
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16 pages, 1621 KiB  
Article
Independent Circulation of Leishmania major and Leishmania tropica in Their Respective Sandfly Vectors for Transmission of Zoonotic and Chronic Cutaneous Leishmaniasis Co-Existing in a Mixed Focus of Central Tunisia
by Mohammed Abdo Saghir Abbas, Jihene Lachheb, Ifhem Chelbi, Dorra Louati, Khalil Dachraoui, Slimene Ben Miled and Elyes Zhioua
Pathogens 2022, 11(8), 855; https://doi.org/10.3390/pathogens11080855 - 29 Jul 2022
Cited by 5 | Viewed by 2198
Abstract
Zoonotic cutaneous leishmaniasis (ZCL) and chronic cutaneous leishmaniasis (CCL) are known to overlap in Central Tunisia. Sandflies were collected using sticky traps and CDC light-traps set in rodent burrows at the ecotones surrounding the village, in houses, and in animal shelters during July–October [...] Read more.
Zoonotic cutaneous leishmaniasis (ZCL) and chronic cutaneous leishmaniasis (CCL) are known to overlap in Central Tunisia. Sandflies were collected using sticky traps and CDC light-traps set in rodent burrows at the ecotones surrounding the village, in houses, and in animal shelters during July–October 2017, 2018, and 2019. A total of 17,175 sandflies were collected during the three sandfly seasons and identified morphologically to species level. Of a total of 18 sandfly species reported in Tunisia, 16 were identified in this mixed focus of ZCL and CCL. Except for the rocky mountainous areas, Phlebotomus papatasi was the most abundant sandfly species in all biotopes. In the mountainous areas, Phlebotomus sergenti is the most abundant sandfly species belonging to the genus Phlebotomus. Female sandflies were tested for the presence of Leishmania species by PCR. The overall infection prevalence of sandflies with Leishmania major and Leishmania tropica was 0.42% and 0.065%, respectively. The sequencing of PCR-amplified ITS1 products showed that L. major is the predominant species in all biotopes and transmitted mostly by P. papaptasi followed by Phlebotomus longicuspis and Sergentomyia species. Leishmania tropica was detected in Phlebotomus sergenti and in Phlebotomus longicuspis collected in bedrooms and in the ecotone of rocky mountainous areas. Our results provided strong evidence that the proximity of human settlements to biotopes of rodent reservoir hosts of L. major and of L. tropica resulted into the cocirculation of both Leishmania species leading to a mixed focus of ZCL and CCL. The epidemiology of leishmaniases in North Africa is highly complex by the high diversity of sandfly vectors and their associated Leishmania species, leading to a mixed form of cutaneous leishmaniasis. It is of major epidemiological importance to point to the risk of spillover from rural to urban areas leading to the anthroponization of cutaneous leishmaniasis. Therefore, efficient control to reduce the indoor abundance of sandfly vectors in order to reduce the incidence of leishmaniases is urgently needed. Full article
(This article belongs to the Special Issue Leishmania & Leishmaniasis)
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15 pages, 2365 KiB  
Article
Eosinophils, but Not Type 2 Innate Lymphoid Cells, Are the Predominant Source of Interleukin 4 during the Innate Phase of Leishmania major Infection
by Carolin Sasse, David Barinberg, Stephanie Obermeyer, Andrea Debus, Ulrike Schleicher and Christian Bogdan
Pathogens 2022, 11(8), 828; https://doi.org/10.3390/pathogens11080828 - 25 Jul 2022
Cited by 5 | Viewed by 2133
Abstract
Interleukin (IL)-4 plays a central role in the initiation of a type 2 T helper cell (Th2) response, which leads to non-healing and progressive infections with the protozoan parasite Leishmania (L.) major. Here, we tested the hypothesis that type 2 [...] Read more.
Interleukin (IL)-4 plays a central role in the initiation of a type 2 T helper cell (Th2) response, which leads to non-healing and progressive infections with the protozoan parasite Leishmania (L.) major. Here, we tested the hypothesis that type 2 innate lymphoid cells (ILC2), which promote the development of Th2 cells, form an important source of IL-4 early after intradermal or subcutaneous L. major infection. Lineage-marker negative CD90.2+CD127+PD1− ILC2 were readily detectable in the ear or foot skin, but hardly in the draining lymph nodes of both naïve and L. major-infected self-healing C57BL/6 and non-healing BALB/c mice and made up approximately 20% to 30% of all CD45+SiglecF− cells. Dermal ILC2 of C57BL/6 mice expressed the inducible T cell-costimulator (ICOS, CD278), whereas BALB/C ILC2 were positive for the stem cell antigen (Sca)-1. Within the first 5 days of infection, the absolute numbers of ILC2 did not significantly change in the dermis, which is in line with the unaltered expression of cytokines activating (IL-18, IL-25, IL-33, TSLP) or inhibiting ILC2 (IL-27, IFN-γ). At day 5 to 6 post infection, we observed an upregulation of IL-4, but not of IL-5, IL-10 or IL-13 mRNA. Using IL-4-reporter (4get) mice, we found that the production of IL-4 by C57BL/6 or BALB/c mice was largely restricted to CD45+SiglecF+ cells of high granularity, i.e., eosinophils. From these data, we conclude that eosinophils, but not ILC2, are a major innate source of IL-4 at the skin site of L. major infection. Full article
(This article belongs to the Special Issue Leishmania & Leishmaniasis)
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16 pages, 1168 KiB  
Article
Pentoxifylline in the Treatment of Cutaneous Leishmaniasis: A Randomized Clinical Trial in Colombia
by Maria del Mar Castro, Alexandra Cossio, Adriana Navas, Olga Fernandez, Liliana Valderrama, Lyda Cuervo-Pardo, Ricardo Marquez-Oñate, María Adelaida Gómez and Nancy Gore Saravia
Pathogens 2022, 11(3), 378; https://doi.org/10.3390/pathogens11030378 - 21 Mar 2022
Cited by 1 | Viewed by 2115
Abstract
Addition of the immunomodulator pentoxifylline (PTX) to antimonial treatment of mucosal leishmaniasis has shown increased efficacy. This randomized, double-blind, placebo-controlled trial evaluated whether addition of pentoxifylline to meglumine antimoniate (MA) treatment improves therapeutic response in cutaneous leishmaniasis (CL) patients. Seventy-three patients aged 18–65 [...] Read more.
Addition of the immunomodulator pentoxifylline (PTX) to antimonial treatment of mucosal leishmaniasis has shown increased efficacy. This randomized, double-blind, placebo-controlled trial evaluated whether addition of pentoxifylline to meglumine antimoniate (MA) treatment improves therapeutic response in cutaneous leishmaniasis (CL) patients. Seventy-three patients aged 18–65 years, having multiple lesions or a single lesion ≥ 3 cm were randomized to receive: intramuscular MA (20 mg/kg/day × 20 days) plus oral PTX 400 mg thrice daily (intervention arm, n = 36) or MA plus placebo (control arm, n = 37), between 2012 and 2015. Inflammatory gene expression was evaluated by RT-qPCR in peripheral blood mononuclear cells from trial patients, before and after treatment. Intention-to-treat failure rate was 35% for intervention vs. 25% for control (OR: 0.61, 95% CI: 0.21–1.71). Per-protocol failure rate was 32% for PTX, and 24% for placebo (OR: 0.50, 95% CI: 0.13–1.97). No differences in frequency or severity of adverse events were found (PTX = 142 vs. placebo = 140). Expression of inflammatory mediators was unaltered by addition of PTX to MA. However, therapeutic failure was associated with significant overexpression of il1β and ptgs2 (p < 0.05), irrespective of study group. No clinical benefit of addition of PTX to standard treatment was detected in early mild to moderate CL caused by Leishmania (V.) panamensis. Full article
(This article belongs to the Special Issue Leishmania & Leishmaniasis)
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Review

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25 pages, 1861 KiB  
Review
From Infection to Death: An Overview of the Pathogenesis of Visceral Leishmaniasis
by Carlos H. N. Costa, Kwang-Poo Chang, Dorcas L. Costa and Francisco Valmor M. Cunha
Pathogens 2023, 12(7), 969; https://doi.org/10.3390/pathogens12070969 - 24 Jul 2023
Cited by 1 | Viewed by 4135
Abstract
Kala-azar, also known as visceral leishmaniasis (VL), is a disease caused by Leishmania infantum and L. donovani. Patients experience symptoms such as fever, weight loss, paleness, and enlarged liver and spleen. The disease also affects immunosuppressed individuals and has an overall mortality [...] Read more.
Kala-azar, also known as visceral leishmaniasis (VL), is a disease caused by Leishmania infantum and L. donovani. Patients experience symptoms such as fever, weight loss, paleness, and enlarged liver and spleen. The disease also affects immunosuppressed individuals and has an overall mortality rate of up to 10%. This overview explores the literature on the pathogenesis of preclinical and clinical stages, including studies in vitro and in animal models, as well as complications and death. Asymptomatic infection can result in long-lasting immunity. VL develops in a minority of infected individuals when parasites overcome host defenses and multiply in tissues such as the spleen, liver, and bone marrow. Hepatosplenomegaly occurs due to hyperplasia, resulting from parasite proliferation. A systemic inflammation mediated by cytokines develops, triggering acute phase reactants from the liver. These cytokines can reach the brain, causing fever, cachexia and vomiting. Similar to sepsis, disseminated intravascular coagulation (DIC) occurs due to tissue factor overexpression. Anemia, hypergammaglobulinemia, and edema result from the acute phase response. A regulatory response and lymphocyte depletion increase the risk of bacterial superinfections, which, combined with DIC, are thought to cause death. Our understanding of VL’s pathogenesis is limited, and further research is needed to elucidate the preclinical events and clinical manifestations in humans. Full article
(This article belongs to the Special Issue Leishmania & Leishmaniasis)
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12 pages, 1500 KiB  
Review
Leishmaniasis Vaccines: Applications of RNA Technology and Targeted Clinical Trial Designs
by Malcolm S. Duthie, Bruna A. S. Machado, Roberto Badaró, Paul M. Kaye and Steven G. Reed
Pathogens 2022, 11(11), 1259; https://doi.org/10.3390/pathogens11111259 - 29 Oct 2022
Cited by 4 | Viewed by 2988
Abstract
Leishmania parasites cause a variety of discrete clinical diseases that present in regions where their specific sand fly vectors sustain transmission. Clinical and laboratory research indicate the potential of immunization to prevent leishmaniasis and a wide array of vaccine candidates have been proposed. [...] Read more.
Leishmania parasites cause a variety of discrete clinical diseases that present in regions where their specific sand fly vectors sustain transmission. Clinical and laboratory research indicate the potential of immunization to prevent leishmaniasis and a wide array of vaccine candidates have been proposed. Unfortunately, multiple factors have precluded advancement of more than a few Leishmania targeting vaccines to clinical trial. The recent maturation of RNA vaccines into licensed products in the context of COVID-19 indicates the likelihood of broader use of the technology. Herein, we discuss the potential benefits provided by RNA technology as an approach to address the bottlenecks encountered for Leishmania vaccines. Further, we outline a variety of strategies that could be used to more efficiently evaluate Leishmania vaccine efficacy, including controlled human infection models and initial use in a therapeutic setting, that could prioritize candidates before evaluation in larger, longer and more complicated field trials. Full article
(This article belongs to the Special Issue Leishmania & Leishmaniasis)
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13 pages, 996 KiB  
Review
Promastigote-to-Amastigote Conversion in Leishmania spp.—A Molecular View
by Joachim Clos, Janne Grünebast and Myrine Holm
Pathogens 2022, 11(9), 1052; https://doi.org/10.3390/pathogens11091052 - 15 Sep 2022
Cited by 7 | Viewed by 5041
Abstract
A key factor in the successful infection of a mammalian host by Leishmania parasites is their conversion from extracellular motile promastigotes into intracellular amastigotes. We discuss the physical and chemical triggers that induce this conversion and the accompanying changes at the molecular level [...] Read more.
A key factor in the successful infection of a mammalian host by Leishmania parasites is their conversion from extracellular motile promastigotes into intracellular amastigotes. We discuss the physical and chemical triggers that induce this conversion and the accompanying changes at the molecular level crucial for the survival of these intracellular parasites. Special emphasis is given to the reliance of these trypanosomatids on the post-transcriptional regulation of gene expression but also to the role played by protein kinases, chaperone proteins and proteolytic enzymes. Lastly, we offer a model to integrate the transduction of different stress signals for the induction of stage conversion. Full article
(This article belongs to the Special Issue Leishmania & Leishmaniasis)
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20 pages, 4362 KiB  
Review
Development of Novel Anti-Leishmanials: The Case for Structure-Based Approaches
by Mohini Soni and J. Venkatesh Pratap
Pathogens 2022, 11(8), 950; https://doi.org/10.3390/pathogens11080950 - 22 Aug 2022
Cited by 10 | Viewed by 2373
Abstract
The neglected tropical disease (NTD) leishmaniasis is the collective name given to a diverse group of illnesses caused by ~20 species belonging to the genus Leishmania, a majority of which are vector borne and associated with complex life cycles that cause immense [...] Read more.
The neglected tropical disease (NTD) leishmaniasis is the collective name given to a diverse group of illnesses caused by ~20 species belonging to the genus Leishmania, a majority of which are vector borne and associated with complex life cycles that cause immense health, social, and economic burdens locally, but individually are not a major global health priority. Therapeutic approaches against leishmaniasis have various inadequacies including drug resistance and a lack of effective control and eradication of the disease spread. Therefore, the development of a rationale-driven, target based approaches towards novel therapeutics against leishmaniasis is an emergent need. The utilization of Artificial Intelligence/Machine Learning methods, which have made significant advances in drug discovery applications, would benefit the discovery process. In this review, following a summary of the disease epidemiology and available therapies, we consider three important leishmanial metabolic pathways that can be attractive targets for a structure-based drug discovery approach towards the development of novel anti-leishmanials. The folate biosynthesis pathway is critical, as Leishmania is auxotrophic for folates that are essential in many metabolic pathways. Leishmania can not synthesize purines de novo, and salvage them from the host, making the purine salvage pathway an attractive target for novel therapeutics. Leishmania also possesses an organelle glycosome, evolutionarily related to peroxisomes of higher eukaryotes, which is essential for the survival of the parasite. Research towards therapeutics is underway against enzymes from the first two pathways, while the third is as yet unexplored. Full article
(This article belongs to the Special Issue Leishmania & Leishmaniasis)
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7 pages, 844 KiB  
Review
Third Case of Visceral Leishmaniasis in COVID-19: Mini Review Article
by Claudia Colomba, Cristoforo Guccione, Raffaella Rubino, Michela Scalisi, Anna Condemi, Sara Bagarello, Salvatore Giordano and Antonio Cascio
Pathogens 2022, 11(8), 913; https://doi.org/10.3390/pathogens11080913 - 14 Aug 2022
Cited by 5 | Viewed by 1582
Abstract
Background: In the currently ongoing coronavirus pandemic, coinfections with unrelated life-threatening febrile conditions may pose a particular challenge to clinicians. Leishmaniasis is a zoonosis that may present general symptoms, including fever, malaise, and arthralgia, rendering it indistinguishable from COVID-19. Methods: In this paper, [...] Read more.
Background: In the currently ongoing coronavirus pandemic, coinfections with unrelated life-threatening febrile conditions may pose a particular challenge to clinicians. Leishmaniasis is a zoonosis that may present general symptoms, including fever, malaise, and arthralgia, rendering it indistinguishable from COVID-19. Methods: In this paper, we aim to draw attention to this issue and analyze the clinical characteristics of the coinfection SARS-CoV-2/Leishmania through a systematic review of the literature. We were motivated by the observation of the first case of visceral leishmaniasis and COVID-19 in a paediatric patient. Conclusion: Our case is a reminder for healthcare providers to consider the diagnosis of visceral leishmaniasis in patients presenting with febrile syndrome in endemic regions during the COVID-19 pandemic. Full article
(This article belongs to the Special Issue Leishmania & Leishmaniasis)
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13 pages, 715 KiB  
Review
Visceral Leishmaniasis and the Skin: Dermal Parasite Transmission to Sand Flies
by Sahaana Arumugam, Breanna M. Scorza and Christine Petersen
Pathogens 2022, 11(6), 610; https://doi.org/10.3390/pathogens11060610 - 24 May 2022
Cited by 6 | Viewed by 4399
Abstract
Visceral leishmaniasis is a parasitic disease with significant dermal tropism. The skin is an important site of infection contributing to parasite transmission to naïve sand flies, but understanding how parasitism of host skin and the related immune microenvironment supports or prevents skin parasite [...] Read more.
Visceral leishmaniasis is a parasitic disease with significant dermal tropism. The skin is an important site of infection contributing to parasite transmission to naïve sand flies, but understanding how parasitism of host skin and the related immune microenvironment supports or prevents skin parasite replication is now the focus of major investigation in the field of leishmaniasis research. Here, we review dermatoimmunology during visceral leishmaniasis (VL), dermal Leishmania parasite burden, and the role of skin parasitism in transmissibility to sand fly vectors. First, we discuss the epidemiology of VL amongst dogs, the primary zoonotic reservoir for human infection. We explore the association between spatial distribution and the burden of parasites in the skin in driving outward transmission. Factors associated with parasite persistence in the skin are examined. We discuss systemic immunity during VL and what is known about immunological correlates in the skin microenvironment. Finally, we touch on factors egested into the skin during Leishmania inoculation by sand flies. Throughout, we discuss factors associated with the early and chronic establishment of Leishmania parasites in the skin and the role of the dermal immune response. Full article
(This article belongs to the Special Issue Leishmania & Leishmaniasis)
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18 pages, 2421 KiB  
Review
Hemoglobin Endocytosis and Intracellular Trafficking: A Novel Way of Heme Acquisition by Leishmania
by Irshad Ansari, Rituparna Basak and Amitabha Mukhopadhyay
Pathogens 2022, 11(5), 585; https://doi.org/10.3390/pathogens11050585 - 16 May 2022
Cited by 5 | Viewed by 2487
Abstract
Leishmania species are causative agents of human leishmaniasis, affecting 12 million people annually. Drugs available for leishmaniasis are toxic, and no vaccine is available. Thus, the major thrust is to identify new therapeutic targets. Leishmania is an auxotroph for heme and must acquire [...] Read more.
Leishmania species are causative agents of human leishmaniasis, affecting 12 million people annually. Drugs available for leishmaniasis are toxic, and no vaccine is available. Thus, the major thrust is to identify new therapeutic targets. Leishmania is an auxotroph for heme and must acquire heme from the host for its survival. Thus, the major focus has been to understand the heme acquisition process by the parasites in the last few decades. It is conceivable that the parasite is possibly obtaining heme from host hemoprotein, as free heme is not available in the host. Current understanding indicates that Leishmania internalizes hemoglobin (Hb) through a specific receptor by a clathrin-mediated endocytic process and targets it to the parasite lysosomes via the Rab5 and Rab7 regulated endocytic pathway, where it is degraded to generate intracellular heme that is used by the parasite. Subsequently, intra-lysosomal heme is initially transported to the cytosol and is finally delivered to the mitochondria via different heme transporters. Studies using different null mutant parasites showed that these receptors and transporters are essential for the survival of the parasite. Thus, the heme acquisition process in Leishmania may be exploited for the development of novel therapeutics. Full article
(This article belongs to the Special Issue Leishmania & Leishmaniasis)
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12 pages, 2681 KiB  
Review
Experimental Hybridization in Leishmania: Tools for the Study of Genetic Exchange
by Tiago R. Ferreira and David L. Sacks
Pathogens 2022, 11(5), 580; https://doi.org/10.3390/pathogens11050580 - 14 May 2022
Cited by 5 | Viewed by 2179
Abstract
Despite major advances over the last decade in our understanding of Leishmania reproductive strategies, the sexual cycle in Leishmania has defied direct observation and remains poorly investigated due to experimental constraints. Here, we summarize the findings and conclusions drawn from genetic analysis of [...] Read more.
Despite major advances over the last decade in our understanding of Leishmania reproductive strategies, the sexual cycle in Leishmania has defied direct observation and remains poorly investigated due to experimental constraints. Here, we summarize the findings and conclusions drawn from genetic analysis of experimental hybrids generated in sand flies and highlight the recent advances in generating hybrids in vitro. The ability to hybridize between culture forms of different species and strains of Leishmania should invite more intensive investigation of the mechanisms underlying genetic exchange and provide a rich source of recombinant parasites for future genetic analyses. Full article
(This article belongs to the Special Issue Leishmania & Leishmaniasis)
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11 pages, 976 KiB  
Review
Protection and Pathology in Leishmania braziliensis Infection
by Augusto M. Carvalho, Olívia Bacellar and Edgar M. Carvalho
Pathogens 2022, 11(4), 466; https://doi.org/10.3390/pathogens11040466 - 14 Apr 2022
Cited by 5 | Viewed by 2829
Abstract
Leishmania killing is mediated by IFN-γ-activated macrophages, but IFN-γ production and macrophage activation are insufficient to control L. braziliensis infection. In American tegumentary leishmaniasis (ATL), pathology results from an exaggerated inflammatory response. This report presents an overview of our contributions regarding ATL pathogenesis, [...] Read more.
Leishmania killing is mediated by IFN-γ-activated macrophages, but IFN-γ production and macrophage activation are insufficient to control L. braziliensis infection. In American tegumentary leishmaniasis (ATL), pathology results from an exaggerated inflammatory response. This report presents an overview of our contributions regarding ATL pathogenesis, highlighting future directions to improve the management of L. braziliensis infection. Monocytes and lymphocytes from individuals exposed to L. braziliensis but who do not develop CL, i.e., subclinical infection (SC), exhibit lower respiratory burst and IFN-γ production, yet more efficiently kill L. braziliensis. As vaccines aimed at inducing IL-12 and IFN-γ do not sufficiently prevent CL, the elucidation of how subjects with SC infection kill Leishmania may lead to new approaches to controlling ATL. While inflammation arising from the recruitment of inflammatory cells via chemokines induced by IFN-γ and TNF or IL-17 is observed and contributes to pathology, cytotoxic CD8+ T cells and NK cells play a key role in the pathogenesis of L. braziliensis infection. The increased transcription of genes related to inflammation and cytotoxicity, e.g., granzyme A, granzyme B, NLRP3 and IL-1β, has been documented in CL tissue samples. The release of products by killed cells leads to NLRP3 inflammasome activation, IL-1β production and additional damage to skin and mucosal tissues. The use of drugs that downmodulate the inflammatory response in combination with chemotherapy improves the ATL cure rate and decreases healing time. Full article
(This article belongs to the Special Issue Leishmania & Leishmaniasis)
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10 pages, 1719 KiB  
Review
New Vistas in the Biology of the Flagellum—Leishmania Parasites
by Scott M. Landfear
Pathogens 2022, 11(4), 447; https://doi.org/10.3390/pathogens11040447 - 07 Apr 2022
Cited by 2 | Viewed by 4543
Abstract
Like other kinetoplastid protozoa, the flagellum in Leishmania parasites plays central roles throughout the life cycle. Discoveries over the past decade have begun to elucidate flagellar functions at the molecular level in both the insect vector stage promastigotes and intra-macrophage amastigotes. This focused [...] Read more.
Like other kinetoplastid protozoa, the flagellum in Leishmania parasites plays central roles throughout the life cycle. Discoveries over the past decade have begun to elucidate flagellar functions at the molecular level in both the insect vector stage promastigotes and intra-macrophage amastigotes. This focused review will highlight recent advances that contribute to understanding flagellar function in the various biological contexts encountered by Leishmania parasites. Full article
(This article belongs to the Special Issue Leishmania & Leishmaniasis)
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16 pages, 1022 KiB  
Review
The History of Live Attenuated Centrin Gene-Deleted Leishmania Vaccine Candidates
by Greta Volpedo, Parna Bhattacharya, Sreenivas Gannavaram, Thalia Pacheco-Fernandez, Timur Oljuskin, Ranadhir Dey, Abhay R. Satoskar and Hira L. Nakhasi
Pathogens 2022, 11(4), 431; https://doi.org/10.3390/pathogens11040431 - 02 Apr 2022
Cited by 12 | Viewed by 14436
Abstract
Leishmaniasis, caused by an infection of the Leishmania protozoa, is a neglected tropical disease and a major health problem in tropical and subtropical regions of the world, with approximately 350 million people worldwide at risk and 2 million new cases occurring annually. Current [...] Read more.
Leishmaniasis, caused by an infection of the Leishmania protozoa, is a neglected tropical disease and a major health problem in tropical and subtropical regions of the world, with approximately 350 million people worldwide at risk and 2 million new cases occurring annually. Current treatments for leishmaniasis are not highly efficacious and are associated with high costs, especially in low- and middle-income endemic countries, and high toxicity. Due to a surge in the incidence of leishmaniases worldwide, the development of new strategies such as a prophylactic vaccine has become a high priority. However, the ability of Leishmania to undermine immune recognition has limited our efforts to design safe and efficacious vaccines against leishmaniasis. Numerous antileishmanial vaccine preparations based on DNA, subunit, and heat-killed parasites with or without adjuvants have been tried in several animal models but very few have progressed beyond the experimental stage. However, it is known that people who recover from Leishmania infection can be protected lifelong against future infection, suggesting that a successful vaccine requires a controlled infection to develop immunologic memory and subsequent long-term immunity. Live attenuated Leishmania parasites that are non-pathogenic and provide a complete range of antigens similarly to their wild-type counterparts could evoke such memory and, thus, would be effective vaccine candidates. Our laboratory has developed several live attenuated Leishmania vaccines by targeted centrin gene disruptions either by homologous recombination or, more recently, by using genome editing technologies involving CRISPR-Cas9. In this review, we focused on the sequential history of centrin gene-deleted Leishmania vaccine development, along with the characterization of its safety and efficacy. Further, we discussed other major considerations regarding the transition of dermotropic live attenuated centrin gene-deleted parasites from the laboratory to human clinical trials. Full article
(This article belongs to the Special Issue Leishmania & Leishmaniasis)
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17 pages, 1156 KiB  
Review
The Dangerous Liaisons in the Oxidative Stress Response to Leishmania Infection
by Marta Reverte, Tiia Snäkä and Nicolas Fasel
Pathogens 2022, 11(4), 409; https://doi.org/10.3390/pathogens11040409 - 28 Mar 2022
Cited by 12 | Viewed by 2410
Abstract
Leishmania parasites preferentially invade macrophages, the professional phagocytic cells, at the site of infection. Macrophages play conflicting roles in Leishmania infection either by the destruction of internalized parasites or by providing a safe shelter for parasite replication. In response to invading pathogens, however, [...] Read more.
Leishmania parasites preferentially invade macrophages, the professional phagocytic cells, at the site of infection. Macrophages play conflicting roles in Leishmania infection either by the destruction of internalized parasites or by providing a safe shelter for parasite replication. In response to invading pathogens, however, macrophages induce an oxidative burst as a mechanism of defense to promote pathogen removal and contribute to signaling pathways involving inflammation and the immune response. Thus, oxidative stress plays a dual role in infection whereby free radicals protect against invading pathogens but can also cause inflammation resulting in tissue damage. The induced oxidative stress in parasitic infections triggers the activation in the host of the antioxidant response to counteract the damaging oxidative burst. Consequently, macrophages are crucial for disease progression or control. The ultimate outcome depends on dangerous liaisons between the infecting Leishmania spp. and the type and strength of the host immune response. Full article
(This article belongs to the Special Issue Leishmania & Leishmaniasis)
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