Vaccines for Human Leishmaniasis: Where Do We Stand and What Is Still Missing?

Cecílio, Pedro; Oliveira, Fátima de Cássia Evangelista de; Cordeiro-da-Silva, Anabela

doi:10.5772/intechopen.75000

Cited by 19 publications

(10 citation statements)

References 169 publications

(230 reference statements)

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“…One of the layers of complexity associated with leishmaniasis relates to the distinct known disease manifestations, a consequence of heterogeneous pathogen-host interactions that will condition the infectious process outcome (Loeuillet et al, 2016; Cecilio et al, 2018). While for some disease forms, such as cutaneous leishmaniasis, we are close to understanding the determinants of resistance vs. susceptibility, for visceral leishmaniasis we are still unable to clearly establish this dichotomy.…”

Section: Discussionmentioning

confidence: 99%

Understanding Resistance vs. Susceptibility in Visceral Leishmaniasis Using Mouse Models of Leishmania infantum Infection

Pérez-Cabezas

Cecílio

Gaspar

et al. 2019

Front. Cell. Infect. Microbiol.

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Every year, up to 90,000 new cases of Visceral Leishmaniasis and 30,000 resultant deaths are estimated to occur worldwide. Such numbers give relevance to the continuous study of this complex form of the disease: a zoonosis and an anthroponosis; two known etiological agents ( Leishmania infantum and L. donovani , respectively); with an estimated average ratio of 1 symptomatic per 10 asymptomatic individuals; and sometimes associated with atypical clinical presentations. This complexity, which results from a long co-evolutionary process involving vector-host, host-pathogen, and pathogen-vector interactions, is still not completely understood. The determinants of visceralization are not fully defined and the dichotomy resistance vs. susceptibility remains unsolved, translating into obstacles that delay the progress of global disease control. Inbred mouse models, with different susceptibility patterns to Leishmania infection, have been very useful in exploring this dichotomy. BALB/c and C57BL/6 mice were described as susceptible strains to L. donovani visceral infection, while SV/129 was considered resistant. Here, we used these three mouse models, but in the context of L. infantum infection, the other Leishmania species that cause visceral disease in humans, and dynamically compared their local and systemic infection-induced immune responses in order to establish a parallel and to ultimately better understand susceptibility vs. resistance in visceral leishmaniasis. Overall, our results suggest that C57BL/6 mice develop an intermediate “infection-phenotype” in comparison to BALB/c and SV/129 mouse strains, considering both the splenic parasite burden and the determined target organs weights. However, the immune mechanisms associated with the control of infection seem to be different in each mouse strain. We observed that both BALB/c and SV/129, but not C57BL/6 mice, show an infection-induced increase of splenic T follicular helper cells. On the other hand, differences detected in terms of CD21 expression by B cells early after infection, together with the quantified anti- Leishmania specific antibodies, suggest that SV/129 are faster than BALB/c and C57BL/6 mice in the assembly of an efficient B-cell response. Additionally, we observed an infection-induced increase in polyfunctional CD4+ T cells in the resistant SV/129 model, opposing an infection-induced increase in CD4+IL-10+ cells in susceptible BALB/c mice. Our data aligns with the observations reported for L. donovani infection and suggest that not only a single mechanism, but an interaction of several could be necessary for the control of this parasitic disease.

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Section: Discussionmentioning

confidence: 99%

Understanding Resistance vs. Susceptibility in Visceral Leishmaniasis Using Mouse Models of Leishmania infantum Infection

Pérez-Cabezas

Cecílio

Gaspar

et al. 2019

Front. Cell. Infect. Microbiol.

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“…Annually an estimated 1.3 million new cases and 20 000 to 30 000 deaths are associated with these diseases [2]. The absence of human vaccines to prevent leishmaniasis [3] and the risks associated with conventional therapies urge for a better understanding of the infectious process.…”

Section: Introductionmentioning

confidence: 99%

More than just exosomes: distinct Leishmania infantum extracellular products potentiate the establishment of infection

Pérez-Cabezas

Cecílio

Silva

et al. 2018

J of Extracellular Vesicle

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The use of secretion pathways for effector molecule delivery by microorganisms is a trademark of pathogenesis. Leishmania extracellular vesicles (EVs) were shown to have significant immunomodulatory potential. Still, they will act in conjunction with other released parasite-derived products that might modify the EVs effects. Notwithstanding, the immunomodulatory properties of these non-vesicular components and their influence in the infectious process remains unknown. To address this, we explored both in vitro and in vivo the immunomodulatory potential of promastigotes extracellular material (EXO), obtained as a whole or separated in two different fractions: EVs or vesicle depleted EXO (VDE). Using an air pouch model, we observed that EVs and VDE induced a dose-dependent cell recruitment profile different from the one obtained with parasites, attracting significantly fewer neutrophils and more dendritic cells (DCs). Additionally, when we co-inoculated parasites with extracellular products a drop in cell recruitment was observed. Moreover, in vitro, while VDE (but not EVs) downregulated the expression of DCs and macrophages activation markers, both products were able to diminish the responsiveness of these cells to LPS. Finally, the presence of Leishmania infantum extracellular products in the inoculum promoted a dose-dependent infection potentiation in vivo, highlighting their relevance for the infectious process. In conclusion, our data demonstrate that EVs are not the only relevant players among the parasite exogenous products. This, together with the dose-dependency observed, opens new avenues to the comprehension of Leishmania infectious process. The approach presented here should be exploited to revisit existing data and considered for future studies in other infection models.

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“…However, Th1 type CD4 + T cell response characterized by the production of IFN-γ and TNF-α, and the production of reactive oxygen species have been shown to be critical in disease resolution in animals and in humans [25,31]. Current leishmania vaccines used in animals and those in human clinical trials contain either fractioned proteins of leishmania (CaniLeish, Leishmune, Leish-Tec) or recombinant proteins (LEISH-F1) formulated with adjuvants such as monophosphoryl lipid A (MPL) and QA-21 designed to enhance Th1 type response [32]. CD8 + T cells are elicited in response to viral and parasitic infections.…”

Section: Lessons From Dengue Vaccine Development and Their Applicability To The Design Of Parasite Vaccinesmentioning

confidence: 99%

What translatable knowledge from dengue vaccine design can we pass onto future anti-parasitic vaccine development?

Srikiatkhachorn

2020

Expert Opinion on Drug Discovery

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Vaccines for Human Leishmaniasis: Where Do We Stand and What Is Still Missing?

Cited by 19 publications

References 169 publications

Understanding Resistance vs. Susceptibility in Visceral Leishmaniasis Using Mouse Models of Leishmania infantum Infection

Understanding Resistance vs. Susceptibility in Visceral Leishmaniasis Using Mouse Models of Leishmania infantum Infection

More than just exosomes: distinct Leishmania infantum extracellular products potentiate the establishment of infection

What translatable knowledge from dengue vaccine design can we pass onto future anti-parasitic vaccine development?

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