Abstract
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.
Highlights
More than a century after the discovery of leishmaniasis and its vector-borne causative agent, Leishmania spp., a lot of ground remains to be covered
To study the determinants of visceral leishmaniasis resistance vs. susceptibility, we compared the evolution of experimental L. infantum infection in three inbred mouse strains
SV/129 is the strain described as resistant while C57BL/6 and BALB/c are defined as susceptible models in the context of L. donovani infection (Lipoldova and Demant, 2006)
Summary
More than a century after the discovery of leishmaniasis and its vector-borne causative agent, Leishmania spp., a lot of ground remains to be covered. The number of species described associated with human disease has been increasing [around 20 species with clinical relevance (Akhoundi et al, 2016)] and, with them, the complexity of the host-parasite interactions equation It is well-accepted that the infection outcome depends on a number of factors including the infecting parasite species, and the “equilibrium” between the host immune response and the parasite immune-evasion strategies (Cecílio et al, 2014). These aspects justify the different known leishmaniasis clinical manifestations (that vary from a localized cutaneous ulcer to skin and mucosa metastatic lesions, or to the colonization of internal organs such as the spleen, liver, and bone marrow), associated with different pathological mechanisms (Bates, 2007; Hartley et al, 2014). In visceral disease, the immunological aspects that condition parasite persistence and their connection with host genetic factors needs to be further explored, in a way to definitively understand resistance vs. susceptibility
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