Abstract
Visceral leishmaniasis (VL) is a chronic and fatal disease in humans and dogs caused by the intracellular protozoan parasites, Leishmania donovani and L. infantum (L. chagasi). Relapse of disease is frequent in immunocompromised patients, in which the number of VL cases has been increasing recently. The present study is aimed to improve the understanding of mechanisms of L. donovani persistence in immunocompromised conditions using alymphoplastic aly/aly mice. Hepatic parasite burden, granuloma formation and induction of regulatory T cells were determined for up to 7 months after the intravenous inoculation with L. donovani promastigotes. While control aly/+ mice showed a peak of hepatic parasite growth at 4 weeks post infection (WPI) and resolved the infection by 8 WPI, aly/aly mice showed a similar peak in hepatic parasite burden but maintained persistent in the chronic phase of infection, which was associated with delayed and impaired granuloma maturation. Although hepatic CD4+Foxp3+ but not CD8+Foxp3+ T cells were first detected at 4 WPI in both strains of mice, the number of CD4+Foxp3+ T cells was significantly increased in aly/aly mice from 8 WPI. Immunohistochemical analysis demonstrated the presence of Foxp3+ T cells in L. donovani–induced hepatic granulomas and perivascular neo-lymphoid aggregates. Quantitative real-time PCR analysis of mature granulomas collected by laser microdissection revealed the correlation of Foxp3 and IL-10 mRNA level. Furthermore, treatment of infected aly/aly mice with anti-CD25 or anti-FR4 mAb resulted in significant reductions in both hepatic Foxp3+ cells and parasite burden. Thus, we provide the first evidence that CD4+Foxp3+ Tregs mediate L. donovani persistence in the liver during VL in immunodeficient murine model, a result that will help to establish new strategies of immunotherapy against this intracellular protozoan pathogen.
Highlights
Visceral leishmaniasis (VL) is a chronic and fatal disease caused by the intracellular protozoan parasites Leishmania donovani and L. infantum, which infect a range of mammalian hosts, including humans, dogs and rodents [1]
The protozoan parasite Leishmania donovani is the causative agent of visceral leishmaniasis (VL) with a variety of outcomes ranging from asymptomatic to fatal infection
To clarify why parasite persistence and disease are caused in an immunocompromised condition, we examined L. donovani infection in alymphoplastic aly/aly mice that completely lack lymph nodes and have disturbed spleen architecture
Summary
Visceral leishmaniasis (VL) is a chronic and fatal disease caused by the intracellular protozoan parasites Leishmania donovani and L. infantum (chagasi), which infect a range of mammalian hosts, including humans, dogs and rodents [1]. Recent experiments in protein energy-, zinc- and iron-deficient mice suggest that this effect is mediated primarily through functional failure of the lymph node barrier and increased early visceralization of the parasites [4,5,6]. Loss of the control of parasite persistence in VL causes the reactivation of parasites and relapse of the disease is frequent in the immunocompromised patients, in which the number of visceral leishmaniasis cases has been increasing recently [7]. To develop effective prophylactic or therapeutic strategies against VL, understanding of the precise immune mechanisms including T-cell functions in the chronic stage of infection is required [8]
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