Dynamics of immune granuloma formation in a Leishmania braziliensis‐induced self‐limiting cutaneous infection in the primate Macaca mulatta

Abstract

In order to unravel the physiopathology of leishmaniasis in humans, it is necessary to better understand how Leishmania are able to survive for years within immunologically active granulomas. In the present study, we used a macaque (Macaca mulatta) model of infection with Leishmania braziliensis as a means of assessing the usefulness of this primate system. This model more closely mirrors human protective immunity to Leishmania than the murine model; therefore, we used it to study the host inflammatory granulomatous response involved in the control of cutaneous leishmaniasis. Infected primates developed localized long-term skin ulcerations, but complete spontaneous clinical healing occurred in all infected animals. The infection induced the recruitment and activation of inflammatory mast cells, granulocytes, mononuclear phagocytes, and lymphocytes at the site of infection. During the acute reaction, polymorphonuclear leukocytes were more prominent than other cell types and apparently destroyed many parasites; macrophages then rapidly engulfed dying neutrophils together with their parasitic cargo. In the chronic phase, persisting parasites induced a typical T helper (Th) cytokine, type 1-mediated, immunity-induced granulomatous reaction. By this time, more or less differentiated macrophage accumulations were found, and these evolved to become mature tissue granulomas consisting of all the specific cell types found within human granulomas. In the healing stage, fibroblasts proliferated at the periphery and finally invaded the granulomas with fibrotic substitution. These findings point to the feasibility of using this model to elucidate the potentially disabling Th1-cell mechanisms that may eventually render the host granulomatous response inadequate for fighting L. braziliensis infections.

Leishmania amazonensis Amastigotes Trigger Neutrophil Activation but Resist Neutrophil Microbicidal Mechanisms

“…Amastigote-laden neutrophils have been isolated from numerous infected hosts, including experimentally infected macaques and naturally infected humans, dogs, and foxes (17,(19)(20)(21). However, the immunological ramifications of amastigote-neutrophil interactions remain largely uncharacterized.…”

The utility of rhesus monkey (Macaca mulatta) and other non-human primate models for preclinical testing of Leishmania candidate vaccines

“…In L. amazonensis-infected macaques it was demonstrated that CD4 + /CD8 + T-cell ratios favour CD8 + cells in both active and healing skin lesions (Amaral et al 2000). A more marked variation in the clinical course of infection was found when groups of macaques were inoculated with different Leishmania braziliensis strains (Teva et al 2003, Souza-Lemos et al 2008. The inocula produced lesions of variable severity, ranging from localized self-healing CL to nonhealing disease (Figs 3A, C).…”

“…Pathological findings included a typical cell-mediated immunity-induced granulomatous reaction (Fig. 3D), which consisted of all cell types found within human granulomas, including the presence of both IFN-γ-or TNF-α-producing CD4 + and CD8 + T-cells, as well as IL-10-producing CD4 + CD25 + T-cells (Souza-Lemos et al 2008). While several groups have described that ML (mucosa lesions) has not been observed in Neotropical monkey models of CL (Lainson & Shaw 1977, Lujan et al 1986a, Cuba Cuba et al 1990, in our own studies (Teva et al 2003, G Grimaldi Jr, unpublished data) two of 30 (6.7%) L. braziliensis-infected macaques developed nasal ML (Fig.…”

“…In addition, IL-10-producing CD4 + CD25 + T cells are known to control acquired immunity in mice (Belkaid et al 2002) and macaques (Souza-Lemos et al 2008) with leishmanial infections.…”

“…There are reminders that the results from rodent models do not automatically translate to humans (MacGregor et al 1998). The use of non-human primates (NHP) as animal models for the study of human diseases (including immunological studies and drug and vaccinedevelopment studies against infectious diseases) has become increasingly important , Delgado et al 2005, Giavedoni 2005, Gibbs et al 2007, Nikolich-Žugich 2007, Souza-Lemos et al 2008. For instance, the SIV-macaque model is widely used for testing vaccine and therapeutic strategies prior to conducting human clinical trials (Nathansson et al 1999, Hu 2005.…”