Visceral leishmaniasis (VL), caused by the intracellular protozoan Leishmania donovani or L. infantum, is one of the ?Neglected Tropical Diseases? that impacts the poor of the world. People are infected when the parasite is deposited in the dermis during the bloodmeal of the sand fly vector. The majority of people who are infected develop a latent infection without clinical disease. However, some individuals develop a chronic progressive infection characterized by fever, cachexia, massive splenomegaly, pancytopenia and ultimately death. The mechanism of parasite dissemination from the skin and the reason that only a minority of infected individuals develop full-blown disease are not understood, but malnutrition has been identified as a major risk factor for the development of active disease. Progress in understanding the pathogenesis of VL has been hindered by the lack of models suitable for study of parasite dissemination from the site of skin inoculation. The research proposed here will use a clinically relevant animal host (malnourished mice) and natural parasite transmission by the bite of an infected sand fly to define the mechanisms of parasite dissemination that lead to VL. Our central hypothesis is that parasite dissemination is driven by altered cutaneous inflammation and myeloid cell-mediated trafficking of the parasite from the skin to visceral organs. Our published and preliminary data suggest a three- component model of parasite dissemination that involves (1) increased influx of inflammatory cells to the site of parasite entry in the skin; (2) hyper-migration of infected myeloid cells (primarily monocytes and neutrophils) from the skin, and (3) increased escape of migrating infected myeloid cells from the draining lymph node. We propose that co-existent malnutrition- and vector-related inflammation, as would occur in endemic regions of the world, will synergistically promote parasite dissemination and active VL.
In Specific Aim 1 we will determine the dynamics of early myeloid cell recruitment and parasite fate in the skin following infection by needle injection and vector-transmission. Our working hypothesis is that dysregulated cutaneous inflammation, in response to malnutrition or sand fly feeding, drives the altered dynamics of myeloid cell trafficking and pathogen capture in the skin. In particular, we will determine how the dysregulated inflammation leads to differences in neutrophil and inflammatory monocyte influx, parasite capture, and cell egress from the skin.
In Specific Aim 2 we will determine the mechanisms of myeloid cell trafficking and L. donovani dissemination from the skin to visceral organs following needle injection and vector-transmission. Our working hypothesis is that increased myeloid cell trafficking through the afferent lymphatic, coupled with reduced cell retention in the draining LN, leads to parasite dissemination. Changes in inflammatory mediators and chemokines and their receptors are likely to underpin parasite trafficking to the visceral organs. Understanding the mechanisms behind parasite visceralization can lead to interventions to reduce the risk for parasite dissemination and development of this devastating disease.
The mechanism through which inoculated parasites disseminate from the skin to cause visceral leishmaniasis is unknown. We will use a murine model of malnutrition and experimental parasite challenge by the bite of the sand fly to dissect the mechanisms of altered leukocyte trafficking and parasite dissemination.
| Ibrahim, Marwa K; Zambruni, Mara; Melby, Christopher L et al. (2017) Impact of Childhood Malnutrition on Host Defense and Infection. Clin Microbiol Rev 30:919-971 |
