# Mechanisms of Parasite Dissemination in Visceral Leishmaniasis

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2021 · $548,179

## Abstract

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 underp...

## Key facts

- **NIH application ID:** 10062846
- **Project number:** 5R01AI130126-04
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Peter C. Melby
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $548,179
- **Award type:** 5
- **Project period:** 2017-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10062846

## Citation

> US National Institutes of Health, RePORTER application 10062846, Mechanisms of Parasite Dissemination in Visceral Leishmaniasis (5R01AI130126-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10062846. Licensed CC0.

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