# Leishmania RNA viruses and pathogenesis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $666,307

## Abstract

Project summary.
Previously we showed that in experimental animal models, the presence of the dsRNA virus LRV1 infecting
strains of Leishmania guyanensis confers elevated pathology and metastasis, mediated by a TLR3-dependent
inflammatory response. The relevancy of this finding to humans was established by recent findings that
patients infected with Leishmania bearing LRV1 show an elevated frequency of drug treatment failures, as well
increased pathology and cytokine responses. Here we extend these studies to L. braziliensis, first by
developing new animal models and tools. The newly discovered bunyavirus- like virus “TOP” will be a high
priority; TOP occurs in >95% of all L. braziliensis strains examined and the majority of related Viannia
species. Extensive preliminary data suggest a strong role in virulence, potentially exceeding that of LRV1. In
Aim 1 we will study mechanisms of LRV1- and TOP-dependent virulence. A well-chosen series of isogenic lines
showing different combinations of LRV1 and/or TOP (virotypes) will be established and their virulence
characterized. These will then be used to probe the mechanism of LRV1-dependent virulence, which is
associated with a strong macrophage response similar to that induced by type I interferons. TOP-dependent
virulence seems to act through a completely different mechanism, independent of interferon and likely
involving dendritic cells. In Aim 2 we focus on molecular virology, especially of TOP, as these studies will likely
inform efforts to inhibit these viruses directly. We established that TOP is a highly divergent lineage within a
new family of the Bunyavirales termed “Leishbunyaviridae”. Since these novel features arose precisely at the
time deep in evolution when Leishmania transitioned from monxenous to dixenous/vertebrate parasitism,
these structural differences are likely to contribute to the TOP pathogenic mechanism. We will explore their
coding potential and the existence and role(s) of predicted proteins, and use genetic approaches to functional
test their role in viral replication and virulence.

## Key facts

- **NIH application ID:** 9928352
- **Project number:** 5R01AI130222-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Stephen M Beverley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $666,307
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928352

## Citation

> US National Institutes of Health, RePORTER application 9928352, Leishmania RNA viruses and pathogenesis (5R01AI130222-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9928352. Licensed CC0.

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