# Implications of mycoviral infection in Talaromyces marneffei: an analysis of human patient samples, RNAi, and hypermutation

> **NIH NIH R21** · DUKE UNIVERSITY · 2021 · $201,250

## Abstract

Abstract
 Talaromyces marneffei (Tm) is one of seven dimorphic human fungal pathogens that are causative
agents of substantial global morbidity and mortality in both immunocompetent and immunocompromised
patients. Tm is endemic throughout Southeast Asia in a geographic region that encompasses more than half of
the global population, and is a frequent cause of infection and death in HIV/AIDS patients. The organism is
present in the environment and in association with bamboo rat species and there is substantial risk of frequent
and repeated exposure. Treatment options are limited and suboptimal, diagnostic modalities remain to be
optimized, and our understanding of virulence determinants is limited. Although studies have shown that Tm is
amenable to transformation and gene deletion via homologous recombination through Agrobacterium mediated
trans-kingdom (AMT) conjugation, little investigation has been done to elucidate virulence factors in Tm. A recent
study reported the presence of a novel dsRNA mycovirus in some clinical isolates, and that presence of this virus
is correlated with enhanced virulence in animal models and the down regulation of the expression of genes
involved in RNAi, a process which can target and degrade dsRNAs.
 In our proposal, we seek to capitalize upon these advances in order to dissect the mycoviral and genetic
determinants of Tm virulence. In aim 1, we will analyze the presence or absence of the recently discovered
mycovirus in a large collection (N=293) of well-validated Tm human clinical isolates with robust mycological and
clinical outcome data and for which whole-genome data is available, and to assess correlations of the presence
of this mycovirus determinant with disease severity and patient outcomes. We will develop approaches to cure
and reintroduce this mycovirus in order to construct congenic strains with and without the virus for direct
laboratory analyses of virulence. In aim 2, we will determine if the supression of RNAi caused by the mycovirus
results in a hypermutator phenotype in virus-infected strains. Using a transposon trap assay, we will screen the
Tm patient sample collection for isolates that produce a larger number of drug-resistant colonies, and determine
if drug resistance is due to the insertion of transposable elements into the gene responsible for resistance. We
will then assess any correlations of the hypermutator phenotype with virus-infected and virus-uninfected Tm
patient samples. We will use AMT to delete components of the RNAi pathway and we will determine the
consequences of these mutations on hypermutation, viral load, and if virulence is altered. These studies will
advance our understanding of Tm mycoviral and genetic virulence determinants and provide insights with
possible implications for patient prognosis and treatment.

## Key facts

- **NIH application ID:** 10191218
- **Project number:** 1R21AI159397-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** JOSEPH HEITMAN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $201,250
- **Award type:** 1
- **Project period:** 2021-04-02 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10191218

## Citation

> US National Institutes of Health, RePORTER application 10191218, Implications of mycoviral infection in Talaromyces marneffei: an analysis of human patient samples, RNAi, and hypermutation (1R21AI159397-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10191218. Licensed CC0.

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