# Single nucleotide variations account for strain specific virulence changes in Cryptococcus neoformans

> **NIH NIH F31** · UNIVERSITY OF MINNESOTA · 2020 · $31,636

## Abstract

PROJECT SUMMARY/ABSTRACT
Cryptococcal meningitis (CM) is a severe central nervous system (CNS) infection caused by the fungal
pathogen Cryptococcus neoformans, primarily in people with compromised immune systems. CM kills 181,000
people annually, with the largest burden on AIDS patients. It is the second most common killer of AIDS
patients in sub-Saharan Africa, behind only tuberculosis. Both the treatment and diagnosis of CM is
complicated by a well-documented variability in disease presentation. Changes in patient outcome have been
associated, in part, with the genotype of C. neoformans. We performed a preliminary genome wide association
study (GWAS) on 40 whole genomes of clinical isolates with associated patient data. The GWAS revealed an
association between single nucleotide polymorphisms (SNPs) and insertions/deletions (INDELs) in C.
neoformans genes and patient outcome. We deleted a sub-set of these genes and showed they play a
previously uncharacterized role in virulence. Furthermore, there is a documented association between
structural variation in the C. neoformans genome and patient outcome. This proposal will test the hypothesis
that individual nucleotide variations cause changes in patient disease presentation. Aim 1 will identify
SNPs/INDELs in a large population of C. neoformans clinical isolates by using amplicon sequencing and will
use long-read sequencing to characterize structural variants in the clinical isolates. We will compare these data
to patient outcome to identify clinically relevant genomic variants. Aim 2 will determine the role of the
nucleotide variations in a biological context by exchanging gene alleles in virulent or avirulent genetic
backgrounds and then analyzing changes in pathogenesis. Aim 2 will define the biological function of the
observed genomic differences through characterization of novel genes identified in the preliminary GWAS
analysis. Finally, we will introduce single nucleotide variations into the reference gene alleles using CRISPR to
define the impact of single genetic changes. The proposed research is innovative in that it is the first to
compare single nucleotide polymorphisms in C. neoformans and differences in patient outcome. The proposed
research will 1) determine the role of SNP/INDELs on C. neoformans phenotype; 2) identify unknown virulence
factors; and 3) build a diagnostic method for identifying the infecting C. neoformans strain, leading to targeted
therapy and improved patient survival.

## Key facts

- **NIH application ID:** 9975614
- **Project number:** 5F31AI148047-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Katrina M Jackson
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $31,636
- **Award type:** 5
- **Project period:** 2019-08-26 → 2022-08-25

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975614

## Citation

> US National Institutes of Health, RePORTER application 9975614, Single nucleotide variations account for strain specific virulence changes in Cryptococcus neoformans (5F31AI148047-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9975614. Licensed CC0.

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