# Genetic and mechanistic analysis of carbon dioxide tolerance in Cryptococcus pathogenesis

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $683,782

## Abstract

Abstract
Cryptococcal meningoencephalitis (CME) is one of the most important opportunistic infections affecting people
with HIV/AIDS. The importance of this disease is due not only to its high incidence and mortality in this and
other patient populations but also to the fact that symptoms of CME are a common sentinel event leading to
the diagnosis of HIV/AIDS. Thus, many patients must first survive CME before they can benefit from the
advances in HIV therapy. Unfortunately, the outcomes for CME therapy are far from acceptable, particularly in
resource-limited regions with high burdens of disease. Consequently, effective and widely available therapies
for CME are an unmet clinical need of global importance. Cryptococcus spp. are basidiomycetous yeasts
whose primary niche is the external environment. As such, only strains and species of Cryptococcus that can
transition to, and replicate within, the human host are able to cause disease. Our central premise is that an
understanding of the biological mechanisms required for Cryptococcus to survive in human beings could
provide new targets for therapy in the same way as studying tumor biology informs the design of new anti-
cancer drugs. An important environmental distinction between the human host and the natural niche of
Cryptococcus is the concentration of carbon dioxide (CO2). We hypothesized that adaptation to host levels of
CO2 may represent a critical step in Cryptococcus pathogenesis. To specifically test this hypothesis, we
compared the growth of C. neoformans var. grubii strains under conditions that varied only in the concentration
of CO2. Consistent with our hypothesis, the growth rate was reduced at concentrations of CO2 experienced in
the host. Next, we tested the CO2 tolerance of a set of environmental strains with known virulence properties
in a mouse model; strains with reduced growth in the presence of host concentrations of CO2 were avirulent
while those with growth rates that matched clinical isolates from human patients were virulent. We, therefore,
have discovered that CO2 tolerance is a previously unrecognized host environment-associated
virulence attribute of C. neoformans. Accordingly, the goal of this proposal is to identify the genetic,
transcriptional, and regulatory responses that allow specific strains of C. neoformans to respond to host
concentrations of CO2 and, thereby, cause CME. To accomplish these goals, we propose the following
specific aims: Aim 1. Characterize the virulence, transcriptional, and genomic distinctions between CO2-
tolerant and -non-tolerant C. neoformans strains; Aim 2. Identify genes required for CO2 tolerance through
targeted and large-scale genetic screening; and Aim 3. Determine the molecular mechanisms of genes
required for C. neoformans CO2 response. Successful execution of these aims will not only further our
understanding C. neoformans pathogenesis and host survival but also identify new molecular targets for future
exploration as drug targe...

## Key facts

- **NIH application ID:** 9997296
- **Project number:** 1R01AI147541-01A1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Damian J Krysan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $683,782
- **Award type:** 1
- **Project period:** 2020-02-18 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997296

## Citation

> US National Institutes of Health, RePORTER application 9997296, Genetic and mechanistic analysis of carbon dioxide tolerance in Cryptococcus pathogenesis (1R01AI147541-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9997296. Licensed CC0.

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