# Cryptococcal Chitin Synthase 3 and Host Immune Responses

> **NIH NIH K22** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2021 · $162,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Cryptococcus neoformans infections are a significant cause of morbidity and mortality among AIDS patients and
the third most common invasive fungal infection in organ transplant recipients. There are an estimated quarter
million cases of cryptococcal meningitis each year resulting in ~200,000 deaths. Because host immune
responses are so vital to the control of cryptococcosis, my long-term goal is to delineate the host: fungal
interactions that impact C. neoformans pathogenesis or clearance. One of the main interfaces between the
fungus and the host is the fungal cell wall. The cell wall in Cryptococcus is unusual in that the chitin is
predominantly deacetylated to chitosan. Chitosan deficient strains of C. neoformans were found to be avirulent
and were rapidly cleared from the murine lung. Moreover, infection with a chitosan deficient C. neoformans
lacking three chitin deacetylases (cda1Δ2Δ3Δ) was found to confer protective immunity to a subsequent
challenge with a virulent wild type counterpart. In addition to the chitin deacetylases, it was previously shown
that chitin synthase 3 (Chs3) is also essential for chitin deacetylase mediated formation of chitosan. Mice
inoculated with
chs3Δ
at a dose previously shown to induce protection with cda1Δ2Δ3Δ die within 36 hours after
installation of the fungal organism. Death is dose dependent as mice given a lower dose did not succumb.
Mortality was not dependent on viable fungi as mice inoculated with heat-killed
chs3Δ
died at the same rate as
mice inoculated with live chs3Δ, suggesting that the rapid onset of death was host mediated likely caused by an
over exuberant immune response. Altogether, these studies lead us to hypothesize that Chs3 plays a critical role
in dampening cryptococcal induced host inflammatory responses. In this application we aim to define the
mechanism(s) within the host that trigger the aberrant immune response to chs3Δ and identify the cellular
component(s) from chs3Δ that elicit this non-protective pro-inflammatory response. The work proposed in this
application will have significant overall impact on basic science knowledge, which will provide insights into other
pathogenic microbes and areas of biology, as well as potentially advance our understanding of a significant
problem in the management of cryptococcal patients. This K22 approach will provide me with opportunities to
not only understand the pathways that drive the host response and the cryptococcal components that drive the
immune response, but also the bifurcation between protective and non-protective innate host responses. The
mentorship received in Drs. Wormley, Doering, and Lodge laboratories, as well as the knowledge and
experiences gained has afforded me the skills and opportunities to become an independent researcher and to
pursue a successful career studying host: pathogen interactions. This work will provide the foundation for future
RO1 applications as well as a career investigating t...

## Key facts

- **NIH application ID:** 10055130
- **Project number:** 1K22AI148724-01A1
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Camaron Reynolds Hole
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $162,000
- **Award type:** 1
- **Project period:** 2021-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10055130

## Citation

> US National Institutes of Health, RePORTER application 10055130, Cryptococcal Chitin Synthase 3 and Host Immune Responses (1K22AI148724-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10055130. Licensed CC0.

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