# Systematic investigation of GPI-anchored mannoproteins in Cryptococcus neoformans

> **NIH NIH R21** · UNIVERSITY OF GEORGIA · 2021 · $226,500

## Abstract

Cryptococcus neoformans causes fatal cryptococcal meningoencephalitis and is responsible for 15% of
deaths in AIDS patients. This fungus can also cause meningoencephalitis in individuals without apparent
immuno-deficiency and such incidences are increasing. The outcome of the current antifungal therapy for
patients with cryptococcal meningoencephalitis is far from acceptable, with mortality rates ranging from 10 to
70%. The challenges of treating this disease motivate us to understand cryptococcal pathogenesis and to
identify cryptococcal factors that shape the interactions between this pathogen and a mammalian host. Our
central premise is that cryptococcal factors that modulate host response or neurotropism could provide targets
for antifungal therapy, diagnosis, or prevention.
 Glycosylphosphatidylinositol (GPI)-modified glycoproteins in various eukaryotic pathogens are
prominent players in modulating host responses. The effect of these glycoproteins to the host can be protective
or deleterious. In C. neoformans, mannoproteins are considered the primary components recognized by the
host anti-cryptococcal cell-mediated immune response. However, only several GPI-anchored mannoproteins
have been studied in this pathogen, including virulence factors chitin deacetylases Cda1-3 and phospholipase
Plb1. We previously found that cryptococcal cells overexpressing an anti-virulence transcription factor Znf2 can
confer rare sterilizing immunity to the host against a subsequent challenge by an otherwise lethal wild type
strain. Remarkably, 25 out of the 49 predicted GPI-anchored mannoprotein genes in the genome of C.
neoformans H99 are regulated by Znf2, with 10 being upregulated and 15 downregulated. This indicates the
importance of Znf2 in controlling mannoprotein presentation in this fungus. A recent study indicates that 13
mannoprotein genes are highly differentially expressed in lungs of both mice and monkeys during cryptococcal
infection. Given that GPI-anchored mannoproteins are the major class of cell wall proteins and they are also
components of the capsule in C. neoformans, we hypothesize that these proteins represent one of the most
important groups of factors modulating cryptococcal interactions with the host.
 Here we will systematically examine the role of these 49 GPI-anchored mannoproteins in modulating
Cryptococcus-host interactions. To achieve this goal, we propose to complete a gene deletion and gene
overexpression library for the GPI-anchored mannoproteins. We will use these mutants to define the roles of
these mannoproteins in cryptococcal interaction with the host in an animal model of cryptococcosis. Successful
completion of the proposed work will reveal cryptococcal factors that can be exploited in the future by us or
others to investigate host immunity, antifungal targets, or diagnostic markers. The exploratory nature of the
proposed work and the potential impact it has on our understanding of the interaction between the host and
th...

## Key facts

- **NIH application ID:** 10117186
- **Project number:** 5R21AI150641-02
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** Xiaorong Lin
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $226,500
- **Award type:** 5
- **Project period:** 2020-03-02 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10117186

## Citation

> US National Institutes of Health, RePORTER application 10117186, Systematic investigation of GPI-anchored mannoproteins in Cryptococcus neoformans (5R21AI150641-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10117186. Licensed CC0.

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