# The role of septins in the adaptation of Cryptococcus neoformans to host temperature in HIV-based cryptococcosis

> **NIH NIH R01** · CLEMSON UNIVERSITY · 2022 · $356,944

## Abstract

PROJECT SUMMARY
The long-term goal of this proposal is to uncover mechanisms of pathogenicity of Cryptococcus neoformans
(Cn) focusing on how Cn adapts to host temperature. Cn is a fungal pathogen that, upon entering the lung and
disseminating through the bloodstream, causes a life-threatening meningo-encephalitis primarily in HIV/AIDS
patients. Current anti-cryptococcal therapies can have devastating side effects. Thus, new treatment strategies
are warranted to eliminate mortality associated with cryptococcosis. The objective of this proposal is to
determine how the temperature is sensed by Cn and transmitted to downstream effector pathways critical for
pathogenicity. The central hypothesis is that filament-forming GTP-ases called septins provide an essential
hub protein complex which links temperature sensing to a compensatory signaling response and plasma
membrane (PM) homeostasis. It is proposed that exposure to host temperature results in increased fluidity and
curvature within the PM and the elevation of PM-associated phosphatidylinositol 4,5-bisphosphate (PIP2)
leading to enrichment of septins at the PM based on PIP2 binding, which has two-fold role in Cn adaptation to
host temperature: it maintains PM homeostasis and facilitates stress signaling via phospholipase C (PLC), and
protein kinase C (PKC) pathways. In support of this hypothesis, experiments with recombinant septins or
studies employing model organisms suggest that septins recognize membrane curvature via their propensity to
bind PIP2. Importantly, recombinant septins prevent temperature-induced changes in lipid bilayer composition.
Preliminary data supporting this application are: 1) Cn PIP2 levels increase at 37°C. 2) Septins associate with
the PM when Cn is shifted to 37°C. 3) Septin-deficient mutants exhibit increased PM permeability and
sensitivity to drugs that perturb PM. Published and preliminary data also demonstrate phenotypic similarity
between septin-deficient and PLC signaling-defective mutants. The central hypothesis will be tested by
pursuing two aims. Aim1: Dynamics of septin assembly at the PM will be defined with TIRF microscopy.
Genetic and pharmacological approaches will determine whether septin complexes are enriched at the PM
based on increased levels of PIP2. An innovative light switchable allele of Cdc42 (GTPase involved in septin
assembly) will help to establish effectors down-stream of Cdc42 acting in septin complex formation. A septin
mutant lacking the amphiphatic helix (AH) will be utilized to test the role of AH in recruiting septin complex to
the PM. Aim2: An impact of septin complexes on PM lipid composition, PM biophysical properties, stress
response signaling dependent on PIP2, and pathogenesis in animal infection model will be determined. The
proposed research is significant because it will elucidate a novel mechanism through which septins contribute
to sensing high temperature and regulating PM-dependent stress response signaling pathways cruci...

## Key facts

- **NIH application ID:** 10619216
- **Project number:** 1R01AI167692-01A1
- **Recipient organization:** CLEMSON UNIVERSITY
- **Principal Investigator:** Lukasz Kozubowski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $356,944
- **Award type:** 1
- **Project period:** 2022-09-21 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10619216

## Citation

> US National Institutes of Health, RePORTER application 10619216, The role of septins in the adaptation of Cryptococcus neoformans to host temperature in HIV-based cryptococcosis (1R01AI167692-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10619216. Licensed CC0.

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