# The Impact of SARS-CoV-2 Immune Dysregulation on Antifungal Immunity

> **NIH NIH R56** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $668,250

## Abstract

Project summary
Unlike most invasive mold infections, COVID Associated Pulmonary Aspergillosis (CAPA) occurs in
individuals with otherwise intact immune systems suggesting novel biological mechanisms mediating
susceptibility to fungal infection. This proposal seeks to evaluate the novel conceptual advancement that
immune responses targeting intracellular viral pathogens compromise essential human neutrophil
antifungal effector functions required to kill large extracellular fungal hyphae. In Aim 1, we will utilize
BAL samples and autopsy formalin-fixed paraffin embedded (FFPE) lung tissues to characterize the
expression of human neutrophil antifungal effectors, epithelial cell necroptosis, iron content, and fungi in
the respiratory tract during SARS-CoV-2 and CAPA infection. In Aim 2, we will use primary bronchiolar
epithelial cell air-liquid interface (ALI) cultures, CRISPR knockout cell lines (MLKL, RIPK1, RIPK3),
chemical inhibitors of cell death pathways, and neutrophil:fungal killing assays to determine the
mechanism by which SARS-CoV-2 mediates epithelial cell death, iron release, mold growth, and human
neutrophil antifungal effector functions. In Aim 3, we will utilize a novel CAPA infection mouse model,
cre-lox knockdown of human ACE2 expression in neutrophils (MRP8-Cre) and lung epithelial cells
(CC10-Cre) along with iron-deficient fungal mutant strains (ΔsidA, ΔftrA), to evaluate the in vivo impact of
SARS-CoV-2 infection on lung epithelial cell necroptosis, iron release, siderophore-dependent fungal
growth, and neutrophil recruitment/activation. We believe that the results of the proposed study will shed
new light on the fundamental biology mediating viral-associated secondary mold infection which may
enable the development of improved therapeutic regimens that mitigate the risk of developing CAPA.

## Key facts

- **NIH application ID:** 10668549
- **Project number:** 1R56AI170719-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Sixto Manuel Leal
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $668,250
- **Award type:** 1
- **Project period:** 2022-08-05 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10668549

## Citation

> US National Institutes of Health, RePORTER application 10668549, The Impact of SARS-CoV-2 Immune Dysregulation on Antifungal Immunity (1R56AI170719-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10668549. Licensed CC0.

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