# GSDMA roles in skin innate immune defense

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $586,464

## Abstract

PROJECT SUMMARY/ABSTRACT
Streptococcus pyogenes (group A Streptococcus; GAS) causes more than half a million deaths annually through
invasive infections and post-infection immune sequelae like rheumatic heart disease. The pathogenesis of these
diseases is poorly understood despite their public health importance, and they carry high mortality even with
treatment. The first barrier to infection is the skin. GAS frequently lives asymptomatically, but can invade further
to cause impetigo and erysipelas, and deeper still to cause the “flesh-eating disease” necrotizing fasciitis. The
long-term goal of this work is to understand the specific cellular processes that GAS virulence factors manipulate
when infections proceed to more severe invasive diseases, in order to develop more effective therapeutic
countermeasures. This proposal tests the hypothesis that keratinocytes sense invasive infection through a new
cell death mechanism of gasdermin A-dependent pyroptosis. The major secretion product of GAS is a protease,
SpeB, which degrades tissue to promote spread and immune factors to protect the bacterium. GAS can also
invade skin keratinocytes, which usually can restrict intracellular pathogens through autophagy, but hypervirulent
GAS escapes this also using SpeB. Notably, the inert cytosolic protein gasdermin A is processed by SpeB into
an active pore-forming effector. Keratinocytes express high gasdermin A and die of gasdermin A-dependent
pyroptosis during GAS infection. Thus, activation of gasdermin A is intrinsically linked to the same virulence
factors essential for invasion and serves as a cell-autonomous sensor of pathogenicity. This proposal dissects
cell death at the host-pathogen interface with three aims. In the first, a panel of defined mutant GAS and clinical
isolates naturally differing in their ability to cause invasive will be used to examine the molecular requirements
for cell death during infection, with specific reporters used to measure SpeB activity, gasdermin A activation, and
bacterial and host cell survival. Then, the molecular effector functions of gasdermin A and how pyroptosis results
in bacterial killing is examined. Lastly, in vivo models are used to separately examine inflammation, wound
healing, and bacterial killing to determine the specific contribution of cell death to the establishment and
progression of skin infection. These studies will lay the foundation for how gasdermin A acts as an immune
sensor of skin infection, dramatically improving our fundamental understanding of GAS pathogenesis and
revealing therapeutic targets to treat disease.

## Key facts

- **NIH application ID:** 10979350
- **Project number:** 1R01AI180089-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Christopher N LaRock
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $586,464
- **Award type:** 1
- **Project period:** 2024-06-17 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979350

## Citation

> US National Institutes of Health, RePORTER application 10979350, GSDMA roles in skin innate immune defense (1R01AI180089-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10979350. Licensed CC0.

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