# Host innate immune mechanisms control temporal expression of flagellin by pathogenic Salmonella

> **NIH NIH R01** · INSTITUTE FOR SYSTEMS BIOLOGY · 2021 · $484,606

## Abstract

Project Summary
Inflammasomes are multiprotein complexes that sense microbial infections and respond by inducing a caspase-
1-mediated form of inflammatory cell death called pyroptosis. Inflammasomes have been implicated in the
detection and clearance of a variety of bacterial pathogens, but little is known about whether there is active
cross-talk between the host sensing mechanism and the expression of stimulatory ligands by the pathogen. We
have found that inflammasome activation regulates expression of the NLRC4 ligand, flagellin, by Salmonella. A
host lipid stimulus released upon NLRC4-mediated macrophage pyroptosis increases expression of flagellin by
extracellular bacteria that enhances pyroptosis upon internalization, establishing a positive feedback loop that
potentiates Salmonella detection and clearance. As infection progresses, a natural type I interferon-dependent
host negative feedback response shuts down expression of NLRC4 and the lysophospholipid biosynthetic
enzyme iPLA2 to sub-baseline levels, switching Salmonella to a flagellin-low phenotype inside macrophages.
Based on these findings we hypothesize that Salmonella has evolved to co-opt NLRC4 activation and lipid
production to initially enhance production of extracellular flagellin that promotes systemic spread of the pathogen
at the risk of NLRC4-mediated clearance, and later on take advantage of decreased NLRC4 and lipid production
(a host strategy likely aimed at limiting excessive NLRC4-mediated immunopathology) to downregulate flagellin
intracellularly within macrophages. In this proposal we will investigate the host cell-intrinsic innate regulatory
circuit involving type I IFN signaling, NLRC4 and iPLA2 activity that regulates the temporal switch of Salmonella
from a flagellin-high to a flagellin-low phenotype inside macrophages. We will conduct these investigations in the
following specific aims: 1) To identify how macrophage pyroptosis promotes early increase in flagellin production
by extracellular Salmonella; 2) To dissect the natural type I interferon-dependent host negative feedback
response that establishes a NLRC4-low and iPLA2-low intracellular environment prompting Salmonella to switch
to a flagellin-low phenotype inside macrophages. Our investigations will identify the temporal and biphasic
regulation of a pathogen-derived inflammasome ligand by the very process of inflammasome activation as a
novel mode of host-pathogen cross-talk and reveal a host mechanism that Salmonella takes advantage of for
flagellin downregulation and immune escape within macrophages. These studies will also have broader
implications for understanding how host innate immunity contributes to modulation of microbial effectors
impacting the development and resolution of infections.

## Key facts

- **NIH application ID:** 10299579
- **Project number:** 1R01AI155685-01A1
- **Recipient organization:** INSTITUTE FOR SYSTEMS BIOLOGY
- **Principal Investigator:** Naeha Subramanian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $484,606
- **Award type:** 1
- **Project period:** 2021-06-10 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10299579

## Citation

> US National Institutes of Health, RePORTER application 10299579, Host innate immune mechanisms control temporal expression of flagellin by pathogenic Salmonella (1R01AI155685-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10299579. Licensed CC0.

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