# Bacterial modulation of noncanonical inflammasome

> **NIH NIH R56** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2023 · $484,035

## Abstract

Project Summary/Abstract
 During host-bacterial pathogen encounters, the host cells are exposed to an array of
microbial components, including virulence factors such as bacterial toxins and pathogen-
associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) and flagellin. The
innate immune system employs germline-encoded pattern recognition receptors to survey the
extra- and intra-cellular milieu for the presence of PAMPs and mount appropriate defense
responses. Concurrently, bacterial virulence factors directly induce and/or rewire cellular
processes that favor bacterial colonization with or without tissue damage. The crosstalk between
the PAMP-induced innate immune responses and virulence factor-induced cellular responses are
vital determinants of the fate of host-pathogen interactions. Therefore, an in-depth understanding
of these interactions is critical for gaining insights into the mechanisms of bacterial diseases.
However, these interactions are poorly characterized in several bacterial infections. This project
will address this knowledge gap utilizing a human pathogen, Enterohemorrhagic Escherichia coli
(EHEC), the causative agent of hemorrhagic colitis and hemolytic uremic syndrome (HUS). During
EHEC infection, host cells encounter bacterial factors, including Shiga toxin, type III secretion
system components, and LPS. A unique noncanonical inflammasome pathway senses EHEC
LPS entering host cell cytosol via outer membrane vesicles; cytosolic LPS binds and activates an
inflammatory caspase, caspase-11, which then mediates cell death, caspase-1 activation, and
downstream IL-1 cytokine production. The studies proposed in three specific aims will
systematically characterize how an EHEC virulence factor subverts the noncanonical
inflammasome-mediated host responses and how the noncanonical inflammasome reciprocally
regulate EHEC disease pathogenesis in a clinically relevant murine model of EHEC infection.
Thus, the findings from this study provides critical molecular and cellular insights into a complex
interplay between a classic bacterial PAMP- and virulence factor-induced host signaling pathways
and its impact on disease pathogenesis in a clinically relevant infection.

## Key facts

- **NIH application ID:** 10893667
- **Project number:** 2R56AI132850-06A1
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Sivapriya Kailasan Vanaja
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $484,035
- **Award type:** 2
- **Project period:** 2018-01-16 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10893667

## Citation

> US National Institutes of Health, RePORTER application 10893667, Bacterial modulation of noncanonical inflammasome (2R56AI132850-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10893667. Licensed CC0.

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