# NLRP11 in non-canonical inflammasome activation in response to Shigella flexneri and cytosolic LPS.

> **NIH NIH F32** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $69,834

## Abstract

Shigella flexneri are intracytosolic bacterial pathogens that cause bacillary dysentery in humans. Determining
how intracytosolic bacteria are detected by the host cell is critical for advancing our understanding of the innate
immune system. Infection of the colon by S. flexneri leads to an immune response that triggers recruitment of
neutrophils and macrophages into the tissue. When S. flexneri enters macrophages, it activates
inflammasomes, leading to pyroptosis, a type of pro-inflammatory cell death. The best studied inflammasome
pathway is the canonical NLRP3 inflammasome, which consists of (1) the NOD-like receptor (NLR) NLRP3, (2)
the adaptor protein ASC, and (3) the inflammatory caspase-1. A non-canonical inflammasome that consists of
caspase-4/5 (caspase-11, in mice) has been described; as yet, no NLR protein has been identified. Activated
inflammatory caspases from either pathway activate gasdermin D. Our preliminary data show that during S.
flexneri infection NLRP11 is required for efficient cell death as well as caspase-4 and gasdermin D activation in
human-derived macrophages, Our data also show that cytosolic LPS (cLPS) is sufficient to trigger NLRP11
dependent cell death in these cells. In addition, my preliminary data show that NLRP11 binds LPS and that
NLRP11 and pro-caspase-4 interact independent of LPS. Based on our data, we propose a novel role for
NLRP11 in the detection of cLPS in the non-canonical inflammasome pathway. My overall hypothesis is that
NLRP11 (1) functions to detect cLPS with caspase-4, (2) binds and activates caspase-4, and (3) is a critical
component of the non-canonical inflammasome. I propose to test this hypothesis with the following aims:
1. Define the molecular function of NLRP11 in non-canonical inflammasome activation
2. Define the requirements for the interaction of NLRP11 with caspase-4
3. Determine whether LPS, NLRP11, and caspase-4 form a ternary complex.
This proposal will generate mechanistic insights into how NLRP11 acts in the non-canonical inflammasome. It
is highly likely to uncover novel functional interactions in the non-canonical inflammasome and deepen our
understanding of the innate immune system in general. The proposed studies will be conducted in Dr. Marcia
Goldberg's laboratory at Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), with the
guidance of my co-sponsor, Dr. Judy Lieberman. Both MGH and HMS are rigorous academic environments
with ample resources support my research and career development. I will have many opportunities to formally
present my research, attend scientific meetings, and attend career development courses. The proposed
studies will provide me with new expertise in microbiology and innate immunology and place me in an ideal
position of reaching my career goals of being an independent researcher.

## Key facts

- **NIH application ID:** 9910652
- **Project number:** 1F32AI145128-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Amanda Soohoo Zajac
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $69,834
- **Award type:** 1
- **Project period:** 2020-02-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9910652

## Citation

> US National Institutes of Health, RePORTER application 9910652, NLRP11 in non-canonical inflammasome activation in response to Shigella flexneri and cytosolic LPS. (1F32AI145128-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9910652. Licensed CC0.

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