# Mechanistic elucidation of inflammasome assembly and regulation.  Supplement: Testing drugs that curtail inflammasome activation to suppress SARS-CoV-2 pathogenesis

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $264,999

## Abstract

Abstract
Inflammasomes are supramolecular signaling complexes that activate a subset of caspases
known as inflammatory caspases such as caspase-1. Upon stimulation by microbial and
damage-associated signals, inflammasomes assemble to elicit the first line of host defense by
proteolytic maturation of cytokines IL-1b and IL-18, and by induction of pyroptotic cell death.
Assembly of an inflammasome requires activation of an upstream sensor, a downstream
effector, and in most cases an adaptor molecule such as apoptosis-associate speck-like protein
containing a caspase recruitment domain (ASC). Depending on whether ASC is required,
inflammasomes can be categorized into ASC-dependent and ASC-independent
inflammasomes. Despite the biological importance of inflammasomes in innate immunity, no
structural and mechanistic information is available.
This proposal seeks to link SARS-CoV-2 infection to inflammasomes and to test whether
inflammasome inhibitors alleviate SARS-CoV-2 pathogenesis. Inflammasome activation, in
particular through the NLRP3 inflammasome and the pore forming protein GSDMD, underlies
the serious, and often fatal cytokine storm, lung inflammation and sepsis that are associated
with SARS-CoV-2 clinical deterioration. It may even contribute to lymphopenia, an important
characteristic of severe COVID-19 cases. These data from SARS-CoV-2 and from related
coronaviruses, SARS-CoV and MERS-CoV, led us to propose the following hypothesis: the
severe acute respiratory syndrome (SARS) pneumonia induced by SARS-CoV-2 is caused by
massive inflammatory cell infiltration and elevated proinflammatory cytokine/chemokine
responses that depend on GSDMD and/or NLRP3 activation.

## Key facts

- **NIH application ID:** 10159600
- **Project number:** 3R01AI124491-05S1
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Judy Lieberman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $264,999
- **Award type:** 3
- **Project period:** 2020-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159600

## Citation

> US National Institutes of Health, RePORTER application 10159600, Mechanistic elucidation of inflammasome assembly and regulation.  Supplement: Testing drugs that curtail inflammasome activation to suppress SARS-CoV-2 pathogenesis (3R01AI124491-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10159600. Licensed CC0.

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