# Role and Mitigation of Inflammasomes and Inflammation During COVID-19

> **NIH NIH R56** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $768,215

## Abstract

Abstract
The COVID-19 pandemic caused by SARS-CoV-2 has resulted in swift and catastrophic losses
of human lives globally. Acute respiratory distress syndrome (ARDS) is one of the most
detrimental outcomes of COVID-19 infection that can lead to the rapid deterioration and death of
patients. ARDS is primarily caused by the cytokine storm which unleashes a plethora of
inflammatory cytokines during the late stages of COVID-19. The master cytokines that are
thought to be responsible for much of the damage are interleukin 1 (IL-1), interleukin 6 (IL-6)
and tumor necrosis factor (TNF). Currently several clinical trials have already been initiated to
test the efficacy of biologic inhibitors to target these pathways. However, in many cases, the
mechanism and impact of these cytokines during ARDS are poorly understood. An indepth
mechanistic understanding of cytokine induction is important because this understanding will
significantly impact the design and success of ARDS treatment. This application focuses on the
role and mitigation of the inflammasome complex which leads to the proinflammatory cytokine,
IL-1β, in ARDS. The inflammasome is a protein supramolecular structure that leads to caspase
1 activation, which then cleaves pro-IL-1β and pro-IL-18 to mature IL-1β and IL-18. In addition to
the release of IL-1β and IL-18, caspase 1 cleaves gasdermin D to cause inflammatory pyroptotic
cell death, thus leading to a cascade of cell death and inflammation. The inflammasome is
comprised of a receptor or sensor, with the most prominent ones represented by NLRP1,
NLRP3, NLRP6, NLRC4 and AIM2. It also includes an adaptor molecule ASC (apoptosis-
associated speck-like protein containing a CARD), and the effector caspase-1. Each receptor
or sensor can be activated by specific pathogen products called PAMPs or cell damage
associated molecules called DAMPs. NLRP3 is the most studied member since it is activated by
a large list of stimulators. Studies of other coronavirus such as SARS show inflammasome
activation by key viral proteins. Expression data from COVID-19 patients also show dramatic
increases of inflammasome sensors in the bronchial alveolar lavage of COVID-19 patients.
However the mechanism of inflammasome activation by SARS-CoV-2, especially in the human
system, remains unknown. This proposal will identify the viral protein that activates human
inflammasome, and further define the specific human inflammasome sensor/receptor that
mediates the response. We will then design ways to reduce inflammasome activation during
SARS-CoV-2 infection using established therapeutics as well as new approaches to broadly
attenuate inflammatory cytokines.

## Key facts

- **NIH application ID:** 10470451
- **Project number:** 1R56AI158314-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Beverly H Koller
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $768,215
- **Award type:** 1
- **Project period:** 2021-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470451

## Citation

> US National Institutes of Health, RePORTER application 10470451, Role and Mitigation of Inflammasomes and Inflammation During COVID-19 (1R56AI158314-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10470451. Licensed CC0.

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