# Targeting innate immune pathways, and inflammatory cell death in cytokine-mediated diseases

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2022 · $763,801

## Abstract

ABSTRACT
The innate immune system is the critical first line of defense against pathogenic infections. In the context of
viral infections, activation of the innate immune response is key to controlling viral replication and eliminating
the infection. However, overactivation of this response can lead to systemic hyperinflammation and significant
morbidity and mortality. Recently, a novel coronavirus, SARS-CoV-2, has emerged, leading to the disease
COVID-19 and a global pandemic. Targeted therapeutic strategies are critically lacking, and there is limited
understanding of the role of innate immune responses in this disease. Clinical data show that patients with
COVID-19 experience a cytokine storm and significant tissue damage, both of which contribute to disease
severity and mortality. Recent work from our group showed that increased TNF-α and IFN-γ levels following
SARS-CoV-2 infection lead to inflammatory cell death, which is detrimental to the host. We found that
neutralizing TNF-α and IFN-γ reduced SARS-CoV-2–induced mortality in mice. But little is known about the
mechanistic basis behind the uncontrolled cytokine release. While several potential therapies to block different
inflammatory cytokines are being explored, balancing proinflammatory responses to clear the virus with
preventing systemic inflammation remains challenging. Improved understanding of the mechanisms by which
the innate immune system recognizes and responds to coronavirus infections will be key to informing and
developing therapeutic strategies. Furthermore, the roles of specific innate immune sensors, inflammasome
activation, and inflammatory cell death in COVID-19 disease development remain unknown. We have
previously elucidated the molecular details of innate immune signaling pathways that regulate inflammation
and pathogenic clearance, identifying upstream sensors and important molecules in these pathways. In this
grant application, we seek to unravel the fundamental mechanisms of novel innate immune sensors and
inflammasome regulators discovered in our lab previously and understand their crosstalk with cell death
regulators in coronavirus infection. Basic science supporting this area of research is critical to understanding
the fundamentals of the innate immune response. The work completed under this proposal will characterize
the major innate immune sensors that are directly sensing SARS-CoV-2 to initiate interferon and inflammatory
cytokine expression and identify the molecular mechanisms that regulate inflammatory cell death in response
to SARS-CoV-2. These discoveries are expected to identify novel signaling pathways that could be targeted
by therapeutic interventions. The findings will be applicable to not only COVID-19, but also other infectious
diseases and conditions associated with a hyperactive innate immune response, cytokine release, and severe
inflammation; this work will be fundamental to inform clinical directions to prevent morbidity and mortality.

## Key facts

- **NIH application ID:** 10428652
- **Project number:** 5R01AI160179-02
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Thirumala-Devi Kanneganti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $763,801
- **Award type:** 5
- **Project period:** 2021-06-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428652

## Citation

> US National Institutes of Health, RePORTER application 10428652, Targeting innate immune pathways, and inflammatory cell death in cytokine-mediated diseases (5R01AI160179-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10428652. Licensed CC0.

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