# Immunoproteasome-Mediated Inflammation in Coronavirus Respiratory Infection

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $234,000

## Abstract

PROJECT SUMMARY
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human coronavirus that has
caused the coronavirus disease 2019 (COVID-19) pandemic. COVID-19 is associated with severe, frequently
life-threatening respiratory illness in a substantial proportion of affected people. Severe COVID-19 is
characterized by an exuberant systemic inflammatory response to SARS-CoV-2 infection. That response aids
in control of viral replication during acute infection, but it also drives virus-induced pathology and disease
manifestations. For reasons that remain incompletely understood, that deleterious inflammatory response is
less likely to develop in children infected with SARS-CoV-2, and children are more likely than adults to have
asymptomatic infection or mild disease. The immunoproteasome (IP), an inducible component of the ubiquitin-
proteasome system, is more efficient than the constitutive proteasome in generating MHC class I epitopes for
recognition by CD8 T cells. IP activity also exerts intrinsic effects on T cell, B cell, macrophage, and DC
functions and contributes to inflammatory responses via mechanisms that include degradation of IκB and
subsequent activation of NF-κB-mediated inflammatory pathways. No studies have addressed contributions of
the IP to the pathogenesis of human or animal coronaviruses. Our published and preliminary data suggest that
IP subunit activity is developmentally regulated in the lungs and other organs, increasing with age. IP subunit
expression increases in mice during acute infection with a murine coronavirus, and IP inhibition suppresses
virus-induced expression of pro-inflammatory cytokines but enhances weight loss and mortality. In this
proposal, we will test the hypothesis that increased IP activity during coronavirus infection drives
immunopathology in an age-dependent manner. We will use a tractable animal model with an animal
coronavirus, murine hepatitis virus type 1 (MHV-1), to define the role of the IP in coronavirus pathogenesis and
identify effects of IP inhibition on virus-induced inflammation and disease during acute infection. In Aim 1, we
will define age-based differences in IP response, inflammation, and disease induced by acute MHV-1
respiratory infection. In Aim 2, we will use pharmacologic inhibition of IP subunit activity to define effects of IP
activity on key immune cells and determine the extent to which the IP contributes to virus-induced inflammation
and disease. There is a clear and pressing need to development effective preventative and therapeutic
measures for COVID-19. Modulation of an inducible host factor, such as the IP, that is predominantly active
during an inflammatory state such as infection would be an appealing strategy if it could facilitate reduction of
detrimental inflammatory responses with minimal impact on essential constitutively active host processes.

## Key facts

- **NIH application ID:** 10449852
- **Project number:** 1R21AI163720-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jason Brice Weinberg
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $234,000
- **Award type:** 1
- **Project period:** 2022-05-16 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10449852

## Citation

> US National Institutes of Health, RePORTER application 10449852, Immunoproteasome-Mediated Inflammation in Coronavirus Respiratory Infection (1R21AI163720-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10449852. Licensed CC0.

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