# Viral inhibition of cell death in host immune responses

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $574,423

## Abstract

Abstract/Summary of Work
 Cell death is a powerful immune defense mechanism to limit viral replication within the infected host. In
response, viruses often encode inhibitors that counteract host cell death. For example, many herpesviruses
and poxviruses encode inhibitors of caspases, the key enzymes that execute apoptosis. By subverting host
cell death and the associated inflammatory response, viral cell death inhibitors can also dramatically alter the
outcome of viral diseases.
 Necroptosis is a lytic form of cell death that is optimally induced in the presence of caspase 8 inhibition.
As such, necroptosis has critical roles in controlling viruses that encode caspase inhibitors. Moreover, the
release of “damage-associated molecular patterns (DAMPs)” from necroptotic cells can further stimulate anti-
viral inflammation. These anti-viral effects suggest that necroptosis may also be a target of viral inhibition. To
test this hypothesis, we conducted a siRNA screen and found a viral inhibitor from cowpox virus that we have
termed “viral inducer of RIPK3 degradation (vIRD)”. In preliminary studies, we found that vIRD functions by
targeting the essential necroptosis kinase RIPK3 for proteasomal degradation.
 Based on these observations, we propose three aims to further elucidate the function and mechanism
of vIRD. In the first aim, we will evaluate the mechanism by which vIRD from cowpox virus and other related
orthopoxviruses promotes RIPK3 degradation. Studies will include mapping the domain and residues within
vIRD and RIPK3 that are responsible for their physical interaction and ubiquitination. In the second aim, we
will interrogate the role of the host SKP1-Cullin-F box (SCF) complex in vIRD-mediated RIPK3 degradation.
We will also evaluate the effect of vIRD on the global ubiquitination landscape of the infected cell. In Aim 3, we
will evaluate the biological function of vIRD using mouse infection as model. We will infect mice with cowpox
virus or vaccinia virus that differ in their expression of vIRD. The effect of vIRD on cell death, inflammation,
viral replication and tissue pathology will be examined. Collectively, these studies will reveal medically relevant
information on how viruses manipulate the immune system and alter the outcome of viral disease. We expect
the knowledge gained from the proposed study will provide important insight in the design of better and more
efficacious vaccines.

## Key facts

- **NIH application ID:** 10833100
- **Project number:** 5R01AI148302-05
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Edward A Miao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $574,423
- **Award type:** 5
- **Project period:** 2020-06-22 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10833100

## Citation

> US National Institutes of Health, RePORTER application 10833100, Viral inhibition of cell death in host immune responses (5R01AI148302-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10833100. Licensed CC0.

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