# Investigating the redox-sensitive E3 ubiquitin ligase Pellino-1 as a driver of T-cell dysfunction during severe lung infection

> **NIH NIH F30** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $53,974

## Abstract

PROJECT SUMMARY
Patients with hematologic cancer are at increased risk of morbidity and mortality from severe lung infections due
to both disease and treatment-associated defects in cell-mediated and humoral immunity. CD8 T cell immunity
is critical for survival from these infections, as evidenced by our laboratory’s findings in patients with hematologic
cancer and severe COVID-19 infection. However, persistent antigen exposure during severe infections leads to
loss of T-cell cytotoxic effector function and proliferative capacity, leading to inefficient pathogen clearance.
Therefore, strategies to reverse CD8 T cell dysfunction represent a critical unmet need in patients with
hematologic cancer and severe lung infections. Our laboratory previously demonstrated that mitochondrial redox
stress drives CD8+ T-cell dysfunction during persistent antigen exposure in a manner that can be reversed by
the antioxidant N-acetylcysteine (N-Ac) and recently completed a clinical trial of N-Ac in cancer patients with
severe COVID-19 infection. In my preliminary studies, I found that circulating CD8 T cells from patients with
cancer and severe COVID-19 had significantly reduced expression of Pellino-1 (PELI1) following N-Ac treatment.
PELI1 is an E3 ubiquitin ligase known to negatively regulate CD8 T-cell activation. However, its role in limiting
CD8 T-cell function during severe infections remains unknown.
Therefore, my hypothesis is PELI1 is a redox-sensitive E3 ligase that limits CD8 T cell immunity during severe
respiratory infections by selectively degrading substrates essential for self-renewal and cytotoxicity. We will
address this hypothesis through the following Specific Aims. In Aim 1, I will test the hypothesis that PELI1 limits
CD8+ T cell immunity during severe respiratory infections in vivo, by analyzing primary samples from
hematologic cancer patients with a variety of respiratory infections as well as by determining the impact of PELI1
knockout on T-cell mediated pathogen clearance in mouse models of severe pneumonia. In Aim 2, I will
determine the mechanism by which PELI-1 restricts CD8+ T-cell function during persistent antigen exposure. By
performing biochemical and proteomic analyses to identify both PELI1 substrates and redox-dependent post-
translational modifications in PELI-1 to gain insight into mechanisms of PELI1 function and regulation. The
information obtained from this project will lay the groundwork for understanding of how redox regulation impacts
T-cell dysfunction, thereby paving the way for innovative therapeutic strategies for patients with severe
respiratory infections, including those with concurrent hematologic cancers.

## Key facts

- **NIH application ID:** 10997678
- **Project number:** 1F30HL175968-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Tiffany Rebecca Merlinsky
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 1
- **Project period:** 2024-08-12 → 2028-08-11

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997678

## Citation

> US National Institutes of Health, RePORTER application 10997678, Investigating the redox-sensitive E3 ubiquitin ligase Pellino-1 as a driver of T-cell dysfunction during severe lung infection (1F30HL175968-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10997678. Licensed CC0.

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