# Dysregulated Co-inhibitory Pathways Associated with Severe COVID-19 Immunopathology

> **NIH NIH P01** · YALE UNIVERSITY · 2020 · $260,931

## Abstract

Abstract
COVID-19, caused by novel coronavirus SARS-CoV-2, has recently affected over 600,000 
people and has caused more than 30,000 deaths worldwide. Dysregulated immune responses against 
SARS-CoV-2 virus are a critical component of COVID-19 that can lead to severe respiratory failure 
(SRF). The dysregulated type 1 interferon (IFN-I) production by innate immune cells are likely 
involved in immunopathogenesis. However, the molecular mechanisms by which the virus causes 
lethality are not known. It has been found that COVID-19 patients with SRF exhibit a cytokine 
storm with hyper activated T cells characterized by pro-inflammatory cytokine production of 
GM-CSF, IFN-γ, and TNF-α, though paradoxically, the T cells express high level of co-inhibitory 
receptors that are thought to limit this aberrant response. These data indicate there are 
inadequate inhibitory signals on T cells in severe disease. We have identified TIGIT as 
 a critical co-inhibitory receptor expressed on T cells that plays a central role in 
orchestrating T cell activation and immune homeostasis in autoimmunity, cancer and viral infection, 
and its expression was found to be coordinated with the PD-1/TIM-3 module in mice. However, our 
 lab recently discovered that while IFN-I drives expression of this module it 
surprisingly decreases TIGIT expression in humans implicating a unique function of TIGIT 
 during IFN-I responses on human T cells. Moreover, we developed a gene regulatory 
network using high resolution transcriptional profiling that allows identification of 
regulatory factors for co-inhibitory receptor expression during IFN-I response. This leads 
 to our overall hypothesis that delayed IFN-I response to SARS-CoV-2 in older individuals 
disrupts the T cell co-inhibitory response, leading to T cell hyperactivation and severe illness. 
Specifically, attenuated TIGIT expression on T cells allows aberrant cytokine release which fuels 
the cytokine storm in severe COVID-19. Moreover, pre-clinical data demonstrated 
that TIGIT signaling limits immunopathology without affecting viral load in vivo. 
Thus, our goals are to: 1) identify the molecular mechanism for the dysregulated immune 
program leading to hyper T cell responses in COVID-19 patients and to identify potential 
targets. We will probe dynamic T cell responses by incorporating comprehensive multi- 
omics single cell analysis in patients with mild and severe manifestation of COVID-19 
compared to healthy individuals; 2) we will explore the mechanism for driving hyperactivation of 
T cells in severe COVID-19. Our previously established gene regulatory network for IFN-I 
response on T cells will be integrated with data acquired from our single cell analysis. 
This will allow us to identify the key regulatory factors controlling TIGIT expression under IFN-I 
response and may allow the identification of novel therapeutic targets; 3) Finally, we will 
determine the therapeutic potential of TIGIT mediated co-inhibi...

## Key facts

- **NIH application ID:** 10136874
- **Project number:** 3P01AI039671-22S1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** David A. Hafler
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $260,931
- **Award type:** 3
- **Project period:** 2020-04-29 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136874

## Citation

> US National Institutes of Health, RePORTER application 10136874, Dysregulated Co-inhibitory Pathways Associated with Severe COVID-19 Immunopathology (3P01AI039671-22S1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10136874. Licensed CC0.

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