# NK cell mobilization as a pathogenic etiology of SARS-CoV-2 gastrointestinal disease

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $402,500

## Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of Coronavirus
Disease 2019 (COVID-19) and its rapid global spread has led to an unprecedented global public health crisis.
Currently, treatment options are very limited and vaccines against SARS-CoV-2 are still pending widespread
use. Host immune responses to SARS-CoV-2 play a crucial role in the containment of the infection. Although
SARS-CoV-2 is generally thought of as a respiratory disease, an unexpected consequence is severe
complications of the gastrointestinal tract (GIT). Indeed, up to two-thirds of COVID-19 patients have some GIT
symptoms and several lines of evidence suggest a breakdown of the epithelial barrier resulting in widespread
inflammation.
 While recent studies in COVID-19 patients and nonhuman primate (NHP) models described T lymphocytes
and antibody responses, less is known about natural killer (NK) cell responses in SARS-CoV-2 infection.
Classically, NK cells are viewed as nonspecific effector cells of the innate immune system that play critical roles
in defense against viral infections. However, besides their ability to rapidly eliminate virus-infected cells without
the need for prior antigen sensitization, NK cells also exhibit adaptive immune functions. Different forms of
adaptive capabilities have been identified among human NK cell subpopulations, including reports of true
antigen-specific memory NK cells as well as adaptive NK cells with enhanced antibody-dependent functions. NK
cells may be crucial for early containment of SARS-CoV-2 and formation of adaptive responses elicited by
infection, yet uncontrolled NK response may also contribute to the hyperinflammatory responses observed in
COVID-19 patients, including in the GIT. In this proposal we will use NHP models, which recapitulate viral
replication, immune responses and disease pathology observed in human COVID-19 infection, to test the
following hypotheses: (i) pathogenic inflammation in the gastrointestinal tract in COVID-19 is a
consequence, in part, of dysregulated or exacerbated NK cell responses, and (ii) specific subsets of NK
cells mediate potent anti-viral responses against SARS-CoV-2, associated with enhanced viral clearance
and reduced disease severity. We will address these hypotheses through two specific aims: 1. Determine the
contribution of systemic and GIT NK cell mobilization to SARS-CoV-2 pathogenesis and clearance in macaque
models; 2. Evaluate the mechanisms by which specific innate and adaptive NK cell subpopulations modulate
SARS-CoV-2 infection in the GIT. If successful, the results of these innovative studies will contribute new
knowledge of human immune responses against SARS-CoV-2 and provide the rationale to develop novel
immunotherapeutic approaches to target specific NK cell subsets that could substantially contribute to prevent
and treat COVID-19.

## Key facts

- **NIH application ID:** 10319735
- **Project number:** 1R01DK130472-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Roger Keith Reeves
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $402,500
- **Award type:** 1
- **Project period:** 2021-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10319735

## Citation

> US National Institutes of Health, RePORTER application 10319735, NK cell mobilization as a pathogenic etiology of SARS-CoV-2 gastrointestinal disease (1R01DK130472-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10319735. Licensed CC0.

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