# Defining the role of natural killer cells in COVID-19

> **NIH NIH F31** · STANFORD UNIVERSITY · 2024 · $11,693

## Abstract

PROJECT SUMMARY
Severe COVID-19 induces strong alterations in the peripheral immune system. Some immune cell types take
on a protective role in this disease, while others contribute to disease pathology. One cell type whose
functional role in COVID-19 is not yet known is the natural killer (NK) cell. I previously demonstrated that NK
cells, which can mediate antiviral activity, are strongly altered by severe COVID-19. I have also generated
preliminary data demonstrating that SARS-CoV-2 modulates the expression of ligands for the NK cell activating
receptor NKG2D and allows infected cells to avoid NK cell killing; however, the mechanisms underlying this
remain unexplored. Moreover, although the NK cells of COVID-19 patients are poor mediators of cytotoxicity
against tumor target cells, the functional responses of NK cells from COVID-19 patients to
SARS-CoV-2-infected cells have not been examined. The proposed research seeks to resolve these critical
gaps in our knowledge of the immune response to SARS-CoV-2 by investigating the mechanisms underlying
the phenotype and function of NK cells in COVID-19. To do this, I will 1) Define the mechanisms by which
SARS-CoV-2 modulates NK cell responses; 2) Characterize the functional responses of NK cells from
COVID-19 patients with a wide range of disease severities against target cells infected with SARS-CoV-2; and
3) Elucidate the role of monocyte-NK cell crosstalk in driving NK cell exhaustion in severe COVID-19. I
hypothesize that the experiments described in my proposal will show that prolonged stimulation of peripheral
NK cells by monocytes contributes to exhaustion in the NK cells of severe COVID-19 patients, driving poor
functional responses against SARS-CoV-2-infected target cells that are exacerbated by immune evasion
mechanisms mediated by SARS-CoV-2. To test this hypothesis, I will utilize NK cells and monocytes from a
large cohort of COVID-19 patients with disease severities ranging from mildly symptomatic to fatal. I will
perform functional assays that test the responses of these NK cells against target cells infected with
replication-competent SARS-CoV-2 in Stanford’s BSL3 facilities. I will also assess the ability of monocytes from
severe COVID-19 patients to induce activation and exhaustion in healthy NK cells by establishing a co-culture
system with these two cell types. Overall, my experiments will uncover the basis for the NK cell phenotype
observed in COVID-19, the effects of this phenotype on NK cell responses to SARS-CoV-2-infected cells, and
the mechanisms by which SARS-CoV-2 modulates the susceptibility of infected cells to NK cell cytotoxicity.
Thoroughly interrogating the responses of NK cells to SARS-CoV-2 will help to determine whether the role of
NK cells in COVID-19 is protective or pathological and will further our collective understanding of NK cell
biology. Moreover, the identification of receptors involved in the modulation of NK cell activation will inform the
development ...

## Key facts

- **NIH application ID:** 10868686
- **Project number:** 5F31AI172319-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Madeline Jane Lee
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $11,693
- **Award type:** 5
- **Project period:** 2022-06-06 → 2024-06-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868686

## Citation

> US National Institutes of Health, RePORTER application 10868686, Defining the role of natural killer cells in COVID-19 (5F31AI172319-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10868686. Licensed CC0.

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