# SARS CoV-2 Immune Evasion Mechanisms

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2022 · —

## Abstract

We propose to characterize SARS-CoV-2 interactions with human T cells and examine how this influences
adaptive and humoral immunity. SARS-CoV-2 (CoV2) is the etiologic agent of COVID-19, the third highly
pathogenic coronavirus to emerge as a human pathogen since 2000. CoV-2 causes disease by dysregulating
host inflammation and may lead to severe pulmonary inflammation, “cytokine storm” and other clinical
outcomes. Despite this immune-mediated pathogenesis, patients with severe COVID-19 paradoxically have
peripheral blood T cells that are not activated. Based on SARS CoV-1 and MERS, T cell responses are
delayed in development and relatively low in magnitude during infection. This, along with clear evidence that
CoV-2 is capable or reinfection and of causing “breakthrough” infection in vaccinated individuals raise
questions regarding CoV-2’s ability to elicit memory T cell responses. The T cell receptor (TCR) must interact
with antigens in the context of MHC class I or II to initiate a complicated cascade of signaling events. Following
TCR engagement, signaling leads to a variety of outcomes including T cell proliferation, development of
effector functions and differentiation. TCR signal strength (avidity and duration) following TCR stimulation is
critical for driving T cell fate, and lower TCR signal strength results in reduced T cell activation, proliferation
and effector responses with a reduction in long-term memory cells compared to higher signal strength
interactions. Low TCR signal strength also promotes a Th17 phenotype associated with autoimmunity and
inflammation. Many viruses have evolved mechanisms to interfere with T cell functions contributing to
replication and immune evasion. Our laboratory has studied how virus particles and structural proteins
interfere with TCR signaling in vitro and in vivo. Although T cell proliferation, differentiation, cytokine release
and ultimate T cell fate are driven by TCR signal strength, the role of viral interference in downstream signaling
has not been well studied. CD4+ T cell signaling equilibrium also supports development of high affinity B cells,
and dysregulated TCR signaling may contribute to an increase the proportion of low-affinity B cells leading to
reduced B cell protection. We have data showing that incubation of primary human T cells with CoV2 particles
or spike (S) protein dysregulates TCR signaling leading to skewing of T cell differentiation away from a Th1
cytokine response. This is mediated at least in part by the S protein activating ERK kinase, with resultant
reduced calcium flow and LAT aggregation following T cell stimulation. ERK is important in regulating the fate
of T cell differentiation, thus our findings provide novel insights into the autoinflammatory cytokine storm
induced during CoV2 infection. Since reinfection and breakthrough infections contribute to the ongoing
pandemic, studies designed to understand how SARS CoV-2 dysregulates T cell function represent are
critica...

## Key facts

- **NIH application ID:** 10485606
- **Project number:** 2I01BX000207-13A2
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Jack T. Stapleton
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2009-04-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10485606

## Citation

> US National Institutes of Health, RePORTER application 10485606, SARS CoV-2 Immune Evasion Mechanisms (2I01BX000207-13A2). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10485606. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*