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Principal Investigator: Jack T. Stapleton
Organization: IOWA CITY VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
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
critically needed. We hypothesize that SARS CoV-2 particles and spike protein interfere with TCR
signaling and that downstream TCR interference reduces T cell responses and skews T cell
differentiation, cytokine response, and memory depending upon the site(s) of signal interference. We
further suggest that viral Cov-2 T cell dysregulation contributes to altered antibody repertoire and
immune pathogenesis and evasion. We will address this hypothesis in three aims. First, we will characterize
T cell signaling pathways regulated by SARS CoV-2 particles and S protein in both focused TCR signaling
pathway studies and using unbiased transcriptomics approaches. Second, we will examine human antibody
repertoire following COVID or vaccination and correlate this with T cell functional readouts. Further, we will
determine the risk of immune evasion from variant Spike sequences. Finally, we will examine how CoV2 and
S protein skew T cell differentiation and evaluate the impact of disease severity and vaccine formulation on
TCR and memory responses following infection and vaccination. These studies will offer new insights into
CoV2 pathogenesis and immune evasion, and identify potential targets for novel antiviral targets.
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infection><COVID-19 years><COVID19 infection><COVID19 virus><CV-19><Calcium><Causality><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Function><Cell Interaction><Cell Physiology><Cell Process><Cell Protection><Cell Signaling><Cell-to-Cell Interaction><Cells><Cellular Function><Cellular Physiology><Cellular Process><Class I Genes><Clinical><CoV-2><CoV2><Complex><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Coronavirus Infectious Disease 2019><Cytoprotection><Data><Development><Disease><Disorder><Dose><Equilibrium><Etiology><Event><Functional impairment><Human><Humoral Immunities><Immune><Immune Evasion><Immune response><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunomodulation><In Vitro><Incubated><Infection><Inflammation><Inflammatory><Intracellular Communication and 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Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Severity of illness><Signal Induction><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Structural Protein><Study Type><Subcellular Process><T Cell Receptor Signaling Pathway><T cell differentiation><T cell regulation><T cell response><T memory cell><T-Cell Activation><T-Cell Antigen Receptors><T-Cell Proliferation><T-Cell Receptor><T-Cell Receptor Interaction><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><TCR Activation><TCR Interaction><Testing><Transphosphorylases><Vaccination><Vaccinee><Vaccines><Variant><Variation><Veterans><Viral><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Interference><Viral Proteins><Virion><Virus><Virus Diseases><Virus Particle><Wuhan coronavirus><activate T cells><acute disease/disorder><acute disorder><adaptive immunity><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after infection by 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