SARS CoV-2 Immune Evasion Mechanisms

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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.