2022 Theses Doctoral
The landscape and interplay of antiviral immunity mounted against SARS-CoV-2 infection across tissues, age, and disease
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has proved to be the greatest global crisis of the 21st century and has led to a devastating state of human health and societal infrastructure. Such calamity was met with immense determination from the scientific community to uncover the immunological and virological basis of its accompanying disease and resulted in remarkable feats of public health response and therapeutic design. As SARS-CoV-2 continues to evolve and elicits a heterogenous disease presentation across different demographics, we aimed to define the circulating and tissue-localized immune memory generated following SARS-CoV-2 infection, as well as determine the immunological properties governing severe disease.
Using human tissues from seropositive organ donors, we showed that SARS-CoV-2-specific immune memory was present in circulation, lymphoid, and mucosal sites up to 6 months post infection. B and T cell populations mounted against SARS-CoV-2 showed significant correlations between circulating and tissue-resident memory lymphocytes, suggesting local and systemic tissue coordination of cellular and humoral immunity against SARS-CoV-2, set for optimal protection against future infectious challenges.
Next, we presented a comprehensive, longitudinal study of the peripheral blood immune system following pediatric SARS-CoV-2 infection and provided new insight on the immunological underpinnings of multisystem inflammatory syndrome in children (MIS-C). Acute MIS-C and pediatric COVID-19 differ in their effector module elicitation, activating opposing type 1 and type 2 immune responses respectively. We reveal that MIS-C presents with a unique peripheral T cell signature marked by activation, exhaustion, and tissue-residency at the proteomic and transcriptional level, along with a major Vβ-biased clonal expansion.
Despite the considerable immune dysregulation during acute disease, children recovered from MIS-C maintain stable humoral immunity up to 18 months post hospitalization at comparable levels to seropositive groups, and generate robust, functional T cell memory in greater magnitude than seropositive children. Together, we report a near-complete restoration in global T cell phenotype and function in children following MIS-C, as well as the robust production of competent SARS-CoV-2 specific memory.
Finally, following our queries into SARS-CoV-2-specific antiviral immunity, we sought to delineate the dynamics of human follicular immune responses and its role in generating and maintaining humoral immunity across a lifespan. Using healthy pediatric and adult donor tissues to examine blood, lymphoid, and mucosal tissues, our results reveal that TFH cells predominate the CD4+ T-cell memory pool in lymphoid sites in early life and decline in frequency with age. Further, pediatric and adult TFH cells differ in their functional capacities, with pediatric TFH cells expressing higher levels of markers associated with signal regulation and germinal center function, while adult TFH cells demonstrate a TH17-like identity. Further, early life TFH cells in lymphoid exhibit marked TCR repertoire overlap.
Together, these results indicate a differential propensity for follicular responses in early life and adulthood, with important implications in considering immunomodulatory strategies in different life stages.
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More About This Work
- Academic Units
- Microbiology, Immunology, and Infection
- Thesis Advisors
- Farber, Donna
- Ph.D., Columbia University
- Published Here
- September 7, 2022