Adaptive Immunity and Persistent SARS-CoV-2 Replication

项目总结/文摘

Project Summary/Abstract The pandemic caused by the novel coronavirus, SARS-CoV-2 (SARS2) has so far infected greater than 3.5 million individuals and resulted in >138,000 deaths in the US. Although it has been suggested that adaptive immunity plays an important role in improving clinical outcomes of patients infected with SARS2, protective immune responses have not been specifically defined. Also, the variability in clinical disease and outcome in patients with SARS2 infection has not been explained based on qualitative and quantitative antiviral immune responses. Interestingly, a significant proportion of children with presumed deficits in immune competence secondary to cancer chemotherapy and hematologic disorders have been observed to shed virus from the upper respiratory tract for prolonged periods of time (>4 weeks), even after complete resolution of clinical symptoms. This finding raises the possibility that specific qualitative or quantitative deficits in adaptive immune responses in some individuals can result in incomplete control of virus replication and prolonged virus shedding. Therefore, an understanding of the immune responses that lead to control of virus shedding could help define correlates of protective immunity and perhaps more importantly, determine the potential value of vaccines to limit spread of SARS2 to unvaccinated populations. The major goal of our studies is to quantify adaptive immune responses to SARS2 in a cohort of children with varying levels immune responsiveness and to relate these responses to the control of virus shedding in the upper respiratory tract, thus allowing stratification immune reactivity and control of virus replication. Defining relationships between variations in immune competence and virus shedding could provide novel insight into the level and nature of adaptive immunity, more specifically antiviral antibodies, that can restrict or eliminate viral shedding in SARS2 infected patients. Our studies will also identify SARS2 variants that arise during poorly controlled virus replication in these patients as prolonged virus replication coupled with ineffective immunity offers an ideal opportunity for the generation of viral variants. Analysis of these variants in terms of the quality and quantity of SARS2 antibody responses will help elucidate the role of SARS2 sequence variation and persistent virus replication as a mechanism for prolonged virus replication. Together, these studies will test our hypothesis that variations in immune responsiveness contribute to prolonged viral replication and shedding.