Diversity and Determinants of the Immune-Inflammatory Response to SARS-CoV-2

ASBTRACT OverviewEvery day, Californians continue to experience high levels of exposure to the novel severe acute respiratorycoronavirus 2 (SARS-CoV-2) virus. There is an ever-growing urgent need to better understand the nature ofexposures, course of illness and recovery, and potential for immunity among persons at particularly heightenedrisk for the worst COVID-19 outcomes. As part of a rapid scientific response to the present public health crisis,we convened on March 18, 2020 a collaborative of frontline clinicians and scientists to form the Coronavirus RiskAssociations and Longitudinal Evaluation (CORALE) studies (corale-study.org). We established two base studycohorts with enrollment centered on (i) patients with suspected or confirmed COVID-19 treated in our healthsystem (currently N>8,300) and on (ii) healthcare workers directly or indirectly involved in delivering their care(currently N=6,679). In response to NIH RFA-CA-20-038, we are now highly motivated and prepared to leverageour existing infrastructure to directly address the critical need for comprehensive longitudinal data collection andanalyses to advanced our understanding of SARS-CoV-2 risks, the course of disease, the nature of recovery,and the potential for immunity across populations at risk. By establishing the CORALE-SeroNet U54 program,our goal will be to form a robust and sustainable structure of academic activities centered on investigating theresponses elicited by SARS-CoV-2 exposure and the extent to which carefully phenotyped clinical and molecularprofiles can signal robust immune reconstitution and complete functional recovery. Our study will be centeredon the ethnically/racially diverse population served by our health system in Los Angeles, given then critical needfor more knowledge regarding the determinants of COVID-19 related risks in these minority subgroups. Ourscientific objectives will be achieved by an outstanding collaborative team of clinician-scientists, epidemiologists,immunologists, basic and translational scientists, analytical chemists, and biostatisticians. Leveraging ourcollective experience, resources, and infrastructure at major academic institutions from across SouthernCalifornia (Cedars Sinai, UCSD, UCLA, and USC), we will advance the scientific enterprise through the threedistinct yet closely integrated research Projects: Project 1 will elucidate the natural history and longitudinaltrajectories that represent the diversity of SARS-CoV-2 exposure, infection, recovery, and clinical immunitypatterns across the spectrum of persons at risk. Project 2 will investigate the determinants of SARS-CoV-2response in persons with altered innate immune function, with a focus on individuals with pre-infectionsusceptibility traits (e.g. metabolic disease states); and, Project 3 will investigate the determinants of SARS-CoV-2 response in persons with altered adaptive immune function, with a focus on individuals with immune-altered status arising from select malignancies, autoimmune disease, and/or their directed therapies. As a wholethis research program will integrate population, clinical, translational, and basic science resources with a world-class investigator team to meet the urgent need for new mechanistic insights and therapeutic approaches toaddress key knowledge gaps regarding SARS-CoV-2 susceptibility and potential for immunity.