BIOREPOSITORY OPTIMIZATION AND USE FOR ENDOTYPING CRITICALLY ILL SARS-COV-2 INFECTED PATIENTS

Abstract. The New York City area has faced a surge of cases early on the COVID-19 pandemic in the United States leading to destabilization of multiple health care systems that could not keep up with the high demand for critical care use and mortality. The heterogenous evolution among critically ill COVID-19 patients, high mortality and prolonged ICU stay highlights the need to better understand individual's endotype that could expose treatable traits among these septic patients. As the first set of cases arrived to NYU, we built a biorepository of samples from the lower airways and blood from these critically-ill SARS-CoV-2 infected patients. We have already explored the lower airway microbial environment including the virome, bacteriome and host immune response. In our recent report using cross sectional lower airway samples from 142 critically ill COVID-19 patients published in Nature Microbiology we identified microbial and host signatures associated with poor outcome, predominantly driven by poorly controlled viral replication, blunted anti-Spike/anti-RBD IgG response and distinct host transcriptomic profile. However, in order to understand the mechanism underlying this poor viral control we need to study samples at earlier time points and longitudinally. We are currently using these samples to characterize the longitudinal viral and host transcriptome dynamics. However, the critical molecular immune mediators need to be explored using metabolomic approaches while the distinct cellular immune responses may require single cell approaches. In this application we will use our existing biorepository and expand it with new cases to test the hypothesis that airway and systemic endotyping with novel scRNA sequencing and metabolomic approaches predicts poor outcome in critically ill SARS-CoV-2 patients. Thus, we propose to expand and optimize our biorepository of airway and systemic samples in critically ill SARS-CoV-2 patients (R21 phase) in order to perform scRNA sequencing and metabolomic approaches in order to endotype the airway and systemic environment to evaluate for associations with poor clinical outcome (R33 phase). To accomplished these aims we will use our expertise in the characterization of the lower airway microbiome (including the viral fraction) and the host immune profile. Therefore, this is an unprecedented opportunity to conduct the necessary exploratory investigations on paired lower airway and systemic samples from critically ill COVID-19 patients. Lay summary. Acute COVID-19 infection has had unprecedented effects on human health with critically ill patients suffering high critical care resources and mortality. In this project, we will use and expand our biorepository of lower airway and blood samples to explore novel ways to determine molecular signatures that can predict patients' poor clinical outcomes.