System Biological Analyses of Innate and Adaptive Responses to Vaccination

ABSTRACTThe recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) pandemicposes a major global health challenge. Coronavirus disease (COVID-19) is caused by SARS-CoV-2 and represents the causative agent of a potentially fatal disease. Science has moved veryrapidly in isolating, sequencing, and cloning the virus, and developing diagnostic kits, within amatter of weeks. However, major knowledge gaps remain about the dynamic interaction betweenthe human immune system and the SARS-CoV-2. In particular, several fundamental questionsregarding its pathogenesis, and the mechanisms of protective immunity that need to be inducedby vaccination, remain unanswered. Learning how the immune system senses SARS-CoV-2infection and orchestrates protective immunity is critical for designing effective vaccines andtherapeutics. Our previous work using systems biology, multi-omics approaches to analyzeimmune responses to vaccination in humans has delineated molecular signatures of innateimmunity to vaccination and infection and have provided rich mechanistic insights into the immuneresponse1-7. In this proposal, we propose a site-specific study to analyze samples from theIMPACC sub-study performed at Emory. We will use an integrated multi-omics approach (singlecell transcriptomics, metabolomics, single cell epigenomics) to study innate immunity to COVID-19 infection in humans. We will obtain PBMCs and tracheal aspirate samples from the IMPACCsub-study that will be conducted at Emory. We will address the following questions: What are themolecular and cellular signatures of the immune response to COVID-19 infection in the blood andtracheal aspirates of infected subjects? Does COVID-19 infection exert an epigenetic imprint ofinnate immunity? What is the molecular landscape and function of myeloid cell subsets and airwayepithelial cells in the healthy lung, and following COVID-19 infection? These questions will beaddressed in the following specific aims: 1) Determine the single cell transcriptional andepigenetic landscape of the immune response to COVID-19 infection in blood and trachealaspirates, and 2) Determine the molecular identity and functions of myeloid cell subsets andepithelial cells in human lung and their response to COVID-19 infection. These studies will providesignificant insight into the human immune response to COVID-19 infection that can be leveragedfor designing vaccines and therapeutics to prevent or treat the infection.