Project 2

ABSTRACT Infants and young children are at higher risk for severe manifestations of certain respiratory viruses, such as influenza and RSV, compared to older children or adults. Interestingly, SARS-CoV-2 infection has shown the opposite trend, with infants being at lower risk of serious outcomes. The molecular and cellular mechanisms underpinning vulnerability to some infections and protection from others are poorly understood, but intrinsic properties of the post-natal immune system might be at their core. Systems biology tools can resolve these knowledge gaps through detailed analysis of the transcriptome, epigenome and function of immune cell populations across the life span. This project capitalizes on our experience in studying the human immune system through childhood in health and disease, and the availability of immune monitoring assays for use with small-volume samples. Recently, we have leveraged innovative technologies, i.e., ATAC-seq for assessing chromatin accessibility, RNA-seq, high-definition cellular immunophenotyping at the bulk and single cell levels as well as custom-built integrative analysis pipelines. Our preliminary data confirm that we can maximally leverage infant samples to capture transcriptional and regulatory genome-wide signatures associated with the developing immune system in response to viral infections and vaccination with unprecedented granularity. We propose to assess the immune responses to infection with two viruses, influenza and SARS-CoV-2, occurring in the first six months of life by leveraging our immune profiling platform. We will track age-related changes in immune cell composition, transcriptome and epigenome during this first encounter with the virus and will subsequently monitor these parameters upon vaccination against these viruses yearly for a period of three years. Aim 1 will define the phenotype/cell composition, transcriptome and epigenome of infant PBMCs upon their first encounter with either Influenza or SARS-CoV-2 viruses. Aim 2 will Characterize the PBMC phenotype/cell composition, transcriptome and epigenome in response to vaccination against influenza and SARS-CoV-2.