Systems Approaches to Immunology in Acute COVID19, Monogenic Immune Disorders, and Childhood Development

Abstract

In recent years advances in immune profiling technologies have allowed us to generate data at anunprecedented scale, and interrogate human immune systems in ways that were not previously possible. In this dissertation, I use these approaches in three different contexts. First, I explore how the cells of the immune system respond to acute COVID-19 infection and how this depends on the severity of the disease. Using CITEseq, simultaneous profiling of surface markers and RNA in peripheral blood mononuclear cells, I identify differentially expressed gene expression programs associated with COVID-19 infection and gene expression programs associated with disease severity. In addition, I explore how phenotypes of memory Tcells including the clonal nature and exhaustion signatures are associated with severity of COVID-19 infection. Second, I address what it means to be immunologically healthy through a multi-omics study of a cohort of patients at the NIH clinical center with various monogenic Immune disorders. I identify supervised and unsupervised axes of immune health that can separate disease from healthy controls, and additionally track changes to the immune system as people age, showing the parallels between disease associated inflammation and aging associated inflammation. I verify the utility of these metrics in several contexts outside of the original cohort and show that the signatures reflect broad changes to various cells of the immune system. Last, I explore the development of the immune system in childhood and the maintenance of temporally stable gene expression patterns. In a cohort of children that was tracked longitudinally over six years in Nicaragua, I utilize whole blood transcriptomics to explore both how the immune system changes as children grow older and which aspects of the immune system show large amounts of individuality or persistent inter-subject variation in their levels. I show that persistent inter-subject variation in gene expression and cellular frequencies is quite pronounced throughout childhood and attempt to identify when certain aspects of the immune system begin to stabilize in terms of their levels for an individual.