iPSC-derived macrophages as a model to study the genetic basis of inter-individual variation in immune responses to pathogens

Project Summary Infectious diseases have always been a major health problem throughout the world, imposing a strong selective pressure on the human genome. Despite the recent advent of vaccines and antibiotics, infectious diseases cause near1y 15 million deaths every year. Although a significant proportion of inter-individual variation in susceptibility to microbes can be attributed to environmental factors, a substantial portion is also due to host genetic factors. The importance of host genetic factors on susceptibility to infectious diseases has been shown by comparative studies involving twins and adopted persons. Yet, very little is known about the underlying genetic factors contributing to differences in susceptibility to infectious diseases at the population level. In addition, the level of epigenetic variation across individuals and populations, and how such variations might impact susceptibility to infectious agents remains unknown. By combining expertise in functional genomics, computational biology, human immunology, population genetics, and infectious diseases, we aim to identify genes and regulatory pathways that contribute to variability of immune response to two of the deadliest infectious agents of our days: Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) in humans, and influenza virus. Specifically, we propose to leverage the power of induced pluripotent stem cells (iPSC)-derived macrophages to: (i) characterize inter-individual and inter-population variability in immune responses to infection with (Mtb) and influenza viruses in humans; (ii) study the contribution of epigenetic variation to inter-individual variation in immune responses; and (iii) map quantitative trait loci (QTL) that are associated with variation in the immune response to infection with Mtb and influenza, and evaluate the impact of natural selection at shaping their allele frequencies across populations. This work will yield unprecedented insight into the genetic and epigenetic basis underlying inter-individual variation in immune responses to two of the deadliest infectious agents of our days. Combined, these efforts will establish innovative, novel, and empirically grounded "immune profiling" strategies for identifying those most at risk for infectious diseases and other immune-related disorders, which together constitute one of the largest health burdens facing modern human populations.