GENETIC REGULATION OF IMMUNE HOMEOSTASIS IN THE COLLABORATIVE CROSS

Variation in immune homeostasis, the state in which the immune system is maintained in the absence of stimulation, is highly variable across populations. This variation is attributed to both genetic and environmental factors. However, the identity and function of specific genes and gene networks contributing to immune homeostasis are largely unknown. We used the Collaborative Cross (CC) mouse genetic reference population to investigate the role of host genetics in both systemic and tissue specific measures of immune homeostasis. Across multiple studies and experimental populations, we showed that aspects of systemic and tissue specific immune homeostasis are highly heritable and identified several quantitative trait loci (QTL) associated with various immune cell populations and serum antibody levels. We identified a novel gene, Mbd1, as a regulator of systemic immune homeostasis using a knockout and allele swap mouse model. We extended the analysis of mapped QTL using computational methods to show additional relationships with other phenotypes, including influenza A virus (IAV) and SARS-CoV-2 (SARS2) induced disease metrics. Overall, this work provides valuable insights into the genetic regulation of immune homeostasis and how immune homeostasis further contributes to virus induced disease. Ultimately, understanding how immune homeostasis is genetically regulated and relationships between immune homeostasis and virus induced disease could allow for the identification of homeostatic predictors of disease and optimization of care post-infection.