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Influenza A virus (IAV) causes an acute respiratory disease, and is estimated to affect 50 million people annually in the United States alone. Among infected individuals, severity of disease varies greatly, from asymptomatic to severe and fatal cases. Likewise, efficacy of the IAV vaccine also varies across the population. Host genetic factors contribute to this variation, however they are challenging to study in humans due to the lack of experimental controls, biological replicates, and access to relevant tissues. We utilized the Collaborative Cross (CC), an experimentally tractable mouse genetic reference population, to study the role of host genetic variation in mediating disease and antibody response to IAV infection and vaccination. Through multiple experimental approaches, we demonstrated that heritable factors play an important role in driving host response to IAV, and genetically mapped quantitative trait loci (QTL) associated with variation in specific outcomes. We extended this analysis by considering relationships between QTL and other related phenotypes to gain further understanding of their breadth of effect and possible mechanisms. We also described a computational software tool to facilitate these types of analyses. Overall, this work provides valuable insights into the genetic regulation of host response to IAV, laying a framework of experimental design as well as a repository of QTL and data to benefit future studies in the CC and beyond. Ultimately, identifying specific genes that underlie variation in IAV infection and vaccine responses could drive optimized design of preventative and therapeutic care to improve global health.

Immune homeostasis is the state that the immune system maintains in the absence of insult. Perturbation of immune homeostasis can impact autoimmunity/allergy and adversely affect infectious responses. To date, much of the analysis of immune homeostasis has focused on systemic immunity, but it is also likely to be important in an organ specific manner. Since the lungs are a major site of environmental exposure and infection, we used the Collaborative Cross (CC) mouse genetic reference population to study the genetic regulation of the breadth of baseline immune cell populations in the lung and identify loci regulating these cells at homeostasis. We found that all 54 immune cell phenotypes measured showed strong genetic variation in cell type abundances. We identified 28 quantitative trait loci associated with variation in 24 immune cell populations or the relationship between cell populations. Further, we identified significant associations between 20 of these loci and responses to either influenza A virus (IAV) or Severe acute respiratory syndrome associated coronavirus (SARS-CoV) disease in the same strains of mice. Notably, a locus mapped for variation in Ly6C+ monocyte abundance was associated with SARS-CoV weight loss, as well as titer at days 2 and 4 post-infection. This locus is also associated with influenza-induced disease, as measured by weight loss post-infection. Our analysis highlights the strong genetic control of immune homeostasis, and the key role that immune homeostasis plays in contributing to downstream infectious responses. In particular, our analysis suggests that the abundance of a variety of lung leukocyte populations prior to infection could serve as predictors of immune responses to respiratory viruses.

Host genetic variation plays an important role in shaping infectious disease susceptibility. Noll et al. review the application of a genetically diverse mouse reference population, the Collaborative Cross, to study variation in disease response across multiple pathogens, highlighting advances in model development and genetic mapping. © 2019 Elsevier Inc.Host genetic variation has a major impact on infectious disease susceptibility. The study of pathogen resistance genes, largely aided by mouse models, has significantly advanced our understanding of infectious disease pathogenesis. The Collaborative Cross (CC), a newly developed multi-parental mouse genetic reference population, serves as a tractable model system to study how pathogens interact with genetically diverse populations. In this review, we summarize progress utilizing the CC as a platform to develop improved models of pathogen-induced disease and to map polymorphic host response loci associated with variation in susceptibility to pathogens.