Local And Systemic Innate Immunity In Viral Infection And Transmission At Barrier Surfaces

Abstract

Viral infections are a source of significant morbidity and mortality. According to the World Health Organization, lower respiratory infections were the fourth leading cause of death globally from 2000-2019. Activation of the innate immune response is an essential step in combating viral infection. Failure of the immune response to control the infection can lead to widespread inflammation and damage within the host as well as transmission to new hosts. Understanding how viruses and hosts interact, both directly and indirectly during infection, is necessary to develop new treatments, understand intra- and inter-species transmission, and prepare for future zoonotic emergences. Furthermore, studying the broader implications of infection beyond the initial site of infection will help discern how highly pathogenic viruses cause more severe disease. Here, I describe two systems in which I explore local and systemic innate immune responses to viral infection. First, I discuss how respiratory influenza virus infection alters intestinal epithelial and innate lymphoid cell homeostasis. I found that infection drives increases in both tuft cells and type 1 and 2 innate lymphoid cells, with the type 2 increase being tuft cell-dependent and independent of the microbiome. Second, I leverage a natural rodent model where pet store animals – which harbor myriad of natural rodent pathogens – are cohoused with laboratory animals to study acute virus transmission, dissemination, and evolution. Using both wildtype and interferon-deficient animals, I evaluate the role of innate immunity in mitigating transmission and within host dissemination of viruses from a variety of viral families. I also report how this model can also be used to study cross-species transmission – including dead-end transmission events, which are invisible to many existing models. Altogether, this model establishes a foundation for which questions about transmission, evolution, and pathogenicity of different viruses within a host, between the same species, and between different species can be studied. Overall, the findings from these studies help inform how both local and systemic innate immunity contribute to the host response to viral infections.