Innate immune control of virus replication and transmission

Abstract

The activation of innate immune pathways is a critical step in the response to virus infection. The failure of infected cells to control virus replication can lead to massive destruction of tissue, resulting in severe illness or death of the host and spread to new hosts. The ongoing coronavirus pandemic highlights the critical need to understand the mechanisms by which infected cells activate the innate immune response following virus infection, and how failure to activate this response leads to virus spread and cross-species transmission. Here, I describe two model systems used to understand the innate immune response to viruses. First, I use genetically engineered reporter influenza A viruses to identify infected cells and characterize the early response in vivo. I have found distinct responses based on the magnitude and round of infection, as well as cell type- and stage-specific antiviral signatures. In the second model system, I aim to understand the dynamics of how viruses transmit between hosts. I leveraged a model whereby pet store mice—which harbor a myriad of mouse pathogens—are co-housed with clean laboratory mice. This ‘dirty’ mouse model offers a platform for studying the acute transmission of viruses between hosts via natural mechanisms—through direct contact, air, and saliva and other fluids. I co-housed pet store mice with wild type laboratory mice and mice deficient in interferon receptors to characterize the role of these important innate immune pathways. Finally, I have co-housed laboratory mice with the bedding of pet store rats to analyze immune and non-immune species barriers to transmission. Overall, the findings of these studies will help elucidate mechanisms of innate immune activation by viruses.