Time-resolved single-cell analysis of innate immune responses to SARS-CoV-2 infection in the upper respiratory tract

In response to viral infection, the host mounts immune defenses to protect itself and limit the spread of the virus. Our immune system's first line of defense is the interferon system, which is activated when cells first detect the presence of a virus and tell surrounding cells to mount protective defenses. People who activate the interferon response early are more likely to have asymptomatic SARS-CoV-2 infection. Yet, we don't understand why interferon is activated early enough to prevent disease in some people but not in others. Timing of both virus replication and host interferon responses is highly dynamic and variable, likely affecting the balance between control and spread of infection. In this proposal, I will use a novel sequencing technique that can measure the dynamics of virus replication and host interferon responses in human nasal epithelial cells. From this data, I will map the communication pathways between cells to determine how viral replication impacts interferon activation and signaling to alert and help neighboring cells resist infection. These studies will tell us why some patients have early, successful interferon-mediated control of SARS-CoV-2 infection. Given the importance of the interferon response for protection from all viruses, this knowledge can be harnessed to identify and develop novel antiviral strategies for SARS-CoV-2 and other respiratory virus infections.