Type I Interferons

Our lab has an interest in understanding type I interferon (IFN) responses. IFNs are a family of multifunctional cytokines that consists of 14 IFN-α subtypes (IFN-α) and single forms of IFN-β, IFN-ε, IFN-κ, and IFN-ω in mice. Their broad, pleiotropic properties include upregulating cell-intrinsic antiviral defense mechanisms, modulating proinflammatory cytokine production, and augmenting innate and adaptive cellular immune responses. Despite signaling through a single, shared receptor, the IFN subtypes have distinct properties, presumably due to different binding affinities and receptor dissociation rates for the individual IFN subtypes. Our lab and others have demonstrated that IFNs are essential to control alphavirus infection, including chikungunya virus (CHIKV). Despite their essential role in limiting CHIKV infection, little is known about the contributions of individual IFN subtypes to protection. To explore this question, we are using genetic deletion mutants and monoclonal antibody blockade to determine the differential functions of IFN-α and IFN-β during acute CHIKV infection.

Chikungunya virus

Chikungunya virus (CHIKV) is an arthritogenic alphavirus that acutely causes fever as well as severe joint and muscle pain. Chronic musculoskeletal pain persists in a substantial fraction of patients for months to years after the initial infection, yet we still have a poor understanding of what promotes chronic disease. While replicating virus has not been detected in joint-associated tissues of patients with persistent arthritis nor in various animal models at convalescent time points, viral RNA is detected months after acute infection. To study chronic CHIKV, we developed a system to visualize and isolate cells that survive CHIKV infection. Using this novel approach, we are currently investigating the nature of the viral RNA that persists, the transcriptional profiles of the cells that survive CHIKV infection, and the contribution of these cells to chronic CHIKV pathogenesis.

Fibroblast Growth Factors and Influenza virus

Influenza A virus (IAV) causes both devastating pandemics and seasonal epidemics resulting in significant morbidity and mortality worldwide. Unfortunately, evolutionary mechanisms of IAV, including high mutation rate and gene reassortment, often render antivirals ineffective at controlling infection in patients. Influenza viruses primarily infect differentiated respiratory epithelial cells; therefore, a mechanistic understanding of how the lung epithelium regulates IAV replication is critical to aid in the design of alternative treatments for severe infection. Nearly every tissue, including the lung epithelium, expresses multiple Fibroblast Growth Factors (FGFs), which regulate tissue development, cell maintenance, and repair. Recently, several studies and our own preliminary data have demonstrated that specific FGFs can regulate the epithelial or immune responses to IAV infection, or regulate repair of the damaged lung epithelium after IAV infection is cleared. We are interested in exploring the mechanisms of how specific FGFs may protect lung epithelial cells from IAV infection and leveraging these insights to propose potential therapies for severe IAV disease.

Images from the Lab

Interferon Stimulated Gene 15

The host response to viral infection is complex and must balance inhibiting replication with limiting damage to the host. A key mediator of the host response to viral infection are type I interferons and the hundreds of interferon stimulated genes they induce. Among these, the ubiquitin-like protein ISG15, functions as an antiviral protein, limiting replication of many viruses. Our studies have demonstrated that ISG15 can also regulate the host response and recovery from viral infection, independent of any effects on viral replication, a process known as disease tolerance. During respiratory viral infection we have detected increased epithelial damage in both cells and mice lacking ISG15. Ongoing efforts to understand these disease tolerance mechanisms have revealed that ISG15 can interact with cellular machinery known as the necrosome to regulate a type of programmed cell death known as necroptosis. Understanding the mechanism by which ISG15 protects the host from viral infection, both through inhibition of viral replication and by limiting the damage induced to the host may lead to the development of therapies that target this pathway and can be used for the treatment of acute viral infections.