Research

Viral interferon antagonists are proteins that block or delay the host immune response to infection. We identified coronavirus EndoU (also called nsp15) as an endoribonuclease that trims viral RNA. This trimming of the viral RNA delays sensing of virus by the host cell. We found that EndoU mutant viruses are highly attenuated in mice, yet elicit a protective immune response. We are investigating the role of EndoU and other conserved viral interferon antagonists in the replication of SARS-CoV-2, and studying how EndoU interacts with the viral replication machinery. Our studies will identify potential targets for developing inhibitors that would block replication of existing and emerging coronaviruses.

Coronaviruses proteases are required to cleave the viral replicase polyprotein and are attractive targets for developing antiviral therapies. We developed a cell-based biosensor that we use to evaluate coronavirus protease activity and screen for inhibitors. We collaborate with multiple groups to identify potential inhibitors of coronavirus proteases. We seek to identify inhibitors that can block the replication of existing and potentially emerging coronaviruses.

We are investigating the emergence of novel variants of concern of SARS-CoV-2 that may arise during the current pandemic. We use deep sequencing and bioinformatic analysis to identify viral variants that are present in immunosuppressed individual and patients with severe disease. These studies will contribute to our understanding of the diversity of the coronavirus sequences and identify pathogens associated with more severe disease.

I have a longstanding collaboration with outstanding physician-scientist Dr. Anne Rowley investigating the etiology and pathogenesis of Kawasaki Disease (KD). KD is an acute childhood disease that can result in coronary artery aneurysms and sudden death. Based on the epidemiology of KD, we hypothesize an infectious etiology and our work has focused on investigating the etiology and immune response in KD patients. We identified and characterized an antigen-driven immune response in KD patients, and found that KD patients recognize a novel amino acid sequence that may be part of a viral protein. We are extending these studies to identify additional proteins recognized by KD patients. The results of these studies will facilitate future development of specific diagnostic tests and therapies to treat this potentially fatal disease.