Influenza and SAR-CoV-2 Vaccine Development
Our goal is to develop a new and more effective live-attenuated influenza vaccine (LAIV). The current LAIV is based on the internal genes of a "master donor virus" that is now 60 years old - and thus divergent from currently circulating influenza viruses. We hypothesize that the vaccine can be improved by updating this master donor virus, and that this can be achieved by inserting known attenuating mutations into the genetic background of contemporary influenza A viruses (including H1N1 pandemic strains). Our ultimate objective is to contribute to the development of a new universal influenza vaccine that leverages LAIV's superior ability to elicit T cell responses and to protect against infection by mismatched influenza viruses.
In parallel, we are also exploring whether LAIV can be used as a gene delivery vehicle to express subdomains from the Spike protein of SARS-CoV-2, the causative agent of COVID-19. The long-term objective of these studies is to develop a novel vaccine that can simultaneously elicit protective immunity against both influenza A virus and SARS-CoV-2.
Understanding Innate Host Immune Responses to Viral Pathogens
We are interested in innate immune responses in respiratory cells infected by influenza virus (including both wild-type virus and LAIV) and by human coronaviruses (including both minimally pathogenic human coronaviruses and SARS-CoV-2). These studies take advantage of sophisticated primary human respiratory cell culture models developed by Tom Mariani and colleagues, and are being conducted in collaboration with his laboratory, as well as Gloria Pryhuber and Juilee Thakar. We are collectively working to develop and refine gene network models, to identify key genes that may regulate differential responses to viral infection, and to determine how age and sex influence those responses.
Finally, we are also collaborating with Brandon Harvey, the Chief of the Molecular Mechanisms of Cellular Stress and Inflammation Unit at the National Institute on Drug Abuse (NIDA) to determine whether SARS-CoV-2 infection of target cells results in Endoplasmic Reticulum (ER) "Exodosis" (or the release of ER protein contents from the cell). This has been observed in other viral infections, including SARS-CoV-1, and may have important consequences (e.g., it may contribute to COVID-19 related comorbidities such as thrombosis).
(Added Note: Brandon is a former URSMD graduate student).
Small Molecule Therapeutics For Viral Pathogens (HIV and other viruses)
We are collaborating with Ben Miller, Clara Kielkopf and Joseph Wedekind to develop and test new first-in-class therapies that apply emerging concepts in RNA biology to the treatment of HIV infection. We are also working with Josh Munger, Isaac Harris and their colleagues to identify novel inhibitors of SARS-CoV-2, using a drug re-purposing strategy.