Entry by the SARS-CoV-2 virus

(to be updated)

SARS-CoV-2 is the virus that causes COVID-19, a disease which has ballooned into a global pandemic and impacted the lives of billions. We are using molecular dynamics simulation methods to study the poorly understood mechanism this enveloped virus uses to invade host lung, nasal mucosa or small intestine cells. Entry of the virus is catalyzed by the surface spike S glycoproteins which cover the virus. The spike protein is a class I fusion protein, a remarkable machine that first binds target cells and then fuses the viral membrane coat with target cell membranes. Fusion requires the native S2 subunit to transit to its potent, fusogenic form, the fusion intermediate (FI). Understanding the entry mechanism will position us to propose and test new antiviral drug strategies with the exciting prospect of pan-coronavirus therapeutics. We work in close collaboration with the groups of Profs. Anne Moscona and Matteo Porotto at Columbia’s Medical School in the Department of Pediatrics to study how the fusion intermediate executes cell entry during infection as revealed by remarkable cryoelectron tomography imaging by Tara Marcink in the Moscona and Porotto labs.

Representative image of influenza virus (left). Schematic diagram of influenza hemagglutinin protein (center). Simulation snapshot of hemagglutinin transmembrane domains (right).

Influenza and other enveloped viruses

Combining experiment and mathematical modeling, we are trying to understand how other membrane-enclosed (enveloped) viruses such as influenza, HIV and ebola gain entry to host cells by fusing their membrane coats with target cell membranes. These pathogens use fusion mechanisms with remarkable parallels to the SNARE-driven mechanisms employed by cells. For example, influenza uses a fusion protein hemagglutinin (HA) that collapses into a cylindrically shaped complex similar to the SNARE complex. We have studied reconstituted influenza fusion systems experimentally, and we use analytical and computational theoretical models to simulate the pathways to infection.

© O'Shaughnessy Group 2018