The human body is under constant attack from bacteria, fungi, parasites, and viruses, all of which express proteins that are needed to establish infection and evade the human immune system. We seek to obtain structural information on these proteins and their interactions with host macromolecules and translate this knowledge into the rational development of therapeutic interventions such as small-molecule inhibitors, protective antibodies and stabilized vaccine immunogens. These efforts are highly collaborative and involve domestic and international investigators from academia, government, and industry.
Pneumoviruses are a family of enveloped negative-sense RNA viruses that includes human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV). Both viruses cause severe lower respiratory tract infections, particularly in young children and the elderly. Entry into host cells is facilitated by a mucin-like attachment glycoprotein (G) and a class I fusion glycoprotein (F) that mediates pH-independent fusion of the viral and host-cell membranes by undergoing a series of dramatic conformational changes down a free-energy gradient. Understanding the entry process at a molecular level is a major focus of our work. We also have on-going projects involving structure-based vaccine design, antibody isolation and characterization, and development of next-generation small-molecule fusion inhibitors.
Coronaviruses are a diverse family of enveloped positive-sense RNA viruses. Some coronaviruses, such as HCoV-OC43 and HCoV-HKU1, circulate annually in humans and generally cause mild respiratory disease, although the infections are more severe in infants and the elderly. In contrast, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) have caused epidemics with high fatality rates after their emergence from animal reservoirs. Host range is largely determined by the coronavirus spike (S), which is the largest known class I viral fusion glycoprotein. Like pneumovirus F proteins, the coronavirus S proteins are the primary targets of neutralizing antibodies and are a critical component of experimental coronavirus vaccines. One of our main goals is to provide a unifying structural framework for the function of coronavirus S proteins, including the mechanisms of receptor-induced triggering of membrane fusion. We are also leveraging the structural and mechanistic information to develop broadly protective antibodies and vaccines to combat current and emerging pathogenic coronaviruses.