Research Interests
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.
Respiratory viruses
Viruses that infect the human respiratory tract have been a major focus of the lab since its inception. We have a long-standing interest in pneumoviruses, which are a family of enveloped negative-sense RNA viruses that includes human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV). We have determined structures of the attachment and fusion proteins, often in complex with monoclonal antibodies and fusion inhibitors, and determined the first structure of the RSV polymerase complex. Our prefusion-stabilized glycoproteins are in various stages of clinical development, as are antibodies that we helped isolate and characterize. We have also worked extensively on coronaviruses and helped determine the first structure of a human coronavirus spike glycoprotein (HKU1). This structure enabled us to design prefusion-stabilizing proline substitutions, which were eventually incorporated into all COVID-19 vaccines authorized for use in the United States. We also work on paramyxoviruses, such as respirovirus 3 (parainfluenza virus 3). For all these pathogens, understanding the entry process at a molecular level is a major focus of our work.
Emerging viruses
There is an urgent need to study viruses that have the potential to cause epidemics or pandemics and begin laying the foundation for the development of medical countermeasures. A molecular understanding of the structure and function of viral surface proteins and their interactions with host-cell receptors and antibodies is critical to the prototype pathogen approach to pandemic preparedness. We have focused on NIAID Category A Priority Pathogens such as bunyaviruses, particularly Crimean-Congo hemorrhagic fever virus (CCHFV), that use class II viral fusion protein complexes for entry into the cell. We have determined some of the first structures of CCHFV glycoproteins and contributed to the isolation and characterization of large panels of human antibodies. We also continue to work on Category C paramyxoviruses, such as Nipah and Hendra virus, as well as tickborne flaviviruses. We have on-going projects involving structure-based vaccine design, antibody isolation and characterization, and development of small-molecule antivirals.
Bacterial pathogens
We are interested in the application of structure-based vaccine design principles to bacterial pathogens, particularly in light of the increasing threat of antibiotic-resistance. Whereas many of the viruses that we study have only 1 or 2 proteins of interest for vaccine development, bacteria can have tens to hundreds of possible vaccine antigens. Our goal here is to define the molecular basis for the mechanism of action of bacterial virulence factors that are secreted or surface-exposed and use this information to down-select and engineer these proteins for use in vaccines. We are currently focusing our efforts on Bordetella pertussis, the causative agent of whooping cough. To date, we have determined the structure of the RTX blocks from the adenylate cyclase toxin (ACT) in complex with its receptor, integrin αMβ2. We also engineered a minimal form of ACT containing RTX blocks 1-3, which is sufficient for integrin binding and binds known neutralizing antibodies. We continue to investigate ACT and its mechanism of cell intoxication, as well as other virulence factors for incorporation into next-generation pertussis vaccines.