Our Cutting Edge Research
Oral streptococci are a major cause of infective endocarditis (IE), a life-threatening infection of heart valves. In this project, we address the host-pathogen interactions that contribute to IE, with a focus on Siglec-like, serine-rich repeat (SRR) adhesins. The recognized target for these adhesins is platelets, which localize to inflamed heart valves. However, three adhesins that recognize different O-linked sialoglycans on the same GPIb receptor differ in their contribution to virulence. Because no current understanding of the pathogenesis of IE can explain this difference, we seek to use three strains that differ only in these adhesins to test a series of hypothesis about host-pathogen interactions that may contribute to virulence versus serve to protect the host. These hypotheses address how cardiovascular infections may be impacted by interaction with blood cells, a hemodynamic process called margination, platelet mechanotransduction, and bacterial regulation of various platelet functions.
This project is a multi-PI collaborative project with Paul Sullam (Microbiologist at UCSF) and Jose Lopez (Hematologist at Bloodworks NW).
Catch bonds are receptor-ligand interactions that can be stabilized by tensile mechanical force, in contrast to slip bonds, that become shorter lived under tensile force. In this project, we address mechanisms by which clusters of catch bonds can work together to produce various types of behaviors. Because cell function depends on multiple bonds, not single bonds, this research is critical to understanding how catch bonds contribute to cell functions such as adhesion, spreading, and migration.
This is a collaborative project with Mechanical Engineer Nate Sniadecki.
E. coli are a major cause of urinary tract infections, and the adhesin FimH is a virulence factor. FimH forms binds to mannosylated proteins in the commensal niches such as the mouth and intestines, as well as in pathogenic niches such as the urinary tract. FimH forms catch bonds with mannose due to a mechanically regulated allosteric conformational change, which appears to help the bacteria bind to immobilized mannose receptors in the presence of high fluid flow and soluble receptors. Remarkably, pathogenic strains of E. coli tend to have point mutations in FimH that modify the allosteric catch bonds to catch even without force. In this project, we study how antibodies inhibit FimH by regulating its conformation. We have discovered an “parasteric inhibitor” antibody that stabilizes an inactive form of the binding pocket and a “dynasteric inhibitor” antibody that blocks that dynamics of conformational changes. We seek to better understand the mechanisms and advantages of these novel forms of conformational inhibition.
This is a collaborative project with Microbiologist Evgeni Sokurenko, and Structural Biologists Rachel Klevit, Pearl Magala, and Ron Stenkamp.
SARS-CoV-2 is the causative agent of COVID-19, as most of us are all too aware. One of the challenges of COVID-19 is that infection is often accompanied by severe cytokine storms that produce high levels of systemic inflammation. SARS-CoV-2 can infect monocytes and macrophages through an ACE-2 independent pathway, leading to pyroptosis, which prevents replication in these immune cells but also contributes greatly to inflammation. We hypothesize that some antibodies can prevent infection of monocytes and macrophages due to their mechanisms of conformational regulation of the SARS-CoV-2 spike protein. We hope to therefore identify antibodies that can reduce inflammation during viral infection.
This is a collaborative project with virologist Stephen Pollyak and Immunologist Susan Fink.