Recent Findings Open New Avenues for Antimicrobials and Vaccine Development
Scientists in the Department of Biophysics have discovered a new mechanism for microbial pathogens to sense and respond to host environmental pH and enhance the production of extracellular vesicles. These spherical nanometer-sized structures originate from the bacterial outer membrane and play key roles in cellular homeostasis, host-pathogen interactions, interbacterial communication, and pathogenesis. Moreover, they represent an attractive platform for biotechnology applications such as vaccine development and drug delivery. The study was published in Nature Communications.
"Despite their importance, a comprehensive mechanistic understanding of extracellular vesicle biogenesis remained elusive," says Francesca Marassi, PhD, senior author of the study and professor and chair of the Department of Biophysics at the Medical College of Wisconsin. "Our findings provide a new way to understand how bacterial surface proteins can regulate vesicle formation and microbial virulence."
To characterize how the salmonella surface protein PagC promotes bacterial cell vesiculation in the mildly acidic intravacuolar environment encountered by the bacteria upon host cell invasion, Marassi and her colleagues performed lipid analysis of the bacterial vesicle membrane, mutational analyses of the PagC protein, cellular assays of vesicle production, and computational simulations that allowed them to visualize PagC in the context of the bacterial membrane. This work revealed that PagC contains pH-sensitive sites that respond to environmental pH by altering the protein conformation from an elongated tube to a wedge-like cone. This exerts differential pressure on the bacterial membrane leading to membrane curvature and vesiculation. Mutation of the pH-sensitive sites of PagC negates pH responsiveness and vesiculation. This information will facilitate the development of PagC as a target for antimicrobial drug development.
Additional authors of the study include Gopinath Tata, PhD, assistant professor of Biophysics the Medical College of Wisconsin; Ruchika Dehinwal, PhD, and Matthew K. Waldor, MD, PhD, at Brigham and Women’s Hospital and Howard Hughes Medical Institute; Richard D. Smith, PhD, and Robert K. Ernst, PhD, at the University of Maryland, Baltimore; and Dieter M. Schifferli, PhD, Dr. med. vet., at the University of Pennsylvania.
The study’s DOI is 10.1038/s41467-024-51364-z
The research was supported by the US National Institutes of Health (GM118186, AI139982, AI042347, AI147314).