Ton-That Lab

Gram-positive and Gram-negative bacterial pathogens employ a wide range of pathogenic strategies to not only thrive in diverse environments but also cause disease. Surface covalently-linked protein polymers known as pili or fimbriae are an example of virulence factors produced by Gram-positive bacteria that enable them to adhere to specific host tissues and initiate a pathogenic program. The laboratory uses the oral colonizers Actinomyces oris and Corynebacterium diphtheriae as experimental models to investigate the mode of pilus assembly and the role of pili in biofilm formation and bacterial pathogenesis. For instance, the lab has recently discovered a mechanism of how C. diphtheriae produces pilus polymers and how A. oris modulates spatial positioning of adhesive pili for cell-to-cell interactions. The lab also discovered that both C. diphtheriae and A. oris employ a thiol-disulfide oxidoreductase – an enzyme similar to protein disulfide isomerase found in mammalian cells – to maintain proper folding of pili and many exported factors. Serendipitously, the studies of surface assembly disclose a facile and versatile platform for protein engineering and bio-conjugation, as well as a high throughput screen for small molecules as anti-virulence strategies to target bacterial infections. While Gram-negative pathogens, like the oral colonizer Fusobacterium nucleatum, do not assemble covalently-linked pili, they produce surface organelles and exofactors that can manipulate the host immune response and cause tissue damage. Current efforts are being made in the lab to reveal virulence determinants and pathogenic strategies that allow F. nucleatum to flourish in the adverse environment of oral biofilms and to spread to extra-oral sites, such as placenta and colorectal tissue, leading to induction of preterm birth and promotion of colon cancer.