Hung Ton-That, Ph.D.

Hung Ton-That received a B.S. degree in Chemistry in 1996 and a Ph.D. degree in Microbiology in 2000 from UCLA. His graduate work aimed to elucidate the mechanism of sortase-catalyzed cell wall anchoring of surface proteins in Staphylococcus aureus. He moved to the University of Chicago for his postdoctoral studies investigating the mechanism of pilus assembly in Gram-positive bacteria. Between 2004 and 2018, he held faculty positions at the University of Connecticut Health Center and the University of Texas McGovern Medical School, continuing his studies of Gram-positive pili and their role in biofilm formation and bacterial pathogenesis. In July 2018, he joined the faculty of the Division of Oral and Systemic Health Sciences at the UCLA School of Dentistry. His research program currently focuses on the molecular assembly on the cell surface of Gram-positive pathogens, oxidative protein folding in these monoderms, and virulence mechanisms of the Gram-negative Fusobacterium nucleatum, and development of novel anti-infective strategies.

Research and Interests

The laboratory primarily focuses on three major areas of research, aiming to elucidate the molecular mechanisms of pathogenicity by Gram-negative and Gram-positive pathogens. We employ a multidisciplinary approach combining classical and modern techniques that include genetics, various biochemical methods, electron microscopy, electron cryo-tomography, X-ray crystallography, biophysics, mass spectrometry, cell-based assays, and rodent models of infection.

1. Virulence Determinants of Fusobacterium nucleatum
The Gram-negative pathogen F. nucleatum is a key colonizer in the development of oral biofilms and well known for its association with human diseases including oral infections, preterm birth, and colorectal cancer. F. nucleatum has an inherent ability to interact with many early and late colonizers of the oral biofilms. It induces inflammatory responses and preterm birth in rodent models of infection, as well as promoting colorectal carcinogenesis in vivo. Despite its pathogenic potential, we have limited knowledge about the mechanisms of fusobacterial virulence and associated factors. A major obstacle limiting progress is the lack of robust genetic tools and systematic investigations. We have begun to tackle this problem with multiple complementary approaches including forward and reverse genetics, cryo-electron tomography, biochemical methods, and rodent models of infection. We are currently characterizing novel factors and pathways resulted from these experimental approaches that affect bacterial virulence and fitness, promotion of colorectal cancer, and induction of autophagy.

2. Molecular assembly on the cell surface of Gram-positive bacteria​
Gram-positive pathogens assemble on their surface covalently linked protein polymers known as pili or fimbriae that enable these bacteria to adhere to specific host tissues and initiate a pathogenic program. A typical pilus contains a major pilin forming the shaft and one or more minor pilin subunits. The heteromeric pilus is assembled by tandem transpeptidase enzymes called sortases. A pilus-specific sortase catalyzes the extension of pilus heteropolymers. The product of this cyclic polymerization is handed directly to the housekeeping sortase SrtA, which completes the assembly process by anchoring the resulting pilus polymer to the bacterial peptidoglycan. Despite significant advances in our understanding of pilus biogenesis, key aspects of this biphasic assembly pathway remain unresolved. We recently identified a conserved transmembrane protein, named SafA, that preserves SrtA membrane homeostasis by preventing its cleavage by the signal peptidase LepB2. Current research in the lab focuses on: (1) elucidating the antagonistic mechanism of SafA-mediated topological modulation of sortase function in polymicrobial interaction and biofilm formation in A. oris, (2) determining the evolutionary conservation of this-SafA-associated mechanism and the co-evolution of SafA with class E sortases throughout the Actinobacteria, and (3) defining how SafA-dependent regulation of sortase function influences A. oris coaggregation with Porphyromonas gingivalis (Pg) and contributes to Pg virulence.

3. Anti-infective strategies against Helicobacter pylori and Fusobacterium nucleatum 
​Gastric cancer remains one of the leading causes of cancer-related mortality worldwide and represents a compelling example of infection-driven carcinogenesis. Among the microbial species associated with gastric cancer, H. pylori and F. nucleatum are prominent Gram-negative pathogens that contribute to disease initiation and progression through distinct yet overlapping virulence mechanisms. Our research integrates structural biology, chemical biology, and structure-based drug design to identify and target conserved pathways shared by these pathogens. By developing inhibitors that disrupt essential bacterial functions, we aim to establish novel anti-infective strategies that mitigate microbial virulence and reduce the burden of infection-associated cancers.