Infections by microbial pathogens continue to be a major burden on global health. The Hang laboratory aims to better understand host-microbe interactions in order to prevent and treat infectious diseases. They are interested in developing new chemical approaches to functionally dissect how endogenous and environmental metabolites regulate host immunity and microbial pathogenesis, and in discovering and characterizing novel anti-infectives.
To elucidate specific mechanisms regulated by key metabolites, the Hang laboratory has developed chemical reporters to image and profile the biochemical targets of metabolites in bacteria, yeast, and mammalian cells. At the heart of this chemical approach is the design and synthesis of specific chemical reporters—metabolites bearing uniquely reactive groups—that can be chemically or enzymatically incorporated into biomolecules in vitro and in vivo and then selectively labeled with bioorthogonal imaging or affinity reagents. Using this strategy, a variety of chemical reporters based on important metabolites (nucleosides, amino acids, lipids, and other cofactors) have been developed for the sensitive detection and analysis of metabolite-protein modifications (short- and long-chain fatty-acylation, prenylation, AMPylation, and ADP-ribosylation).
The Hang laboratory has been especially interested in the protein targets of short- and long-chain fatty acids in host-microbe interactions. They have focused on understanding how fatty-acylation of specific proteins (IFITMs, TLRs) regulates host immunity, and how microbial pathogens co-opt or subvert these pathways for infection. Hang has also employed site-specific fluorophore labeling and photocrosslinking methods to functionally characterize specific cellular pathways. These studies highlight how chemical approaches can be used to explore and understand the mechanisms of host immunity and microbial pathogenesis.
To discover novel anti-infectives, the Hang lab is working to develop inhibitors of bacterial virulence pathways and to explore the protective mechanisms of beneficial bacteria. The type III protein secretion system (T3SS) is an important virulence mechanism for many Gram-negative enteric pathogens, but has thus far been challenging to specifically target with small molecules. Using a high-throughput assay for T3SS, Hang and colleagues discovered that specific medicinal plant metabolites (flavonoids) can covalently label and inactivate T3SS substrates to attenuate bacterial virulence. These researchers are continuing to explore these and other small molecule inhibitors.
To complement these studies, Hang has employed C. elegans as a model system for exploring the protective activity and complex mechanisms of specific commensal bacteria and probiotics. The lab has discovered that a secreted peptidoglycan hydrolase (SagA) from E. faecium is sufficient to trigger innate immune pathways, improve intestinal barrier function, and protect worms from enteric pathogens (S. typhimurium). Working with Rockefeller’s Daniel Mucida, they also showed that the SagA protection mechanisms are conserved in mice and can be used to enhance the activity of existing probiotics to prevent enteric infections, including C. difficile. With these studies, the Hang lab continues an ongoing effort to establish more efficient systems to discover and characterize novel anti-infectives.
Hang is a faculty member in the David Rockefeller Graduate Program, the Tri-Institutional M.D.-Ph.D. Program, and the Tri-Institutional Ph.D. Program in Chemical Biology.