Scientists led by Karla Satchell, PhD, the Anne Stewart Youmans Professor of Microbiology, have discovered previously unknown molecular mechanisms that help a type of foodborne bacteria recognize host cells and initiate infection at the cell surface, according to a recent study published in Science Advances.
Multifunctional autoprocessing repeats-in-toxin (MARTX) toxins are secreted by bacteria and support the spread of many Gram-negative bacteria, including Vibrio vulnificus, a lethal food-borne bacterium commonly found in raw or undercooked shellfish.
MARTX toxins use precise intracellular mechanisms to infiltrate host cells and cause life-threatening infections, as detailed in previous work led by Satchell. However, the mechanisms these toxins use to identify and recognize host cells have remained poorly understood.
“We wanted to understand the surface interactions and why this toxin is so pervasive,” said Satchell, who is also a professor of Microbiology-Immunology and director of the Center for Structural Biology of Infectious Diseases.
In the current study, the investigators used a combination of cellular techniques to map the small portion of the large MARTX toxin from Vibrio vulnificus that directly interacts with the surface of cells.
The scientists found this domain binds N-acetylglucosamine (GlcNAc) — an amino sugar and key building block of complex glycans on the exposed surfaces of epithelial cells — on N-glycans — sugar molecules that decorate proteins on the surface of the host cell — with select preference for the L1CAM protein and clusters of N-glycans on host cell surfaces.
“Different cell types have different kinds of sugars on them, and this is one way that toxins can discriminate one cell versus a different kind of cell,” Satchell said.
The scientists also found that this domain is essential for Vibrio vulnificus infection during intestinal infection.
“We showed for the first time that this ubiquitous N-glycan structural motif present on diverse host surfaces can be recognized by a virulence factor, which explains why MARTX toxin is so pervasive,” said Jiexi Chen, a graduate student in the Driskill Graduate Program in Life Sciences (DGP) and lead author of the study.
Future work, according to Chen, will include understanding the structure of how this protein binds to the glycan, as well as identifying other receptor binding domains that promote infection.
This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) grants R21 AI149061, R37 AI092825 and F31 AI172382; Danish National Research Foundation DNRF107; Novo Nordisk Foundation (NNF24OC0088218 and NNF21OC0071658) and Lundbeck Foundation (R223-2016-563); Northwestern Molecular Biophysics Training Program NIGMS T32 GM008382; European Molecular Biology Organization (EMBO) postdoctoral fellowship ALTF 105-2023; NEYE Foundation ID 24030064; and EMBO postdoctoral fellowship ALTF 336-2021.
