In a recent study published in Science Signaling, Northwestern scientists determined that a toxin secreted by Vibrio cholerae bacteria, the pathogen responsible for cholera, suppresses the body’s normal immune response to both the bacteria and the cell damage caused by its toxins.
Cholera is a diarrheal illness caused by consuming food or water contaminated with the Vibrio cholerae bacteria; it is seen most commonly in areas with inadequate water treatment, or poor sanitation and hygiene. It is classified as a noninflammatory disease – meaning it doesn’t provoke an inflammatory immune response like similar diseases.
The study, led by graduate student Patrick Woida, demonstrated that multifunctional autoprocessing repeats-in-toxin (MARTX) toxins enhance the virulence and colonization of V. cholerae by inhibiting the intestinal epithelial cells from signaling the recruitment of immune cells to kill the bacteria.
“MARTX toxin suppression of innate immune signaling protects the bacteria from being cleared from the intestines by host immune cells,” Woida said. “Therefore, V. cholerae strains that have MARTX toxins may be better equipped to colonize the intestine during infection.”
MARTX toxins act like bacterial “cluster bombs” that deploy multiple enzymatic toxins into a target cell all from a single protein. Furthermore, the study indicated how the enzymatic functions of MARTX toxins halt the inflammation caused by V. cholerae bacterial infection, resulting in the disease’s non-inflammatory designation.
“We found that the damage caused by the toxin itself is highly inflammatory, but the silencing of the immune system is so rapid, it even suppresses the inflammation caused by the toxin itself,” said Karla Satchell, PhD, professor of Microbiology-Immunology. “The overall effect is a disease that can rapidly progress without any defense from the human host.”
Satchell is Woida’s advisor in the Driskill Graduate Training Program in Life Sciences and is also a co-director of the Center for Structural Genomics of Infectious Diseases (CSGID), as well as a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Hypervirulent strains of V.cholerae, including those currently found in Yemen, Haiti and Africa, have natural mutations that alter the presence or absence and amount of different toxins produced, and thus can cause varying levels of inflammation, explained Satchell.
“The strains lacking MARTX toxin actually cause more tissue inflammation and damage that could contribute to worse outcomes,” said Satchell. “Inflammatory diarrhea can be particularly fatal.”
The study indicates that the specific nature of MARTX toxins produced by a particular V. cholerae strain must be considered when planning for treatment of outbreaks.
Woida noted that the multiple enzymatic activities of MARTX toxins also has implications beyond the disease cholera.
“This study shows that one activity can significantly impact the host response to another activity, which is how V. cholerae can damage cells with one function but suppress inflammation with another,” explained Woida. “MARTX toxins are also found in other foodborne bacterial pathogens such as Vibrio vulnificus, but toxins from these bacteria can have different sets of enzymatic activities than the ones found in the V. cholerae MARTX toxin. Therefore, insight gained from this study on how these different enzymatic functions interact may reveal which combination is most lethal to humans.”
This work was supported by the NIH Ruth L. Kirschstein Institutional National Research Service Award Training Grant in Immunology and Microbial Pathogenesis T32AI007476 and National Institutes of Health (NIH) grants R01AI092825 and R01AI098369.
