Grant: Project Grant

Neisseria gonorrhoeae is considered an urgent threat to global health due to recent dramatic increases in the number of infections, both within Canada and globally, and the emergence of multi-drug resistant 'superbug' strains that are resistant to treatment. While trying to understand why gonorrhea increases the transmission of HIV-1 between sexual partners, we discovered that N. gonorrhoeae releases a class of small sugar metabolites called heptose phosphates (HPs) that trigger an inflammatory response by human cells. Humans do not produce HPs, so its presence within tissues is a clear signal of infection. Nearly all gram-negative bacteria produce HPs, yet these sugars are retained within their cytoplasm and thereby avoid alerting the immune system; Neisseria are unique in that they actively shed HPs. Beyond being immune stimulatory, neisserial release of HPs is unexpected because it is energetically expensive to produce these metabolites and then shed them. A possible explanation for this activity was revealed when we compared the inflammatory response of human or mouse cells that are unable to express TIFA, the protein that we discovered to be critical for the detection of HPs. While these cells are no longer able to detect purified HPs, they counter-intuitively have an exacerbated response to N. gonorrhoeae, suggesting that the cellular response to HPs turns down inflammation during infection. This research program aims to test the hypothesis that HPs misdirect the immune response in a manner that facilitates the establishment and persistence of infection in humans, and explains why gonococcal infection does not elicit an immune memory response that should protect individuals from being reinfected by this pathogen. Once we understand this process, then we will exploit it to combat neisserial infections and, more broadly, use it to suppress the overzealous inflammatory response that occurs during infection, autoimmunity and other conditions.