This proposal examines the role of the pro-resolving lipid mediators, resolvins, protectins, and maresins, in mycobacterial pathogenesis. These recently discovered lipids effectively combat sterile inflammation, but their role in infection-induced inflammation remains largely unexplored. Such an exploration seems particularly warranted for TB, which is increasingly recognized as a disease of excess as well as failed inflammation. Indeed, the use of the zebrafish has revealed a dual role for lipoxins in TB: pathogenic in excess, yet restoring resistance when administered pharmacologically in the setting of excess inflammation. Importantly, key aspects of these zebrafish findings have been validated in humans and should enter the clinical arena before long. It is very likely that the other pro-resolving mediators will play complex roles in TB that offer important therapeutic approaches. Thus, completion of these Aims will not only contribute to our understanding of how immunopathology is interwoven with mycobacterial pathogenesis, but also potentially suggest new treatments for diseases with an immunopathology component.
Susceptibility to tuberculosis (TB), which infects 1 in 3 people worldwide, can result from diametrically opposite inflammatory states: too little inflammation or too much. Recently discovered lipid mediators promoting the resolution of inflammation may effect susceptibility to TB. In those who respond to TB with excessive inflammation, these lipids and the pathways they stimulate may suggest a new source of TB treatments.
|Madigan, Cressida A; Cambier, C J; Kelly-Scumpia, Kindra M et al. (2017) A Macrophage Response to Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage in Leprosy. Cell 170:973-985.e10|