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 and promote repair of injured tissue, but their role in inflammation caused by infection remains largely unexplored. Severity of tuberculosis can be increased by two diametrically opposed states: too little inflammation or too much. In both humans and M. marinum-infected zebrafish, a model for tuberculosis, those with high and low activity of leukotriene A4 hydroxylase (LTA4H) had increased infection severity. This was due to excessive production of pro-inflammatory leukotriene B4,causing excess TNF and inflammation in those with the high- LTA4H genotype. In the low-LTA4H genotype, excessive production of anti-inflammatory lipoxin A4 caused inadequate TNF, inhibiting protective inflammation.
In Aim 1, this proposal will identify resolvins, protectins, and maresins for the first time in zebrafish using mass spectrometry and determine if these lipids are regulated in response to M. marinum infection. To demonstrate similar functions of these lipids in zebrafish and mammals, their ability to inhibit neutrophil recruitment and TNF production will be assayed.
In Aim 2, low- LTA4H and high-LTA4H zebrafish will be generated using morpholino technology and injection of LTA4H transcript. After infection, pro-resolving lipid mediators will be administered to measure the effect of these lipids on hosts of each genotype. If pro-resolving lipid mediators attenuate M. marinum infection in high- LTA4H zebrafish, these lipids have great potential as new treatments for tuberculosis, as a stabilized resolvin analogue is currently in Phase II clinical trials. 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|