The purpose of the project is to find out how microbial molecules, such as bacterial lipopolysaccharides, induce the accumulation of triglycerides (i.e., fat droplets) in macrophages. This process is important for the pathogenesis of the foamy macrophages that are found at sites of infection (especially within granulomas) and in arterial walls (where macrophages contribute substantially to atherosclerosis). In FY 2013 we showed that inactivation of microbial lipopolysaccharides (LPS) can be required for animals to recover from the innate immune tolerance that follows exposure to Gram-negative bacteria. When wildtype mice are exposed to small parenteral doses of LPS or Gram-negative bacteria, their macrophages become reprogrammed (tolerant) for a few days before they resume normal function. Mice that are unable to inactivate LPS, in contrast, remain tolerant for several months;during this time they respond sluggishly to Gram-negative bacterial challenge, with high mortality. We showed that prolonged macrophage reprogramming is maintained in vivo by the persistence of stimulatory LPS molecules within the cells'in vivo environment, where nave cells can acquire LPS via cell-cell contact or from the extracellular fluid. The findings provide strong evidence that inactivation of a stimulatory microbial molecule can be required for animals to regain immune homeostasis following parenteral exposure to bacteria. Measures that disable microbial molecules might enhance resolution of tissue inflammation and help restore innate defenses in individuals recovering from many different infectious diseases

Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2013
Total Cost
$614,727
Indirect Cost
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State
Country
Zip Code
Bachovchin, Daniel A; Koblan, Luke W; Wu, Wengen et al. (2014) A high-throughput, multiplexed assay for superfamily-wide profiling of enzyme activity. Nat Chem Biol 10:656-63
Huang, Ying-ling; Morales-Rosado, Joel; Ray, Jessica et al. (2014) Toll-like receptor agonists promote prolonged triglyceride storage in macrophages. J Biol Chem 289:3001-12