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
City
State
Country
Zip Code
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
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
Lu, Mingfang; Varley, Alan W; Munford, Robert S (2013) Persistently active microbial molecules prolong innate immune tolerance in vivo. PLoS Pathog 9:e1003339
Shao, Baomei; Munford, Robert S; Kitchens, Richard et al. (2012) Hepatic uptake and deacylation of the LPS in bloodborne LPS-lipoprotein complexes. Innate Immun 18:825-33
Shao, Baomei; Kitchens, Richard L; Munford, Robert S et al. (2011) Prolonged hepatomegaly in mice that cannot inactivate bacterial endotoxin. Hepatology 54:1051-62
Lu, Mingfang; Munford, Robert S (2011) The transport and inactivation kinetics of bacterial lipopolysaccharide influence its immunological potency in vivo. J Immunol 187:3314-20
Suffredini, Anthony F; Munford, Robert S (2011) Novel therapies for septic shock over the past 4 decades. JAMA 306:194-9