title: Host inactivation of bacterial lipopolysaccharide prevents prolonged tolerance following gram-negative bacterial infection.
abstract: A transient state of tolerance to microbial molecules accompanies many infectious diseases. Such tolerance is thought to minimize inflammation-induced injury, but it may also alter host defenses. Here we report that recovery from the tolerant state induced by Gram-negative bacteria is greatly delayed in mice that lack acyloxyacyl hydrolase (AOAH), a lipase that partially deacylates the bacterial cell-wall lipopolysaccharide (LPS). Whereas wild-type mice regained normal responsiveness within 14 days after they received an intraperitoneal injection of LPS or Gram-negative bacteria, AOAH-deficient mice had greatly reduced proinflammatory responses to a second LPS injection for at least 3 weeks. In contrast, LPS-primed Aoah- knockout mice maintained an anti-inflammatory response, evident from their plasma levels of interleukin-10 (IL-10). LPS-primed Aoah-knockout mice experiencing prolonged tolerance were highly susceptible to virulent E. coli challenge. Inactivating LPS, an immunostimulatory microbial molecule, is thus important for restoring effective host defenses following Gram-negative bacterial infection in animals.
authors.affiliation: Infectious Disease Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9113, USA. mingfang.lu@utsouthwestern.edu
authors.forename: Mingfang
authors.initials: M
authors.lastname: Lu
authors.forename: Alan W
authors.initials: AW
authors.lastname: Varley
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Ohta
authors.forename: John
authors.initials: J
authors.lastname: Hardwick
authors.forename: Robert S
authors.initials: RS
authors.lastname: Munford
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism*; D006090:Gram-Negative Bacteria / Q000276:immunology*; D016905:Gram-Negative Bacterial Infections / Q000201:enzymology* / Q000276:immunology* / Q000382:microbiology; D054884:Host-Pathogen Interactions; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000097:blood; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D000907:Antibodies, Bacterial; D008070:Lipopolysaccharides; D016753:Interleukin-10; D002265:Carboxylic Ester Hydrolases; C048964:acyloxyacyl hydrolase
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