title: TCA cycle inactivation in Staphylococcus aureus alters nitric oxide production in RAW 264.7 cells.
abstract: Inactivation of the Staphylococcus aureus tricarboxylic acid (TCA) cycle delays the resolution of cutaneous ulcers in a mouse soft tissue infection model. In this study, it was observed that cutaneous lesions in mice infected with wild-type or isogenic aconitase mutant S. aureus strains contained comparable inflammatory infiltrates, suggesting the delayed resolution was independent of the recruitment of immune cells. These observations led us to hypothesize that staphylococcal metabolism can modulate the host immune response. Using an in vitro model system involving RAW 264.7 cells, the authors observed that cells cultured with S. aureus aconitase mutant strains produced significantly lower amounts of nitric oxide (NO(•)) and an inducible nitric oxide synthase as compared to those cells exposed to wild-type bacteria. Despite the decrease in NO(•) synthesis, the expression of antigen-presentation and costimulatory molecules was similar in cells cultured with wild-type and those cultured with aconitase mutant bacteria. The data suggest that staphylococci can evade innate immune responses and potentially enhance their ability to survive in infected hosts by altering their metabolism. This may also explain the occurrence of TCA cycle mutants in clinical S. aureus isolates.
authors.affiliation: School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Room 202, Bldg VBS, Lincoln, NE 68583, USA.
authors.forename: Chandirasegaran
authors.initials: C
authors.lastname: Massilamany
authors.forename: Arunakumar
authors.initials: A
authors.lastname: Gangaplara
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Gardner
authors.forename: James M
authors.initials: JM
authors.lastname: Musser
authors.forename: David
authors.initials: D
authors.lastname: Steffen
authors.forename: Greg A
authors.initials: GA
authors.lastname: Somerville
authors.forename: Jay
authors.initials: J
authors.lastname: Reddy
mesh_terms: D000154:Aconitate Hydratase / Q000235:genetics; D056704:Adaptive Immunity; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics; D002460:Cell Line; D002952:Citric Acid Cycle; D018920:Coculture Techniques; D015870:Gene Expression; D055786:Gene Knockout Techniques; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D054884:Host-Pathogen Interactions; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013207:Staphylococcal Skin Infections / Q000378:metabolism* / Q000473:pathology; D013211:Staphylococcus aureus / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D014456:Ulcer / Q000382:microbiology / Q000473:pathology; D014774:Virulence
chemical_list: D015703:Antigens, CD; D001426:Bacterial Proteins; D000949:Histocompatibility Antigens Class II; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D051195:Toll-Like Receptor 2; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D000154:Aconitate Hydratase