| Title: | Nox2 modification of LDL is essential for optimal apolipoprotein B-mediated control of agr type III Staphylococcus aureus quorum-sensing |
| Author(s): | Hall PR; Elmore BO; Spang CH; Alexander SM; Manifold-Wheeler BC; Castleman MJ; Daly SM; Peterson MM; Sully EK; Femling JK; Otto M; Horswill AR; Timmins GS; Gresham HD; |
| Address: | "Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, New Mexico, USA. phall@salud.unm.edu" |
| DOI: | 10.1371/journal.ppat.1003166 |
| ISSN/ISBN: | 1553-7374 (Electronic) 1553-7366 (Print) 1553-7366 (Linking) |
| Abstract: | "Staphylococcus aureus contains an autoinducing quorum-sensing system encoded within the agr operon that coordinates expression of virulence genes required for invasive infection. Allelic variation within agr has generated four agr specific groups, agr I-IV, each of which secretes a distinct autoinducing peptide pheromone (AIP1-4) that drives agr signaling. Because agr signaling mediates a phenotypic change in this pathogen from an adherent colonizing phenotype to one associated with considerable tissue injury and invasiveness, we postulated that a significant contribution to host defense against tissue damaging and invasive infections could be provided by innate immune mechanisms that antagonize agr signaling. We determined whether two host defense factors that inhibit AIP1-induced agrI signaling, Nox2 and apolipoprotein B (apoB), also contribute to innate control of AIP3-induced agrIII signaling. We hypothesized that apoB and Nox2 would function differently against AIP3, which differs from AIP1 in amino acid sequence and length. Here we show that unlike AIP1, AIP3 is resistant to direct oxidant inactivation by Nox2 characteristic ROS. Rather, the contribution of Nox2 to defense against agrIII signaling is through oxidation of LDL. ApoB in the context of oxLDL, and not LDL, provides optimal host defense against S. aureus agrIII infection by binding the secreted signaling peptide, AIP3, and preventing expression of the agr-driven virulence factors which mediate invasive infection. ApoB within the context of oxLDL also binds AIP 1-4 and oxLDL antagonizes agr signaling by all four agr alleles. Our results suggest that Nox2-mediated oxidation of LDL facilitates a conformational change in apoB to one sufficient for binding and sequestration of all four AIPs, demonstrating the interdependence of apoB and Nox2 in host defense against agr signaling. These data reveal a novel role for oxLDL in host defense against S. aureus quorum-sensing signaling" |
| Keywords: | "Animals Apolipoproteins B/*metabolism Bacterial Proteins/*metabolism Blotting, Western Disease Models, Animal Female Gene Expression Regulation, Bacterial Immunity, Innate Immunoassay Male Membrane Glycoproteins/*physiology Mice Mice, Inbred C57BL Mice, K;" |
| Notes: | "MedlineHall, Pamela R Elmore, Bradley O Spang, Cynthia H Alexander, Susan M Manifold-Wheeler, Brett C Castleman, Moriah J Daly, Seth M Peterson, M Michal Sully, Erin K Femling, Jon K Otto, Michael Horswill, Alexander R Timmins, Graham S Gresham, Hattie D eng R01 AI064926/AI/NIAID NIH HHS/ AI078921/AI/NIAID NIH HHS/ ZIA AI000904/ImNIH/Intramural NIH HHS/ R01 AI091917/AI/NIAID NIH HHS/ AI064926/AI/NIAID NIH HHS/ R01 AI078921/AI/NIAID NIH HHS/ UL1 TR000041/TR/NCATS NIH HHS/ AI091917-03S1/AI/NIAID NIH HHS/ UL1 TR001449/TR/NCATS NIH HHS/ AI000904-10/AI/NIAID NIH HHS/ AI090917/AI/NIAID NIH HHS/ T32 AI007538/AI/NIAID NIH HHS/ T32-AI007538/AI/NIAID NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 2013/03/06 PLoS Pathog. 2013 Feb; 9(2):e1003166. doi: 10.1371/journal.ppat.1003166. Epub 2013 Feb 14" |
