Open AccessNox2 Modification of LDL Is Essential for Optimal Apolipoprotein B-mediated Control of agr Type III Staphylococcus aureus Quorum-sensing
Author(s) -
Pamela R. Hall,
Bradley O. Elmore,
Cynthia H. Spang,
Susan Alexander,
Brett C. Manifold-Wheeler,
Moriah J. Castleman,
Seth M. Daly,
M. Michal Peterson,
Erin K. Sully,
Jon Femling,
Michael Otto,
Alexander R. Horswill,
Graham S. Timmins,
Hattie D. Gresham
Publication year - 2013
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1003166
Subject(s) - context (archaeology) , quorum sensing , virulence , biology , innate immune system , staphylococcus aureus , signal transduction , phenotype , apolipoprotein b , microbiology and biotechnology , gene , immune system , genetics , bacteria , biochemistry , paleontology , cholesterol
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 agr I signaling, Nox2 and apolipoprotein B (apoB), also contribute to innate control of AIP3-induced agr III 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 agr III signaling is through oxidation of LDL. ApoB in the context of oxLDL, and not LDL, provides optimal host defense against S. aureus agr III 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.