Nox2 Modification of LDL Is Essential for Optimal Apolipoprotein B-mediated Control of agr Type III Staphylococcus aureus Quorum-sensing

PLoS Pathogens

Hattie D. Gresham¹  Seth M. Daly²  Cynthia H. Spang²  Jon K. Femling²  Susan M. Alexander²  Erin K. Sully²  Pamela R. Hall²  Bradley O. Elmore³  Alexander R. Horswill³  Graham S. Timmins³  M. Michal Peterson³  Michael Otto³  Moriah J. Castleman³  Brett C. Manifold-Wheeler³ 

[1] Department of Emergency Medicine, University of New Mexico, Albuquerque, New Mexico, United States of America;Department of Pharmaceutical Sciences, University of New Mexico College of Pharmacy, Albuquerque, New Mexico, United States of America;Research Service, New Mexico Veterans Affairs Health Care Service, Albuquerque, New Mexico, United States of America

关键词: Oxidation;    Staphylococcus aureus;    Virulence factors;    Lipoproteins;    Signal peptides;    Redox signaling;    Lipids;    Quorum sensing;   

DOI  :  10.1371/journal.ppat.1003166

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY