Antibiotic resistant Staphylococcus aureus infections are emerging as a major public health threat in the US and around the world. Particularly problematic are methicillin resistant S. aureus (MRSA) infections of the USA300 and USA400 PFGE types that cause necrotic skin and lung infections. While progress has been made in elucidating the MRSA virulence factors that contribute to infection and their control by a quorum sensing operon, agr, very little is known about host factors that contribute to susceptibility. Typically, S. aureus causes opportunistic infections in those at the extremes of age and with serious medical conditions. However, USA300 and USA400 MRSA infections are presenting in young immunocompetent adults suggesting that barriers previously unrecognized are essential to control these infections. Quorum sensing in S. aureus is regulated in part by a four gene operon, agr, which includes a thiolactone peptide pheromone (AIP) and a two component sensor regulator that upon activation leads to transcriptional control of over 160 different genes involved in virulence. We identified apolipoprotein B, a component of lipid metabolism, as an essential barrier to invasive S. aureus skin infection and that the mechanism involves control of agr signaling. Specifically, apoB binds to and sequesters AIP thus preventing activation of the agr operon. Because dermonecrotic skin infections predominate in these MRSA infections, extravasation of plasma apoB into infected skin could provide early control of agr and thus limit the production of virulence factors required to evade innate immune killing and clearance of the bacteria. Because apoB is the major structural protein of both VLDL and LDL, aspects of lipoprotein metabolism, including clearance by scavenger receptors (e.g. CD36), could contribute to this host defense mechanism. Therefore, the hypothesis we are testing is that the amino terminal domain of apoB and subsequent clearance through CD36 are essential for host defense against invasive MRSA infection. To test this hypothesis we will pursue the following specific aims: 1) To define the domain(s) of apoB sufficient for binding and functional antagonism of AIP in vitro; 2) To determine the in vivo contribution of apoB to the outcome of agr-dependent invasive infections of strains from the most clinically relevant community-acquired MRSA agr types: USA300 (agr1) and USA400 (agr3): 3) To determine the contribution of CD36 clearance of apoB-AIP complexes to protection against agr dependent invasive MRSA infections.
Antibiotic resistant Staphylococcus aureus infections are a major public health threat, and the community acquired strains are particularly virulent. We identified a human lipoprotein that can prevent upregulation of S. aureus virulence genes. We aim to define the mechanism used by this lipoprotein to control virulence and to determine if this control is effective against community acquired S. aureus strains. This work will broaden the conventional view of innate immunity beyond direct bacterial killing to host factors that regulate virulence gene expression.
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