| Staphylococcus aureus is a colonizer of the human skin and mucosa that can cause minor to severe disease. Originally afflicting patients at the extremes of age or those with immunocompromising co-morbidities, S. aureus strains have emerged that cause invasive disease in otherwise healthy populations with no health-care associated risk factors. In addition, these community-acquired strains predominately contain antibiotic resistance genes, making them difficult to treat with conventional interventions. Invasive disease in S. aureus is partly regulated by a quorum sensing signaling system that relies on the secretion and signaling function of a bacterial peptide pheromone (AIP). S. aureus strains that lack this virulence regulator system still cause disease, but it is much less severe and is typified by a colonizing, rather than an invasive, phenotype. Therapeutics or host factors that inhibit virulence instead of viability can limit both invasive disease as well as the development of resistance.;During infection, the inflammatory process causes serum to extravasate into the affected tissue site. Serum has been shown to inhibit virulence signaling in S. aureus, though the mechanism is unknown. This dissertation identifies apolipoprotein B (apoB), the major protein component of very low and low density lipoproteins, as a potent inhibitor of virulence signaling in S. aureus by binding the bacterial signaling pheromone AIP. Though binding of host lipoproteins to bacterial products has been described in Gram-negative infections, this is the first demonstration of a lipoprotein component having protective effects in a Gram-positive infection. This work further describes the inhibitory action of apoB on virulence signaling and subsequent invasive infection in multiple S. aureus strains and identifies the globular amino terminal domain of apoB as the AIP binding site. These findings have important implications for understanding the host-pathogen interaction and for developing therapeutics that can be effective without causing bacterial resistance. |
