Innate immune defense against community associated methicillin-resistant S.aureus

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DESCRIPTION (provided by applicant): Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) frequently cause necrotizing infections that are more severe than those seen with other SA. Their epidemic spread and high morbidity and mortality in otherwise healthy individuals have raised alarm in the biomedical community. Reasoning that the clinical characteristics of CA-MRSA infections reflect unique features of its interactions with the host, our attention will be focused on the dynamic interplay between CA-MRSA (vs control SA) and elements of innate immunity that defend against SA. Critical determinants may be manifested during the initial interaction, later during infection as surviving bacteria escape the phagocyte, or both. We have recently identified a novel synergy between the O2-dependent phagocyte NADPH oxidase and the extracellular O2-independent Group IIA phospholipase A2 (GpIIA-PLA2) in the killing and degradation of SA. Our data suggest that CA-MRSA are relatively resistant not only to polymorphonuclear neutrophil (PMN) but also to GpIIA-PLA2. Furthermore, we found that CA-MRSA more readily escape from PMN and that escaped CA-MRSA are more resistant to GpIIA-PLA2 than are naive CA-MRSA. Phagocytosed SA exhibit robust metabolic responses to ingestion by PMN, including expression of genes encoding cell wall modifications that may be important for intracellular survival, lysis of PMN, and persistent inflammation. Our data demonstrate that the increased resistance of CA- MRSA to GpIIA-PLA2 requires expression of the dlt operon, a critical determinant of cell wall synthesis. Within this context, we propose the following novel hypotheses: (1) the role of PMN in resolution of SA infection depends on the integrated effects of intrinsic PMN antibacterial action with the activity of mobilized extracellular anti-SA factors, including GpIIA-PLA2 and longer lived phagocytes such as macrophages; (2) differences in initial SA-PMN interactions alter the fate of CA-MRSA within PMN as well as the prompt resolution of infection, manifested by altered susceptibility of surviving CA-MRSA to the actions of GpIIA-PLA2 or macrophages; and (3) the necrosis characteristic of CA-MRSA infection reflects the less effective collective actions of PMN, GpIIA-PLA2 and macrophages. To test these hypotheses, we will employ novel experimental design to pursue the following aims: 1. To determine the mechanism(s) underlying the increased resistance of CA-MRSA to phagocyte (PMN) and extracellular (Group IIA PLA2) cytotoxicity. 2. To determine the effects of PMN-CA-MRSA interaction on the fate of each cell 3. To assess the contribution of specific CA-MRSA responses to PMN- GpIIA-PLA2 to the outcome of their interaction with PMN or subsequent fate. Project Narrative A recently identified type of staphylococcus (community-associated methicillin-resistant Staphylococcus aureus, CA-MRSA) has emerged as a significant and common cause of infection in the community (i.e. in non hospitalized individuals). Affected individuals are generally young and previously healthy, and suffer severe infection, often necrotizing pneumonia and soft-tissue disease. Our studies will advance understanding of how CA-MRSA resist human host defenses and thereby produce such severe and devastating disease.