Epigenomic Mechanisms & Contextual Immunity in Persistent MRSA Bacteremia

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PROJECT SUMMARY/ABSTRACT Staphylococcus aureus (SA) is the most common etiologic agent of bacteremia and hematogenous sequelae. In methicillin-resistant SA (MRSA) bacteremia, up to 35% of patients succumb even on gold-standard antibiotic therapy, equating to nearly 20,000 deaths/year in the U.S. alone. In many cases of MRSA bacteremia, isolates are susceptible to antibiotics in vitro but not cleared from the bloodstream even on appropriate therapy. Survival of MRSA in vivo despite antibiotic susceptibility in vitro is termed antibiotic persistence. Persistent MRSA bacteremia (PB) is a life-threatening emergency correlating with worsened outcomes and escalation of antibiotic use. This vicious cycle of persistence driving antibiotic escalation driving antibiotic resistance is an NIH high–priority concern. A long-standing mystery is central to PB infections: the MRSA isolate is susceptible to antibiotics in laboratory testing—but not in the human being. Importantly, persistence reflects a unique type of treatment-refractory infections distinct from biofilm-mediated or classical antibiotic tolerance or resistance. Rather, persistent MRSA are elusive: they adapt to host immune responses and antibiotic stresses in vivo and then revert quickly in vitro. Presently, there are few therapeutic options for PB due to MRSA. Further, despite several meritorious attempts, vaccines targeting MRSA have not achieved efficacy in clinical trials to date. Thus, there is a critical, unmet need to define the interactions of the human, MRSA pathogen and antibiotic factors driving persistence outcomes. To address these challenges, we have designed independent Specific Aims that are highly synergistic with those of other Projects & Cores to: 1) specify the genetic and epigenetic mechanisms by which MRSA adaptively persists in vivo; 2) discern how persistent MRSA subvert immune memory; and 3) define protective vs. non-protective immune contexts that differentiate MRSA persistence vs. resolving outcomes. We will apply state-of-the-art technologies to comprehensively analyze dynamic host-pathogen relationships leading to PB outcomes in context of antibiotic, host sex and time in vitro and in experimental models. In turn, these data will be analyzed using powerful bioinformatics and computational methods to detect hidden patterns within large complex datasets. Beyond new mechanistic insights, our innovative studies are designed to discover translatable interventions that overcome MRSA persistence. This knowledge will accelerate new strategies to predict, prevent and treat PB infections to improve and save lives. Strategies successful in addressing MRSA persistence may also be applied to infections caused by other high-priority MDR pathogens. Our systems-based approach to achieving these goals is ideally aligned with priorities of the National Institutes of Health.