The overall goal of this competitive renewal is to further understand why some individuals develop Staphylococcus aureus infection; and of those with S. aureus bacteremia (SAB), why only some develop adverse outcomes. Increasing rates of S. aureus infection and the identification of clinical S. aureus strains resistant to all currenly available antibiotics demand an increased understanding of the genetic basis for host response to this emerging pathogen. The specific hypothesis to be tested in this application is that identifiable host genetic factors are important determinants of susceptibility to S. aureus infection. This hypothesis is based upon 1) higher rates of SAB among ethnically distinct populations, including African Americans; 2) higher rates of SAB among patients with specific rare genetic conditions; and 3) our discovery in the original application of differing genetic susceptibility to S. aureus in inbred mice. Despite recent advances in human and molecular genetics, no large-scale studies of human genetic susceptibility to S. aureus have been published. This is largely due to the lack of a well-characterized collection of DNA and corresponding bacterial isolate from patients with S. aureus infection. Our group has created the S. aureus Bacteremia Group (SABG), one of the world's largest collections of paired human DNA and bloodstream isolates from patients with SAB. Building upon the discoveries of our original R01, our renewal combines the unique SABG resource with state of the art technology and strong collaborations with authorities in human genetics to pursue a multi-faceted approach to discovering novel genetic variants in patients with SAB. To do this we propose four Specific Aims: 1) identify candidate genes associated with susceptibility to S. aureus infection in a murine sepsis model; 2) identify candidate genes associated with susceptibility to S. aureus infection in African Americans (AA) using admixture mapping; 3) identify and prioritize genes containing rare, functional, coding sequence variants underlying SAB overall, and complicated SAB in particular, via exome sequencing; and 4) test the relevance of existing candidate genes discovered in the original R01 and new candidate genes in Aims 1-3 in the overall SABG cohort (1200cases/1200controls). The long-term objectives of this project are to: 1) identify genes responsible for susceptibility to S. aureus; 2) investigate the clinical importance of these genes in humans with S. aureus bacteremia; and 3) ultimately use these genes to identify novel interventions for the control of S. aureus infections. The products of this grant will include an increased understanding of the role of genetic susceptibility to S. aureus in determining the development and severity of infection. The full value of the current application also includes the potential benefit to the research community as a whole if links between host genotype and clinical outcome (only possible to identify using such a large and well-characterized collection of DNA from infected patients) can be defined. This work is critical to furthering the understanding of a crucial medical problem because: 1) S. aureus is an emerging pathogen, and 2) interventions to reduce S. aureus morbidity require a better knowledge of the determinants of both the development and severity of infection. Understanding the host genetic determinants of this disease will advance our understanding of staphylococcal pathogenesis and will enable key advances in protecting the public health from this pathogen.
competitive renewal is highly relevant to the health of the American Public, as it seeks to understand the pathophysiology of Staphylococcus aureus. S. aureus is one of the leading pathogens plaguing the American public. Rates of both infections and antibiotic resistance in S. aureus are increasing. These alarming trends indicate the possibility of a pathogen impervious to all currently approved therapy. This application seeks to improve our understanding of this persistent pathogen by pursuing the question, 'Why do some, but not all patients develop S. aureus bacteremia, and of those infected, why do only some go on to develop life- threatening complications?' By increasing our understanding of the genetic basis of host response to S. aureus, this application could aid our ability to intervene in the disease process, focus healthcare resources onto S. aureus-infected patients at highest risk for complications, and lead to improved interventions and diagnostics.
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