HLA Fine Mapping to Elucidate S. aureus Susceptibility

This application uses a large human prospective cohort to identify the host genetic determinants of susceptibility to Staphylococcus aureus bacteremia (SAB), a common and potentially lethal infection. The overarching hypothesis to be tested in this study is that specific variants in the Human Leukocyte Antigen

(HLA) class II region are important determinants of susceptibility to SAB in humans, and that these determinants can be identified by studying large, well-characterized cohorts of patients. This hypothesis is based upon our two separate studies that 1) identified genome-wide significant associations of variants in HLA

class II with an increased risk for S. aureus infections in individuals of European descent; and 2) identified a genome-wide association of European-derived HLA Class II variants and SAB in African-American patients. In the proposed study, we will further refine the genetic risk factors for SAB in the HLA class II region. We created

the S. aureus Bacteremia Group (SABG), one of the world’s largest collections of paired human DNA and bloodstream bacteria from patients with SAB. We assembled an experienced multidisciplinary team to link the unique SABG cohort resources to state-of-the-art genotyping technology and innovative in vivo model systems,

pushing the boundaries of the field. We propose three Specific Aims. In Aim 1, we will identify the genetic risk factors in HLA class II for developing SAB, using high-density genotyping and imputation to saturate the HLA region in 2300 individuals with SAB and 2300 unaffected controls enrolled in the longitudinal, prospective

SABG cohort. In Aim 2, we will examine the association of HLA class II alleles and haplotypes with complicated SAB in the 2300 patients with SAB genotyped in SA1, and consider the impact of bacterial genotype on the risk for complicated SAB by genotyping the bloodstream S. aureus isolates from all of the

2300 SAB patients. In this way, we will test whether the association of complicated SAB with HLA class II alleles and haplotypes is modified by the specific genetic lineage of the bloodstream S. aureus. In Aim 3, we will evaluate the functional consequences of the HLA alleles identified in Aim 1, Aim 2, and in our previous

studies with in vivo and in vitro experiments. We will evaluate whether specific HLA class II alleles significantly alter host T cell responses to S. aureus using 1) a S. aureus sepsis model in transgenic mice expressing human HLA class II alleles; and 2) stimulation of T cells from SAB patients using S. aureus infected antigen

presenting cells expressing different HLA alleles. The long-term objectives of this project are 1) to fully characterize HLA variation in a multi-ethnic sample of individuals with SAB and unaffected controls; and 2) to provide biological evidence for the clinical relevance of the HLA class II variants identified in this project. Taken

together, the impact of this proposal is to increase our understanding of how host genetic variation influences the initiation and severity of S. aureus infections. Elucidating the genetic basis of susceptibility to S. aureus infection will improve our understanding, treatment, and prevention of this urgent unmet medical crisis.