R01AI165671

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.

Duke University

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Durham, North Carolina 277051104 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 366% from $807,042 to $3,757,863.