Staphylococcus aureus is an opportunistic pathogen that colonizes the skin (primarily the anterior nasal vestibule) of as many as 1 out 4 individuals without causing clinical disease symptoms. Humans are either persistently or intermittently colonized or never colonized with S. aureus i.e., defined as carriers, intermittent carriers or non-carriers. An individual's carriage status affects their likelihood of becoming infected and the nature of their immune response by S. aureus exposure. In addition, carriage status affects the severity of the infection(s) that range from minor skin infections to lethal infections associated with abscess formation, endocarditis and pneumonia. Certain antibiotics are available for the treatment of S. aureus-mediated disease, but the number of antibiotic-resistant strains is increasing rapidly. S. aureus is one of the most common causes of modern bacterial infections, in part due to increasing resistance to antibiotics and the recent emergence of infections caused by Community-Associated MRSA strains (CA-MRSA). In 2005, there were 94,360 invasive cases of MRSA in the United States, 18,650 resulted in death (incidence rate of 31.8/100,000 persons) much higher than S. pneumoniae and H. influenzae. The changing epidemiology of infections caused by S. aureus and increased antibiotic resistance necessitates the development of novel treatment modalities. Host susceptibility to S. aureus carriage status is at least partially under the control of underlying genetic factors. Their identification would provide targets for developing intervention strategies e.g., identification of novel pathways associated with carriage or genes associated with susceptibility will allow for the development of new interventions to eliminate carriage or treat infections. We will shortly complete genome-wide genotyping on 1000 nondiabetic and 1000 Type-2 diabetic Mexican-Americans from Starr County, Texas using the Affymetrix 6.0 platform. We have recently piloted procedures for determining carriage strains in this population and propose to determine S. aureus carriage status for 800 of the controls and 600 of diabetes cases for whom we will have nearly 1 million SNPs and 1 million copy number variants to carry out the proposed studies. Identification of these SNPs/genes will improve risk prediction and shed light on novel biological pathways bridging health and disease. It will also allow determining the role/interaction of Type-2 diabetes and S. aureus carriage/disease susceptibility. Success of genome-wide association studies depends on innovative and rigorous data analysis and replication in independent samples. We will use a combination of computer science- based informatics and statistical methods to prioritize genes and regions for follow-up. Understanding the genetics of susceptibility or resistance to this organism shall significantly accelerate and improve vaccine design strategies e.g., identification of novel pathways associated with carriage or genes associated with susceptibility will allow for the development of new interventions to eliminate carriage or treat infections.

Public Health Relevance

Community-acquired S. aureus infections are a growing problem and the increasing number of antibiotic resistant strains is limiting available treatment options. This proposal aims to develop an understanding of the human genetic components associated with S. aureus carriage as means of identifying novel genes or pathways associated with carriage/disease. This information may then be used to develop novel treatment and prevention strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI085014-02
Application #
8099018
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Huntley, Clayton C
Project Start
2010-07-01
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2011
Total Cost
$659,724
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Internal Medicine/Medicine
Type
Schools of Public Health
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Hanis, C L; Garrett, K E; Essigmann, H T et al. (2017) Household aggregation of Staphylococcus aureus by clonal complex and methicillin resistance profiles in Starr County, Texas. Eur J Clin Microbiol Infect Dis :
Graff, Mariaelisa; Emery, Leslie S; Justice, Anne E et al. (2017) Genetic architecture of lipid traits in the Hispanic community health study/study of Latinos. Lipids Health Dis 16:200
Reid, Michael J A; Fischer, Rebecca S B; Mannathoko, Naledi et al. (2017) Prevalence of Staphylococcus aureus Nasal Carriage in Human Immunodeficiency Virus-Infected and Uninfected Children in Botswana: Prevalence and Risk Factors. Am J Trop Med Hyg 96:795-801
Cade, Brian E; Chen, Han; Stilp, Adrienne M et al. (2016) Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans. Am J Respir Crit Care Med 194:886-897
Tolo, Isaiah; Thomas, Jonathan C; Fischer, Rebecca S B et al. (2016) Do Staphylococcus epidermidis Genetic Clusters Predict Isolation Sources? J Clin Microbiol 54:1711-9
Hanis, Craig L; Redline, Susan; Cade, Brian E et al. (2016) Beyond type 2 diabetes, obesity and hypertension: an axis including sleep apnea, left ventricular hypertrophy, endothelial dysfunction, and aortic stiffness among Mexican Americans in Starr County, Texas. Cardiovasc Diabetol 15:86
Brown, Eric L; Below, Jennifer E; Fischer, Rebecca S B et al. (2015) Genome-Wide Association Study of Staphylococcus aureus Carriage in a Community-Based Sample of Mexican-Americans in Starr County, Texas. PLoS One 10:e0142130
Rodin, Andrei S; Gogoshin, Grigoriy; Boerwinkle, Eric (2011) Systems biology data analysis methodology in pharmacogenomics. Pharmacogenomics 12:1349-60
Vandenesch, Fran├žois; Couzon, Florence; Boisset, Sandrine et al. (2010) The Panton-Valentine leukocidin is a virulence factor in a murine model of necrotizing pneumonia. J Infect Dis 201:967-9; author reply 969-70