Genome-wide association to Staphylococcus carriage

全基因组与葡萄球菌携带的关联

• 批准号: 8502236
• 负责人: ERIC L BROWN
• 金额: $ 42.64万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502236
• 关键词: Abscess; Affect; Alleles; Amish; Anterior; Antibiotic Resistance; Antibiotics; Bacterial Infections; Biological; Cessation of life; Clinical; Collaborations; Communities; County; DNA Microarray Chip; Data Analyses; Development; Diabetes Mellitus; Disease; Disease susceptibility; Endocarditis; Epidemiology; France; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genome; Genotype; Genus staphylococcus; Haemophilus influenzae; Health; Human; Human Genetics; Immune response; Incidence; Individual; Infection; Infectious Skin Diseases; Informatics; Intervention; Investigation; Laboratories; Letters; Light; Maryland; Mediating; Methicillin Resistance; Methods; Mexican Americans; Minor; Modality; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nose; Organism; Pathway interactions; Patients; Persons; Pneumonia; Population; Predisposition; Prevention strategy; Procedures; Process; Proteins; Recording of previous events; Resistance; Risk; Role; SNP genotyping; Sampling; Severities; Skin; Staphylococcus aureus; Statistical Methods; Streptococcus pneumoniae; Swab; Symptoms; Testing; Texas; Time; United States; Universities; Vaccine Design; Variant; Vestibule; Virulence Factors; base; computer science; diabetic; follow-up; gene interaction; genome wide association study; genome-wide; improved; innovation; medical schools; methicillin resistant Staphylococcus aureus; non-diabetic; novel; pathogen; public health relevance; resistant strain; success; treatment strategy

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：金黄色葡萄球菌是一种机会性病原体，可在多达四分之一的个体的皮肤（主要是前鼻前庭）中定植，但不会引起临床疾病症状。人类要么持续或间歇性地被金黄色葡萄球菌定殖，要么从未被金黄色葡萄球菌定殖，即定义为携带者、间歇性携带者或非携带者。个人的携带状况会影响他们被感染的可能性以及他们因接触金黄色葡萄球菌而产生的免疫反应的性质。此外，携带状态会影响感染的严重程度，从轻微的皮肤感染到与脓肿形成、心内膜炎和肺炎相关的致命感染。某些抗生素可用于治疗金黄色葡萄球菌介导的疾病，但抗生素耐药菌株的数量正在迅速增加。金黄色葡萄球菌是现代细菌感染的最常见原因之一，部分原因是对抗生素的耐药性增加以及最近出现的社区相关 MRSA 菌株 (CA-MRSA) 引起的感染。 2005年，美国有94,360例MRSA侵袭性病例，18,650人死亡（发病率为31.8/10万人），远高于肺炎链球菌和流感嗜血杆菌。金黄色葡萄球菌引起的感染流行病学的变化和抗生素耐药性的增加需要开发新的治疗方式。宿主对金黄色葡萄球菌携带状态的易感性至少部分受潜在遗传因素的控制。它们的鉴定将为制定干预策略提供目标，例如，鉴定与携带相关的新途径或与易感性相关的基因将允许开发新的干预措施以消除携带或治疗感染。我们很快将使用 Affymetrix 6.0 平台对来自德克萨斯州斯塔尔县的 1000 名非糖尿病患者和 1000 名 2 型糖尿病墨西哥裔美国人完成全基因组基因分型。我们最近在该人群中试行了确定携带菌株的程序，并建议确定 800 名对照者和 600 名糖尿病病例的金黄色葡萄球菌携带状态，我们将拥有近 100 万个 SNP 和 100 万个拷贝数变异来执行拟议的研究。这些 SNP/基因的鉴定将改善风险预测，并揭示连接健康和疾病的新生物途径。它还可以确定 2 型糖尿病和金黄色葡萄球菌携带/疾病易感性的作用/相互作用。全基因组关联研究的成功取决于独立样本中创新且严格的数据分析和复制。我们将结合使用基于计算机科学的信息学和统计方法来确定后续基因和区域的优先顺序。了解对该生物体的易感性或抗性的遗传学将显着加速和改进疫苗设计策略，例如，识别与携带相关的新途径或与易感性相关的基因将允许开发新的干预措施以消除携带或治疗感染。

项目成果

The Panton-Valentine leukocidin is a virulence factor in a murine model of necrotizing pneumonia.

Panton-Valentine 杀白细胞素是坏死性肺炎小鼠模型中的毒力因子。

• DOI: 10.1086/651026
• 发表时间: 2010
• 期刊: The Journal of infectious diseases
• 作者: Vandenesch,François;Couzon,Florence;Boisset,Sandrine;Benito,Yvonne;Brown,EricL;Lina,Gerard;Etienne,Jerome;Bowden,MGabriela
• 通讯作者: Bowden,MGabriela

Characterization of peripheral blood mononuclear cells gene expression profiles of pediatric Staphylococcus aureus persistent and non-carriers using a targeted assay.

• DOI: 10.1016/j.micinf.2020.07.006
• 发表时间: 2020-11
• 期刊: Microbes and infection
• 影响因子: 5.8
• 作者: Israelsson E;Chaussabel D;Fischer RSB;Moore HC;Robinson DA;Dunkle JW;Essigmann HT;Record S;Brown EL
• 通讯作者: Brown EL