Mechanisms of community MRSA virulence

社区 MRSA 毒力机制

• 批准号: 8555989
• 负责人: Frank DeLeo
• 金额: $ 101.81万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8555989
• 关键词: Antibiotic Resistance; Bacteria; Cells; Communities; Development; Diagnostic; Disease; Epidemic; Gene Proteins; Hospitals; Human; Incidence; Individual; Infection; Laboratories; Lower Respiratory Tract Infection; Modeling; Molecular; Multi-Drug Resistance; New Agents; Nosocomial Infections; Pathogenesis; Predisposition; Research; Research Project Grants; Risk Factors; Sepsis; Severities; Skin Tissue; Soft Tissue Infections; Staphylococcus aureus; Testing; United States; Virulence; base; disorder control; human disease; killings; methicillin resistant Staphylococcus aureus; neutrophil; pathogen; prophylactic

In 2012, a primary focus of research in my laboratory investigated how bacterial pathogens such as Staphylococcus aureus cause human disease. Although most bacteria are killed readily by PMNs, certain strains of S. aureus have evolved mechanisms to circumvent destruction by neutrophils and thereby cause human infections. Notably, S. aureus is the most frequent etiologic agent causing bloodstream infection, skin and soft tissue infection, and lower respiratory tract infection in much of the world, including the United States. In addition, the pathogen has become increasingly resistant to antibiotics over the past few decades and methicillin-resistant S. aureus (MRSA) is a leading cause of hospital-acquired infections. Thus, treatment options are limited. Hospital-acquired MRSA infections are also typical of individuals with predisposing risk factors. In contrast, community-associated (or acquired) MRSA (CA-MRSA) cause disease in otherwise healthy individuals, and these infections can be severe/fatal. There has been a relatively high number of CA-MRSA infections worldwide, and this includes an ongoing epidemic of CA-MRSA infections in the United States. The molecular basis for the increased incidence and severity of CA-MRSA disease is not known. We hypothesize that the ability of bacteria to cause disease is largely due to pathogen-derived factors that alter normal neutrophil function and individual host susceptibility. Therefore, a better understanding of the bacteria-PMN interface at the cell and molecular levels will provide information critical to our understanding, treatment, and control of disease caused by bacterial pathogens. S. aureus is an ideal model pathogen with which to test our hypothesis because it is an important cause of human disease, it can be multi-drug resistant and thus hard to eradicate, and neutrophils are the first line of defense against S. aureus infections. To date, our studies include identification of genes and proteins used by CA-MRSA to evade destruction by human neutrophils, hence contributing to virulence, survival and pathogenesis.

2012年，我实验室的一个主要研究重点是调查金黄色葡萄球菌等细菌病原体如何引起人类疾病。尽管大多数细菌容易被中性粒细胞杀死，但某些S.金黄色葡萄球菌已经进化出机制来避免嗜中性粒细胞的破坏，从而引起人类感染。值得注意的是，S.金黄色葡萄球菌是世界上包括美国在内的许多国家中引起血流感染、皮肤和软组织感染以及下呼吸道感染的最常见的病原体。此外，在过去的几十年里，该病原体对抗生素的耐药性越来越强，耐甲氧西林的S。金黄色葡萄球菌（MRSA）是医院获得性感染的主要原因。因此，治疗选择有限。医院获得性MRSA感染也是具有易感风险因素的个体的典型特征。相比之下，社区相关（或获得性）MRSA（CA-MRSA）在其他健康个体中引起疾病，并且这些感染可能是严重/致命的。在全球范围内，CA-MRSA感染的数量相对较高，这包括在美国持续流行的CA-MRSA感染。CA-MRSA疾病发病率和严重程度增加的分子基础尚不清楚。 我们假设细菌致病的能力主要是由于病原体衍生的因子改变了正常的中性粒细胞功能和个体宿主易感性。因此，在细胞和分子水平上更好地理解细菌-PMN界面将为我们理解、治疗和控制由细菌病原体引起的疾病提供关键信息。S.金黄色葡萄球菌是检验我们假设的理想模式病原体，因为它是人类疾病的重要原因，它可以是多药耐药性的，因此难以根除，而嗜中性粒细胞是抵抗金黄色葡萄球菌的第一道防线。金黄色葡萄球菌感染迄今为止，我们的研究包括鉴定CA-MRSA用于逃避人类中性粒细胞破坏的基因和蛋白质，从而有助于毒力，存活和发病机制。