Interaction Of Pathogenic Bacteria With Human Phagocytic

人类多形核白细胞（PMN或中性粒细胞）是对抗入侵微生物的先天免疫应答所必需的。与获得性免疫应答不同，获得性免疫应答需要时间来发展，并且依赖于先前与特定病原体的相互作用，中性粒细胞杀死感染性微生物的能力是立即的、非特异性的，并且不依赖于先前的病原体暴露。由于中性粒细胞产生有毒的杀微生物成分，并且是大多数细菌感染中的主要免疫细胞，因此感染诱导的炎症的缓和对于限制宿主组织破坏至关重要。最近的证据表明，中性粒细胞凋亡促进细菌感染的解决，病原体改变中性粒细胞凋亡存活的发现支持了这一观点。我们研究的一个关键方面是研究中性粒细胞如何摄取和杀死细菌，并阐明吞噬后的后遗症，如细胞凋亡，这是炎症消退阶段的关键过程。这些研究建立了宿主细胞-病原体相互作用的全球模型，为人类感染的解决提供了基本的见解。 我实验室的第二个研究重点是研究细菌病原体如金黄色葡萄球菌如何引起人类疾病。尽管大多数细菌很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。全世界CA-MRSA感染的数量出现了惊人的增长，其中包括美国CA-MRSA的持续流行。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。

Human polymorphonuclear leukocytes (PMNs or neutrophils) are essential to the innate immune response against invading microorganisms. In contrast to the acquired immune response, which requires time to develop and is dependent on previous interaction with specific pathogens, the ability of PMNs to kill infectious microorganisms is immediate, non-specific, and not dependent on previous pathogen exposure. Inasmuch as PMNs produce toxic microbicidal components and are the predominant immune cell in most bacterial infections, moderation of infection-induced inflammation is critical for limiting host tissue destruction. Recent evidence suggests PMN apoptosis facilitates resolution of bacterial infections, an idea supported by the finding that pathogens alter neutrophil apoptosis to survive. A key aspect of our research investigates how PMNs ingest and kill bacteria, and elucidates post-phagocytosis sequelae such as apoptosis, processes crucial for the resolution phase of inflammation. These studies established a global model of host cell-pathogen interaction that provides fundamental insight into the resolution of infection in humans. A second focus of research in my laboratory investigates 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 an alarming increase in the number of CA-MRSA infections worldwide, which includes an ongoing epidemic of CA-MRSA 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.