Mechanisms of community MRSA virulence

2014财年，我实验室(部分)的一个主要研究重点调查了金黄色葡萄球菌等细菌病原体如何导致人类疾病。虽然大多数细菌很容易被PMN杀死，但一些金黄色葡萄球菌菌株已经进化出避开中性粒细胞破坏的机制，从而导致人类感染。值得注意的是，在包括美国在内的世界大部分地区，金黄色葡萄球菌是导致血液、皮肤和软组织以及下呼吸道感染的最常见原因之一。此外，在过去的几十年里，这种病原体对抗生素的耐药性越来越强，耐甲氧西林金黄色葡萄球菌(MRSA)是医疗保健相关感染的主要原因。因此，治疗选择是有限的。与医疗保健相关的耐甲氧西林金黄色葡萄球菌感染是具有易感风险因素的典型个人。相比之下，社区相关MRSA(CA-MRSA)会在其他健康的个人中引起疾病，这些感染可能是严重的或致命的。CA-MRSA出现在20世纪90年代，然后在接下来的十年里蔓延到世界各地。尽管最近医院MRSA感染人数有所下降，但CA-MRSA感染水平保持相对稳定。CA-MRSA菌株毒力增强和成功的分子基础尚未完全确定。因此，该科的一个重要组成部分旨在解决这一知识不足的问题。 例如，我们最近发现了一种新的金黄色葡萄球菌双组分白毒素(白毒素GH，LukGH)，并继续研究其在细菌毒力中的作用。我们发现LukGH促进了中性粒细胞外陷阱(Net)的释放，Net反过来诱捕但不杀死金黄色葡萄球菌(Malachowa等人，J免疫，2014)。此外，我们发现，人中性粒细胞的电通透性--作为在中性粒细胞质膜上创造毛孔的一种单独手段--类似地诱导Net的形成，这一发现与Net可以在非特异性细胞溶解过程中形成的概念一致。因此，LukGH促进Net形成的能力可能有助于炎症反应和宿主对金黄色葡萄球菌感染的防御。 与爱荷华大学医学博士William Nauseef合作完成的研究报告了人类中性粒细胞的程序性坏死(Greenlee-Wacker等人，《免疫学杂志》2014)。与Michael Otto，Ph.D.(LHBP)合作开展的工作研究了金黄色葡萄球菌苯酚可溶性调制素与人中性粒细胞的相互作用(Cheung等人，FASEB J，2014)。 这些只是我的部分研究的几个精选例子，下面提供了一个完整的出版物清单。

In FY2014, a primary focus of research in my laboratory (Section) investigated how bacterial pathogens such as Staphylococcus aureus cause human disease. Although most bacteria are killed readily by PMNs, some strains of S. aureus have evolved mechanisms to circumvent destruction by neutrophils and thereby cause human infections. Notably, Staphylococcus aureus is among the most frequent causes of bloodstream, skin and soft tissue, and lower respiratory tract infections in much of the world, including the United States. In addition, the pathogen has become increasingly resistant to antibiotics over the past several decades and methicillin-resistant S. aureus (MRSA) is a leading cause of healthcare-associated infections. Thus, treatment options are limited. Healthcare-associated MRSA infections are typical of individuals with predisposing risk factors. In contrast, community-associated MRSA (CA-MRSA) cause disease in otherwise healthy individuals, and these infections can be severe or fatal. CA-MRSA emerged in the 1990s and then spread worldwide over the next decade. Although there has been a recent decrease in the number of hospital MRSA infections, the level of CA-MRSA infections has remained relatively constant. The molecular basis for the increased virulence potential and success of CA-MRSA strains is incompletely defined. Thus, a significant component of the Section is directed to address this deficiency in knowledge. For example, we recently identified a novel S. aureus bi-component leukotoxin (leukotoxin GH, LukGH) and continue to investigate its role in bacterial virulence. We found that LukGH promoted release of neutrophil extracellular traps (NETs), which in turn, ensnared but did not kill S. aureus (Malachowa et al., J Immunol, 2014). Furthermore, we found that electropermeabilization of human neutrophils--used as a separate means to create pores in the neutrophil plasma membrane--similarly induced formation of NETs, a finding consistent with the notion that NETs can form during non-specific cytolysis. Thus, the ability of LukGH to promote formation of NETs likely contributes to the inflammatory response and host defense against S. aureus infection. Studies done in collaboration with William Nauseef, M.D. at The University of Iowa reported programmed necrosis in human neutrophils (Greenlee-Wacker et al., J Immunol 2014). Work performed in collaboration with Michael Otto, Ph.D. (LHBP) investigated the interaction of S. aureus phenol-soluble modulins with human Neutrophils (Cheung et al., FASEB J, 2014). These are only a few selected examples of studies performed in my Section, and a complete list of publications is provided below.