Mechanisms of community MRSA virulence

在2014财年，我的实验室（分部）的一个主要研究重点是研究金黄色葡萄球菌等细菌病原体如何引起人类疾病。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了规避中性粒细胞破坏的机制，从而引起人类感染。值得注意的是，在包括美国在内的世界许多地方，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，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。医疗保健相关的MRSA感染是具有易感危险因素的个体的典型。相比之下，社区相关性MRSA （CA-MRSA）在其他健康个体中引起疾病，这些感染可能是严重或致命的。CA-MRSA出现于20世纪90年代，然后在接下来的十年里传播到世界各地。虽然最近医院MRSA感染的数量有所下降，但CA-MRSA感染的水平保持相对稳定。CA-MRSA菌株增加的毒力潜力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是针对这方面知识的不足。

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.