Voyich Jovanka M, Braughton Kevin R, Sturdevant Daniel E, Whitney Adeline R, Saïd-Salim Battouli, Porcella Stephen F, Long R Daniel, Dorward David W, Gardner Donald J, Kreiswirth Barry N, Musser James M, DeLeo Frank R
Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT 59840, USA.
J Immunol. 2005 Sep 15;175(6):3907-19. doi: 10.4049/jimmunol.175.6.3907.
Polymorphonuclear leukocytes (PMNs, or neutrophils) are critical for human innate immunity and kill most invading bacteria. However, pathogens such as Staphylococcus aureus avoid destruction by PMNs to survive, thereby causing human infections. The molecular mechanisms used by pathogens to circumvent killing by the immune system remain largely undefined. To that end, we studied S. aureus pathogenesis and bacteria-PMN interactions using strains originally isolated from individuals with community-acquired (CA) and hospital-acquired infections. Compared with strains from hospital infections (COL and MRSA252), strain MW2 and a methicillin-susceptible relative, MnCop, were significantly more virulent in a mouse model of S. aureus infection, and caused the greatest level of pathology in major vital organs. Although phagocytosis of each strain triggered production of reactive oxygen species and granule-phagosome fusion, those from CA infections were significantly more resistant to killing by human PMNs and caused greater host cell lysis. Microarray analysis of the strains during neutrophil phagocytosis identified genes comprising a global S. aureus response to human innate host defense. Genes involved in capsule synthesis, gene regulation, oxidative stress, and virulence, were up-regulated following ingestion of the pathogen. Notably, phagocytosis of strains from CA infections induced changes in gene expression not observed in the other strains, including up-regulation of genes encoding virulence factors and hypothetical proteins. Our studies reveal a gene transcription program in a prominent human pathogen that likely contributes to evasion of innate host defense.
多形核白细胞（PMNs，即中性粒细胞）对人类先天免疫至关重要，可杀死大多数入侵细菌。然而，金黄色葡萄球菌等病原体可避免被PMNs破坏从而存活，进而引发人类感染。病原体用于规避被免疫系统杀灭的分子机制在很大程度上仍不明确。为此，我们使用最初从社区获得性（CA）感染和医院获得性感染个体中分离出的菌株，研究了金黄色葡萄球菌的发病机制以及细菌与PMNs的相互作用。与来自医院感染的菌株（COL和MRSA252）相比，MW2菌株及其甲氧西林敏感的相关菌株MnCop在金黄色葡萄球菌感染的小鼠模型中致病性显著更强，并在主要重要器官中导致了最严重的病理变化。尽管每种菌株的吞噬作用都会触发活性氧的产生和颗粒-吞噬体融合，但来自CA感染的菌株对人类PMNs的杀伤作用具有显著更强的抵抗力，并导致更大程度的宿主细胞裂解。对中性粒细胞吞噬过程中这些菌株的微阵列分析确定了一组构成金黄色葡萄球菌对人类先天宿主防御整体反应的基因。摄入病原体后，参与荚膜合成、基因调控、氧化应激和毒力的基因被上调。值得注意的是，来自CA感染的菌株的吞噬作用诱导了其他菌株未观察到的基因表达变化，包括编码毒力因子和假定蛋白的基因上调。我们的研究揭示了一种在主要人类病原体中的基因转录程序，该程序可能有助于逃避先天宿主防御。
