McEachern Elisa K, Hwang John H, Sladewski Katherine M, Nicatia Shari, Dewitz Carola, Mathew Denzil P, Nizet Victor, Crotty Alexander Laura E
Medicine Service, Veterans Affairs San Diego Healthcare System, San Diego, California, USA Department of Medicine, University of California, San Diego, California, USA.
Medicine Service, Veterans Affairs San Diego Healthcare System, San Diego, California, USA Department of Medicine, University of California, San Diego, California, USA Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
Infect Immun. 2015 Jun;83(6):2443-52. doi: 10.1128/IAI.00303-15. Epub 2015 Mar 30.
Cigarette smoking is the leading preventable cause of death, disease, and disability worldwide. It is well established that cigarette smoke provokes inflammatory activation and impairs antimicrobial functions of human immune cells. Here we explore whether cigarette smoke likewise affects the virulence properties of an important human pathogen, Staphylococcus aureus, and in particular methicillin-resistant S. aureus (MRSA), one of the leading causes of invasive bacterial infections. MRSA colonizes the nasopharynx and is thus exposed to inhalants, including cigarette smoke. MRSA exposed to cigarette smoke extract (CSE-MRSA) was more resistant to macrophage killing (4-fold higher survival; P < 0.0001). CSE-MRSA demonstrated reduced susceptibility to cell lysis (1.78-fold; P = 0.032) and antimicrobial peptide (AMP) (LL-37) killing (MIC, 8 μM versus 4 μM). CSE modified the surface charge of MRSA in a dose-dependent fashion, impairing the binding of particles with charge similar to that of AMPs by 90% (P < 0.0001). These changes persisted for 24 h postexposure, suggesting heritable modifications. CSE exposure increased hydrophobicity by 55% (P < 0.0001), which complemented findings of increased MRSA adherence and invasion of epithelial cells. CSE induced upregulation of mprF, consistent with increased MRSA AMP resistance. S. aureus without mprF had no change in surface charge upon exposure to CSE. In vivo, CSE-MRSA pneumonia induced higher mouse mortality (40% versus 10%) and increased bacterial burden at 8 and 20 h postinfection compared to control MRSA-infected mice (P < 0.01). We conclude that cigarette smoke-induced immune resistance phenotypes in MRSA may be an additional factor contributing to susceptibility to infectious disease in cigarette smokers.
吸烟是全球可预防的死亡、疾病和残疾的首要原因。众所周知，香烟烟雾会引发炎症激活并损害人类免疫细胞的抗菌功能。在此，我们探究香烟烟雾是否同样会影响一种重要的人类病原体——金黄色葡萄球菌，尤其是耐甲氧西林金黄色葡萄球菌（MRSA）的毒力特性，MRSA是侵袭性细菌感染的主要原因之一。MRSA定殖于鼻咽部，因此会接触包括香烟烟雾在内的吸入物。暴露于香烟烟雾提取物的MRSA（CSE-MRSA）对巨噬细胞杀伤的抵抗力更强（存活率高4倍；P < 0.0001）。CSE-MRSA对细胞裂解的敏感性降低（1.78倍；P = 0.032），对抗菌肽（AMP）（LL-37）杀伤的敏感性也降低（MIC，8 μM对4 μM）。CSE以剂量依赖的方式改变了MRSA的表面电荷，使与AMP电荷相似的颗粒的结合减少了90%（P < 0.0001）。这些变化在暴露后24小时持续存在，表明存在可遗传的修饰。CSE暴露使疏水性增加了55%（P < 0.0001），这与MRSA对上皮细胞的粘附和侵袭增加的结果相符。CSE诱导mprF上调，这与MRSA对AMP的抗性增加一致。没有mprF的金黄色葡萄球菌在暴露于CSE后表面电荷没有变化。在体内，与对照MRSA感染的小鼠相比，CSE-MRSA肺炎诱导更高的小鼠死亡率（40%对10%），并在感染后8小时和20小时增加细菌载量（P < 0.01）。我们得出结论，香烟烟雾诱导的MRSA免疫抗性表型可能是导致吸烟者易患传染病的另一个因素。
