Reactive oxygen species induce antibiotic tolerance during systemic Staphylococcus aureus infection
Reactive oxygen species induce antibiotic tolerance during systemic Staphylococcus aureus infection
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DOI：
10.1038/s41564-019-0627-y
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发表时间：
2020-02-01
影响因子：
28.3
通讯作者：
Conlon, Brian P.
中科院分区：
文献类型：
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作者：
Rowe, Sarah E.;Wagner, Nikki J.;Conlon, Brian P.
金黄色葡萄球菌是一种主要的人类病原体，可引起一系列感染，从轻微的皮肤感染到更严重的感染，包括骨髓炎、心内膜炎、坏死性肺炎和败血症。这些更严重的感染通常由最初的血液感染引起，并且经常对抗生素治疗顽固不化(1)。巨噬细胞和中性粒细胞的吞噬作用是免疫系统控制金黄色葡萄球菌感染的主要机制。巨噬细胞已被证明是体内金黄色葡萄球菌的主要储存库[3]，但巨噬细胞在诱导抗生素耐受中的作用尚未被探索。在这里，我们发现巨噬细胞不仅不能有效地杀死吞噬的金黄色葡萄球菌，而且还能诱导对多种抗生素的耐受。呼吸爆发攻击含有铁硫簇的蛋白质，包括TCA循环酶所产生的活性氧物种，导致呼吸减少，ATP降低，抗生素耐受性增加。我们进一步证明，在小鼠全身感染期间，呼吸爆发会导致脾对抗生素的耐受。这些结果表明，先天免疫反应的一个主要组成部分是对抗抗生素的杀菌活性。巨噬细胞感染金黄色葡萄球菌后产生的反应氧物种攻击细菌的含铁硫簇蛋白，从而导致细菌代谢的变化，从而增加他们对抗生素的耐受性。
Staphylococcus aureus is a major human pathogen that causes an array of infections ranging from minor skin infections to more serious infections, including osteomyelitis, endocarditis, necrotizing pneumonia and sepsis(1). These more serious infections usually arise from an initial bloodstream infection and are frequently recalcitrant to antibiotic treatment(1). Phagocytosis by macrophages and neutrophils is the primary mechanism through which S. aureus infection is controlled by the immune system(2). Macrophages have been shown to be a major reservoir of S. aureus in vivo(3), but the role of macrophages in the induction of antibiotic tolerance has not been explored. Here, we show that macrophages not only fail to efficiently kill phagocytosed S. aureus, but also induce tolerance to multiple antibiotics. Reactive oxygen species generated by respiratory burst attack iron-sulfur cluster-containing proteins, including TCA-cycle enzymes, result in decreased respiration, lower ATP and increased antibiotic tolerance. We further show that respiratory burst induces antibiotic tolerance in the spleen during a murine systemic infection. These results suggest that a major component of the innate immune response is antagonistic to the bactericidal activities of antibiotics.Reactive oxygen species produced by macrophages following infection with Staphylococcus aureus attack bacterial iron-sulfur cluster-containing proteins, thereby leading to alterations in bacterial metabolism that increase their tolerance to antibiotics.