Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Nat Microbiol. 2020 Feb;5(2):282-290. doi: 10.1038/s41564-019-0627-y. Epub 2019 Dec 9.
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. These more serious infections usually arise from an initial bloodstream infection and are frequently recalcitrant to antibiotic treatment. Phagocytosis by macrophages and neutrophils is the primary mechanism through which S. aureus infection is controlled by the immune system. Macrophages have been shown to be a major reservoir of S. aureus in vivo, 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.
金黄色葡萄球菌是一种主要的人类病原体，可引起多种感染，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源于初始的血液感染，并且经常对抗生素治疗有抗药性。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。已经表明巨噬细胞是体内金黄色葡萄球菌的主要储存库，但巨噬细胞在诱导抗生素耐药性方面的作用尚未得到探索。在这里，我们表明巨噬细胞不仅不能有效地杀死吞噬的金黄色葡萄球菌，而且还诱导对多种抗生素的耐药性。呼吸爆发产生的活性氧攻击含铁硫簇的蛋白质，包括三羧酸循环酶，导致呼吸减少、ATP 降低和抗生素耐药性增加。我们进一步表明，呼吸爆发在小鼠全身感染期间诱导脾脏中的抗生素耐药性。这些结果表明，先天免疫反应的一个主要组成部分与抗生素的杀菌活性相拮抗。
