Staphylococcal DNA Repair Is Required for Infection.
Staphylococcal DNA Repair Is Required for Infection.
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葡萄球菌感染需要DNA修复。
DOI：
10.1128/mbio.02288-20
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发表时间：
2020-11-17
期刊：
影响因子：
6.4
通讯作者：
Edwards AM
中科院分区：
文献类型：
--
作者：
Ha KP;Clarke RS;Kim GL;Brittan JL;Rowley JE;Mavridou DAI;Parker D;Clarke TB;Nobbs AH;Edwards AM
为了引起感染，细菌必须在宿主免疫系统的攻击下存活。对于许多细菌，包括主要的人类病原体金黄色葡萄球菌，最大的威胁是由中性粒细胞构成的。这些免疫细胞摄取入侵的生物体，并试图用包括活性氧（ROS）的化学物质混合物杀死它们。S.金黄色葡萄球菌在这种攻击中存活对于感染的进展至关重要。然而，尚不清楚ROS如何损害S。金黄色葡萄球菌以及细菌如何修复这种损伤。在这项工作中，我们表明ROS导致葡萄球菌DNA断裂，必须由称为RexAB的双蛋白复合物修复;否则，细菌被杀死，它不能维持感染。这提供了中性粒细胞引起S.金黄色葡萄球菌和修复这种损伤的机制，使感染。为了引起感染，金黄色葡萄球菌必须承受宿主免疫防御造成的损害。然而，葡萄球菌DNA在感染过程中受损和修复的机制知之甚少。使用一组转座子突变体，我们确定了rexBA操纵子对于金黄色葡萄球菌在人全血中的存活是重要的。缺乏rexB的突变体在全身和皮肤感染的小鼠模型中的毒力也被减弱。然后，我们证明了RexAB是负责启动DNA双链断裂修复的解旋酶/核酸酶复合物的AddAB家族的成员。使用荧光报告系统，我们能够表明，中性粒细胞通过呼吸爆发产生的活性氧（ROS）引起葡萄球菌DNA双链断裂，由RexAB修复，导致诱导诱变SOS反应。我们发现粪肠球菌和戈登链球菌中的RexAB同源物也促进了这些病原体在人体血液中的存活，这表明革兰氏阳性菌在宿主组织中存活需要DNA双链断裂修复。总之，这些数据表明，DNA是宿主免疫细胞的靶标，导致双链断裂，并且AddAB家族酶对这种损伤的修复使革兰氏阳性病原体能够在感染期间存活。
To cause infection, bacteria must survive attack by the host immune system. For many bacteria, including the major human pathogen Staphylococcus aureus, the greatest threat is posed by neutrophils. These immune cells ingest the invading organisms and try to kill them with a cocktail of chemicals that includes reactive oxygen species (ROS). The ability of S. aureus to survive this attack is crucial for the progression of infection. However, it was not clear how the ROS damaged S. aureus and how the bacterium repaired this damage. In this work, we show that ROS cause breaks in the staphylococcal DNA, which must be repaired by a two-protein complex known as RexAB; otherwise, the bacterium is killed, and it cannot sustain infection. This provides information on the type of damage that neutrophils cause S. aureus and the mechanism by which this damage is repaired, enabling infection. To cause infection, Staphylococcus aureus must withstand damage caused by host immune defenses. However, the mechanisms by which staphylococcal DNA is damaged and repaired during infection are poorly understood. Using a panel of transposon mutants, we identified the rexBA operon as being important for the survival of Staphylococcus aureus in whole human blood. Mutants lacking rexB were also attenuated for virulence in murine models of both systemic and skin infections. We then demonstrated that RexAB is a member of the AddAB family of helicase/nuclease complexes responsible for initiating the repair of DNA double-strand breaks. Using a fluorescent reporter system, we were able to show that neutrophils cause staphylococcal DNA double-strand breaks through reactive oxygen species (ROS) generated by the respiratory burst, which are repaired by RexAB, leading to the induction of the mutagenic SOS response. We found that RexAB homologues in Enterococcus faecalis and Streptococcus gordonii also promoted the survival of these pathogens in human blood, suggesting that DNA double-strand break repair is required for Gram-positive bacteria to survive in host tissues. Together, these data demonstrate that DNA is a target of host immune cells, leading to double-strand breaks, and that the repair of this damage by an AddAB-family enzyme enables the survival of Gram-positive pathogens during infection.