Mitochondrial ROS production by neutrophils is required for host antimicrobial function against Streptococcus pneumoniae and is controlled by A2B adenosine receptor signaling.
Mitochondrial ROS production by neutrophils is required for host antimicrobial function against Streptococcus pneumoniae and is controlled by A2B adenosine receptor signaling.
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DOI：
10.1371/journal.ppat.1010700
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发表时间：
2022-11
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影响因子：
6.7
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中科院分区：
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--
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多形核白细胞（PMNs）通过多种抗菌活性控制肺炎链球菌（肺炎球菌）感染。我们以前发现活性氧（ROS）是最佳抗菌功能所必需的，然而，NADPH氧化酶是已知的中性粒细胞杀死肺炎球菌的能力。在这项研究中，我们探讨了由线粒体产生的ROS在PMN抗肺炎球菌抗菌防御中的作用。我们发现，线粒体是一个重要来源的整体细胞内的活性氧产生的小鼠中性粒细胞在感染。我们研究了所涉及的宿主和细菌因素，发现线粒体ROS（MitROS）是独立于细菌荚膜或肺炎球菌溶血素产生的，但与PMN直接接触的活细菌的存在增强了反应。我们进一步发现，MyD 88-/- PMNs响应于肺炎球菌感染产生较少的MitROS，这表明释放的细菌产物作为TLR配体足以诱导PMNs中的MitROS产生。为了测试MitROS在PMN功能中的作用，我们使用了调理吞噬细胞杀伤试验，发现MitROS是PMN杀伤肺炎球菌的能力所必需的。然后，我们研究了MitROS在宿主抵抗中的作用，发现MitROS是由PMNs响应肺炎球菌感染而产生的。重要的是，在全身性攻击之前用MitROS清除剂处理小鼠导致感染宿主的存活率降低。在探索控制MitROS的宿主途径时，我们专注于细胞外腺苷，已知其控制PMN抗肺炎球菌活性，并发现通过A2 B腺苷受体的信号传导抑制PMN的MitROS产生。A2 BR-/-小鼠产生更多的MitROS，对感染的抵抗力明显更强。最后，我们使用人类中性粒细胞验证了我们研究结果的临床相关性。总之，我们发现了一种新的途径，它控制PMNs产生MitROS，形成宿主对S。肺炎。尽管存在抗生素和疫苗，但肺炎链球菌感染仍然是全球死亡率和发病率的严重原因。了解保护性宿主反应是设计改进的抗感染疗法的关键。中性粒细胞是先天性免疫细胞，对控制S。肺炎感染。本研究探讨了中性粒细胞杀伤S.肺炎。我们发现，线粒体的主要作用是产生能量，也产生活性氧（ROS），这对中性粒细胞杀死S。肺炎。我们探讨了参与中性粒细胞线粒体活性氧（MitROS）生产的细菌和宿主因素。我们发现中性粒细胞对细菌产物的识别触发了这种反应，宿主A2 B腺苷受体调节了这种反应。肺炎。这项研究描述了一种控制抗微生物反应的新途径，可以成为未来的治疗靶点。
Polymorphonuclear cells (PMNs) control Streptococcus pneumoniae (pneumococcus) infection through various antimicrobial activities. We previously found that reactive oxygen species (ROS) were required for optimal antibacterial function, however, the NADPH oxidase is known to be dispensable for the ability of PMNs to kill pneumococci. In this study, we explored the role of ROS produced by the mitochondria in PMN antimicrobial defense against pneumococci. We found that the mitochondria are an important source of overall intracellular ROS produced by murine PMNs in response to infection. We investigated the host and bacterial factors involved and found that mitochondrial ROS (MitROS) are produced independent of bacterial capsule or pneumolysin but presence of live bacteria that are in direct contact with PMNs enhanced the response. We further found that MyD88-/- PMNs produced less MitROS in response to pneumococcal infection suggesting that released bacterial products acting as TLR ligands are sufficient for inducing MitROS production in PMNs. To test the role of MitROS in PMN function, we used an opsonophagocytic killing assay and found that MitROS were required for the ability of PMNs to kill pneumococci. We then investigated the role of MitROS in host resistance and found that MitROS are produced by PMNs in response to pneumococcal infection. Importantly, treatment of mice with a MitROS scavenger prior to systemic challenge resulted in reduced survival of infected hosts. In exploring host pathways that control MitROS, we focused on extracellular adenosine, which is known to control PMN anti-pneumococcal activity, and found that signaling through the A2B adenosine receptor inhibits MitROS production by PMNs. A2BR-/- mice produced more MitROS and were significantly more resistant to infection. Finally, we verified the clinical relevance of our findings using human PMNs. In summary, we identified a novel pathway that controls MitROS production by PMNs, shaping host resistance against S. pneumoniae. Despite the presence of antibiotics and vaccines, Streptococcus pneumoniae infections remain a serious cause of mortality and morbidity globally. Understanding protective host responses is key for designing improved therapies against infection. Neutrophils are innate immune cells that are crucial for control of S. pneumoniae infection. In this study we explored the mechanisms by which neutrophils kill S. pneumoniae. We found that the mitochondria, whose primary role is energy production, also produce reactive oxygen species (ROS) that are critical for the ability of neutrophils to kill S. pneumoniae. We explored the bacterial and host factors involved in mitochondrial ROS (MitROS) production by neutrophils. We found that recognition of bacterial products by neutrophils triggers this response and that the host A2B adenosine receptor regulates it. Importantly, MitROS were required for host resistance against S. pneumoniae. This study describes a novel pathway that controls anti-microbial responses and can be a future therapeutic target.
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影响因子：
6.7
作者：
Greene NG;Narciso AR;Filipe SR;Camilli A
通讯作者：
Camilli A
影响因子：
7.4
作者：
Dikalov, Sergey
通讯作者：
Dikalov, Sergey
DOI：
10.1084/jem.20161621
发表时间：
2017-05-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Deniset JF;Surewaard BG;Lee WY;Kubes P
通讯作者：
Kubes P
影响因子：
5.7
作者：
Bou Ghanem EN;Lee JN;Joma BH;Meydani SN;Leong JM;Panda A
通讯作者：
Panda A
影响因子：
3.1
作者：
Bhalla, Manmeet;Heinzinger, Lauren R.;Ghanem, Elsa N. Bou
通讯作者：
Ghanem, Elsa N. Bou