Phagosomal Acidification Is Required to Kill Streptococcus pneumoniae in a Zebrafish Model
Phagosomal Acidification Is Required to Kill Streptococcus pneumoniae in a Zebrafish Model
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在斑马鱼模型中需要吞噬体酸化来杀死肺炎链球菌
DOI：
10.1155/2022/9429516
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发表时间：
2022
影响因子：
3.4
通讯作者：
Prajsnar T
中科院分区：
文献类型：
--
作者：
Prajsnar T
肺炎链球菌（Streptococcus pneumoniae）（肺炎球菌）是引起侵袭性疾病（包括社区获得性菌血症）的主要人类病原体，并且仍然是全球死亡率的主要原因。对吞噬细胞在杀灭细菌中的作用的了解仍然有限，特别是在体内。在这项研究中，我们建立了一个斑马鱼模型，研究静脉注射肺炎球菌和专业吞噬细胞，如巨噬细胞和中性粒细胞之间的相互作用，以解开这些免疫细胞的细菌杀伤机制。我们的模型证实了多糖荚膜通过抑制吞噬作用在促进肺炎球菌毒力中的关键作用。相反，我们发现缺乏荚膜的肺炎球菌被巨噬细胞迅速内化。低剂量的氯化钠。肺炎球菌在感染后48小时内（hpi）的死亡率接近100%，而50倍以上剂量的未包囊肺炎球菌很容易被清除。体内细菌数量的时程分析表明，虽然包囊肺炎球菌在宿主死亡时增殖到超过105CFU的水平，但未包囊的细菌无法生长，并在20 hpi内被清除。使用遗传诱导的巨噬细胞耗竭，我们证实了巨噬细胞在细菌清除中的重要作用。此外，我们表明，在吞噬巨噬细胞，吞噬体进行快速酸化。空泡ATP酶（v‐ ATP酶）的遗传和化学抑制可防止细胞内细菌杀伤并诱导宿主死亡，表明吞噬体酸化在对入侵肺炎球菌的免疫中起关键作用。我们还表明，我们的模型可用于研究抗菌药物对体内肺炎球菌的疗效。总的来说，我们的数据证实，幼斑马鱼可用于解剖体内肺炎球菌感染期间的杀伤机制，并强调巨噬细胞吞噬体酸化对病原体清除的关键作用。
Streptococcus pneumoniae(the pneumococcus) is a major human pathogen causing invasive disease, including community‐acquired bacteraemia, and remains a leading cause of global mortality. Understanding the role of phagocytes in killing bacteria is still limited, especiallyin vivo. In this study, we established a zebrafish model to study the interaction between intravenously administered pneumococci and professional phagocytes such as macrophages and neutrophils, to unravel bacterial killing mechanisms employed by these immune cells. Our model confirmed the key role of polysaccharide capsule in promoting pneumococcal virulence through inhibition of phagocytosis. Conversely, we show pneumococci lacking a capsule are rapidly internalised by macrophages. Low doses of encapsulatedS. pneumoniaecause near 100% mortality within 48 hours postinfection (hpi), while 50 times higher doses of unencapsulated pneumococci are easily cleared. Time course analysis ofin vivobacterial numbers reveals that while encapsulated pneumococcus proliferates to levels exceeding 105CFU at the time of host death, unencapsulated bacteria are unable to grow and are cleared within 20 hpi. Using genetically induced macrophage depletion, we confirmed an essential role for macrophages in bacterial clearance. Additionally, we show that upon phagocytosis by macrophages, phagosomes undergo rapid acidification. Genetic and chemical inhibition of vacuolar ATPase (v‐ATPase) prevents intracellular bacterial killing and induces host death indicating a key role of phagosomal acidification in immunity to invading pneumococci. We also show that our model can be used to study the efficacy of antimicrobials against pneumococciin vivo. Collectively, our data confirm that larval zebrafish can be used to dissect killing mechanisms during pneumococcal infectionin vivoand highlight key roles for phagosomal acidification in macrophages for pathogen clearance.
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影响因子：
2.9
作者：
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影响因子：
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作者：
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影响因子：
1.8
作者：
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影响因子：
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作者：
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