In vivo evolution of a Klebsiella pneumoniae capsule defect promotes complement-mediated opsono-phagocytosis and persistence during recurrent infection.
In vivo evolution of a Klebsiella pneumoniae capsule defect promotes complement-mediated opsono-phagocytosis and persistence during recurrent infection.
复制标题
肺炎克雷伯菌荚膜缺陷的体内进化促进补体介导的调理吞噬作用和复发感染期间的持续存在。
DOI：
10.1101/2023.05.31.542722
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Bachman,Will
中科院分区：
文献类型：
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作者：
Bain,William;Ahn,Brian;Peñaloza,HernánF;McElheny,ChristiL;Tolman,Nathanial;vanderGeest,Rick;Gonzalez-Ferrer,Shekina;Chen,Nathalie;An,Xiaojing;Hosuru,Ria;Tabary,Mohammadreza;Papke,Erin;Kohli,Naina;Farooq,Nauman;Bachman,Will
产碳青霉烯酶肺炎克雷伯菌肺炎克雷伯氏菌（KPC-Kp）血流感染很少压倒宿主，但与高死亡率相关。补体系统是抵抗血流感染的关键宿主防御。然而，KPC-Kp分离株中存在不同的血清耐药性报告。我们评估了59株KPC-Kp临床分离株在人血清中的生长情况，发现16/59株（27%）的耐药性增加。我们确定了5个遗传相关的血流分离株，从一个单一的患者在延长住院期间收集不同的血清耐药谱，标志着复发KPC-Kp血流感染。我们注意到在感染过程中出现的荚膜生物合成基因wcaJ的功能缺失突变与多糖荚膜含量降低和对补体介导的杀伤的抵抗有关。令人惊讶的是，与野生型菌株相比，wcaJ的破坏增加了补体蛋白在微生物表面上的沉积，并导致人全血中补体介导的调理吞噬作用增加。在急性肺部感染模型中，小鼠气隙中调理素吞噬功能的丧失损害了wcaJ功能丧失突变体的体内控制。这些发现描述了一种荚膜突变的出现，该突变通过使血流适应性增加和组织毒力降低共存来促进宿主内的KPC-Kp持久性。
Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) bloodstream infections rarely overwhelm the host but are associated with high mortality. The complement system is a key host defense against bloodstream infection. However, there are varying reports of serum resistance among KPC-Kp isolates. We assessed growth of 59 KPC-Kp clinical isolates in human serum and found increased resistance in 16/59 (27%). We identified five genetically-related bloodstream isolates with varying serum resistance profiles collected from a single patient during an extended hospitalization marked by recurrent KPC-Kp bloodstream infections. We noted a loss-of-function mutation in the capsule biosynthesis gene, wcaJ, that emerged during infection was associated with decreased polysaccharide capsule content, and resistance to complement-mediated killing. Surprisingly, disruption of wcaJ increased deposition of complement proteins on the microbial surface compared to the wild-type strain and led to increased complement-mediated opsono-phagocytosis in human whole blood. Disabling opsono-phagocytosis in the airspaces of mice impaired in vivo control of the wcaJ loss-of-function mutant in an acute lung infection model. These findings describe the rise of a capsular mutation that promotes KPC-Kp persistence within the host by enabling co-existence of increased bloodstream fitness and reduced tissue virulence.