In Vivo Evolution of a Klebsiella pneumoniae Capsule Defect With wcaJ Mutation Promotes Complement-Mediated Opsonophagocytosis During Recurrent Infection.

IF 5 2区 医学 Q2 IMMUNOLOGY
William Bain, Brian Ahn, Hernán F Peñaloza, Christi L McElheny, Nathanial Tolman, Rick van der Geest, Shekina Gonzalez-Ferrer, Nathalie Chen, Xiaojing An, Ria Hosuru, Mohammadreza Tabary, Erin Papke, Naina Kohli, Nauman Farooq, William Bachman, Tolani F Olonisakin, Zeyu Xiong, Marissa P Griffith, Mara Sullivan, Jonathan Franks, Mustapha M Mustapha, Alina Iovleva, Tomeka Suber, Robert Q Shanks, Viviana P Ferreira, Donna B Stolz, Daria Van Tyne, Yohei Doi, Janet S Lee
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Abstract

Background: Klebsiella pneumoniae carbapenemase-producing K pneumoniae (KPC-Kp) bloodstream infections are associated with high mortality. We studied clinical bloodstream KPC-Kp isolates to investigate mechanisms of resistance to complement, a key host defense against bloodstream infection.

Methods: We tested growth of KPC-Kp isolates in human serum. In serial isolates from a single patient, we performed whole genome sequencing and tested for complement resistance and binding by mixing study, direct enzyme-linked immunosorbent assay, flow cytometry, and electron microscopy. We utilized an isogenic deletion mutant in phagocytosis assays and an acute lung infection model.

Results: We found serum resistance in 16 of 59 (27%) KPC-Kp clinical bloodstream isolates. In 5 genetically related bloodstream isolates from a single patient, we noted a loss-of-function mutation in the capsule biosynthesis gene, wcaJ. Disruption of wcaJ was associated with decreased polysaccharide capsule, resistance to complement-mediated killing, and surprisingly, increased binding of complement proteins. Furthermore, an isogenic wcaJ deletion mutant exhibited increased opsonophagocytosis in vitro and impaired in vivo control in the lung after airspace macrophage depletion in mice.

Conclusions: Loss of function in wcaJ led to increased complement resistance, complement binding, and opsonophagocytosis, which may promote KPC-Kp persistence by enabling coexistence of increased bloodstream fitness and reduced tissue virulence.

带有 wcaJ 突变的肺炎克雷伯菌囊缺陷的体内演化在复发性感染过程中促进了补体介导的嗜蛋白吞噬作用。
背景:产碳青霉烯酶肺炎克雷伯菌(KPC-Kp)血流感染与高死亡率有关。我们研究了临床血流中的 KPC-Kp 分离株,以探究其对补体的抗性机制,补体是宿主抵御血流感染的关键防御机制:我们检测了 KPC-Kp 分离物在人类血清中的生长情况。我们对来自单个患者的连续分离株进行了全基因组测序,并通过混合研究、直接酶联免疫吸附试验、流式细胞术和电子显微镜检测了补体抗性和结合力。我们在吞噬试验和急性肺部感染模型中使用了一个同源缺失突变体:结果:我们在 59 个 KPC-Kp 临床血液分离株中的 16 个(27%)中发现了血清耐药性。在一名患者的 5 个基因相关的血液分离株中,我们发现了胶囊生物合成基因 wcaJ 的功能缺失突变。wcaJ 基因缺失与多糖胶囊减少、抗补体介导的杀灭有关,令人惊讶的是,与补体蛋白的结合增加了。此外,同源的wcaJ缺失突变体在体外表现出更强的嗜溶蛋白吞噬能力,而在体内,小鼠气腔巨噬细胞耗竭后对肺部的控制能力受损:结论:wcaJ 的功能缺失会导致补体抗性、补体结合和嗜蛋白吞噬能力增强,这可能会使血流适应性增强和组织毒力降低并存,从而促进 KPC-Kp 的持续存在。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Infectious Diseases
Journal of Infectious Diseases 医学-传染病学
CiteScore
13.50
自引率
3.10%
发文量
449
审稿时长
2-4 weeks
期刊介绍: Published continuously since 1904, The Journal of Infectious Diseases (JID) is the premier global journal for original research on infectious diseases. The editors welcome Major Articles and Brief Reports describing research results on microbiology, immunology, epidemiology, and related disciplines, on the pathogenesis, diagnosis, and treatment of infectious diseases; on the microbes that cause them; and on disorders of host immune responses. JID is an official publication of the Infectious Diseases Society of America.
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