The microbiota conditions a gut milieu that selects for wild-type Salmonella Typhimurium virulence.

IF 7.8 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY PLoS Biology Pub Date : 2023-08-31 eCollection Date: 2023-08-01 DOI:10.1371/journal.pbio.3002253
Ersin Gül, Erik Bakkeren, Guillem Salazar, Yves Steiger, Andrew Abi Younes, Melanie Clerc, Philipp Christen, Stefan A Fattinger, Bidong D Nguyen, Patrick Kiefer, Emma Slack, Martin Ackermann, Julia A Vorholt, Shinichi Sunagawa, Médéric Diard, Wolf-Dietrich Hardt
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Abstract

Salmonella Typhimurium elicits gut inflammation by the costly expression of HilD-controlled virulence factors. This inflammation alleviates colonization resistance (CR) mediated by the microbiota and thereby promotes pathogen blooms. However, the inflamed gut-milieu can also select for hilD mutants, which cannot elicit or maintain inflammation, therefore causing a loss of the pathogen's virulence. This raises the question of which conditions support the maintenance of virulence in S. Typhimurium. Indeed, it remains unclear why the wild-type hilD allele is dominant among natural isolates. Here, we show that microbiota transfer from uninfected or recovered hosts leads to rapid clearance of hilD mutants that feature attenuated virulence, and thereby contributes to the preservation of the virulent S. Typhimurium genotype. Using mouse models featuring a range of microbiota compositions and antibiotic- or inflammation-inflicted microbiota disruptions, we found that irreversible disruption of the microbiota leads to the accumulation of hilD mutants. In contrast, in models with a transient microbiota disruption, selection for hilD mutants was prevented by the regrowing microbiota community dominated by Lachnospirales and Oscillospirales. Strikingly, even after an irreversible microbiota disruption, microbiota transfer from uninfected donors prevented the rise of hilD mutants. Our results establish that robust S. Typhimurium gut colonization hinges on optimizing its manipulation of the host: A transient and tempered microbiota perturbation is favorable for the pathogen to both flourish in the inflamed gut and also minimize loss of virulence. Moreover, besides conferring CR, the microbiota may have the additional consequence of maintaining costly enteropathogen virulence mechanisms.

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微生物群调节肠道环境,选择野生型鼠伤寒沙门氏菌的毒力。
鼠伤寒沙门氏菌通过昂贵的HilD控制的毒力因子的表达引发肠道炎症。这种炎症减轻了由微生物群介导的定植抗性(CR),从而促进了病原体的繁殖。然而,发炎的肠道环境也可以选择hilD突变体,这些突变体不能引发或维持炎症,因此导致病原体毒力的丧失。这就提出了一个问题,即哪些条件支持鼠伤寒杆菌毒力的维持。事实上,目前尚不清楚为什么野生型hilD等位基因在天然分离株中占主导地位。在这里,我们表明,从未感染或恢复的宿主转移微生物群会导致以毒力减弱为特征的hilD突变体的快速清除,从而有助于毒力鼠伤寒沙门氏菌基因型的保存。使用具有一系列微生物群组成和抗生素或炎症引起的微生物群破坏的小鼠模型,我们发现微生物群的不可逆破坏会导致hilD突变体的积累。相反,在具有短暂微生物群破坏的模型中,由Lachnospirales和Oscillospirales主导的再生微生物群群落阻止了对hilD突变体的选择。引人注目的是,即使在不可逆的微生物群破坏之后,来自未感染供体的微生物群转移也阻止了hilD突变体的增加。我们的研究结果表明,鼠伤寒沙门氏菌强大的肠道定殖取决于优化其对宿主的操作:短暂而温和的微生物群扰动有利于病原体在发炎的肠道中繁殖,并将毒力损失降至最低。此外,除了赋予CR外,微生物群还可能具有维持昂贵的肠道病原体毒力机制的额外后果。
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来源期刊
PLoS Biology
PLoS Biology 生物-生化与分子生物学
CiteScore
14.40
自引率
2.00%
发文量
359
审稿时长
3 months
期刊介绍: PLOS Biology is an open-access, peer-reviewed general biology journal published by PLOS, a nonprofit organization of scientists and physicians dedicated to making the world's scientific and medical literature freely accessible. The journal publishes new articles online weekly, with issues compiled and published monthly. ISSN Numbers: eISSN: 1545-7885 ISSN: 1544-9173
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