Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota.
Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota.
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DOI：
10.1371/journal.pbio.0050244
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发表时间：
2007-10
期刊：
影响因子：
9.8
通讯作者：
Hardt, Wolf-Dietrich
中科院分区：
文献类型：
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作者：
Stecher, Barbel;Robbiani, Riccardo;Walker, Alan W;Westendorf, Astrid M;Barthel, Manja;Kremer, Marcus;Chaffron, Samuel;Macpherson, Andrew J;Buer, Jan;Parkhill, Julian;Dougan, Gordon;von Mering, Christian;Hardt, Wolf-Dietrich
哺乳动物身体的大多数粘膜表面都定居有微生物群落（“微生物群”）。高密度的共生微生物群栖息在肠道中并防止感染（“定植抵抗”）。人们对肠道致病菌成功与微生物群竞争并克服定植抗性的毒力策略知之甚少。在这里，我们在小鼠结肠炎模型中研究了肠道病原菌肠沙门氏菌亚种 1 血清型鼠伤寒 (S. Tm) 对肠道微生物群的操纵：我们发现 S. Tm 诱导的炎症宿主反应改变了微生物群组成并抑制其生长。与野生型 S.Tm 相比，无法引发结肠炎的无毒 invGsseD 突变体在微生物群的竞争中被击败。如果与野生型 S.Tm 混合感染或患有炎症性肠病的小鼠（IL10−/−，VILLIN-HACL4-CD8）同时产生炎症，则这种竞争性缺陷会得到恢复。因此，炎症对于克服定植抵抗是必要且充分的。这揭示了传染病的一个新概念：与当前的想法相反，炎症并不总是对病原体有害。触发宿主的免疫防御可以改变保护性微生物群和病原体之间的平衡，使之有利于病原体。密集的微生物群落在哺乳动物的肠道中，有助于健康和营养，并提供有效的保护，抵御大多数病原入侵者。肠道病原体可以克服这种定植抵抗力并引起疾病；然而，用于做到这一点的机制仍然难以捉摸。在这项研究中，我们分析了模型病原体肠沙门氏菌亚种 1 鼠伤寒血清型 (S. Tm) 的肠道感染。我们表明，有毒的野生型病原体通过诱导宿主的炎症免疫反应并利用其达到其目的来克服定植抵抗力。相比之下，缺乏引发炎症的无毒沙门氏菌突变体本身无法克服定植抗性。如果在患有炎症性肠病（遗传性和诱导性）的小鼠中同时提供炎症或通过与野生型 S.Tm. 共感染，则该突变体的定植会恢复。这些发现揭示了病原菌克服定植抗性的一种先前未被认识的策略：滥用宿主的炎症免疫反应以获得对抗肠道正常微生物群落的优势。这代表着揭示宿主、微生物群和病原体三向相互作用的分子机制的第一步。诱导炎症是强毒病原体鼠伤寒沙门氏菌在肠道定植竞赛中战胜保护性常驻微生物群的能力的关键。
Most mucosal surfaces of the mammalian body are colonized by microbial communities (“microbiota”). A high density of commensal microbiota inhabits the intestine and shields from infection (“colonization resistance”). The virulence strategies allowing enteropathogenic bacteria to successfully compete with the microbiota and overcome colonization resistance are poorly understood. Here, we investigated manipulation of the intestinal microbiota by the enteropathogenic bacterium Salmonella enterica subspecies 1 serovar Typhimurium (S. Tm) in a mouse colitis model: we found that inflammatory host responses induced by S. Tm changed microbiota composition and suppressed its growth. In contrast to wild-type S. Tm, an avirulent invGsseD mutant failing to trigger colitis was outcompeted by the microbiota. This competitive defect was reverted if inflammation was provided concomitantly by mixed infection with wild-type S. Tm or in mice (IL10−/−, VILLIN-HACL4-CD8) with inflammatory bowel disease. Thus, inflammation is necessary and sufficient for overcoming colonization resistance. This reveals a new concept in infectious disease: in contrast to current thinking, inflammation is not always detrimental for the pathogen. Triggering the host's immune defence can shift the balance between the protective microbiota and the pathogen in favour of the pathogen. A dense microbial community colonizes the intestinal tract of mammals, contributing to health and nutrition and conferring efficient protection against most pathogenic intruders. Intestinal pathogens can overcome this colonization resistance and cause disease; however, the mechanisms used to do this are still elusive. In this study we analyzed intestinal infection by the model pathogen Salmonella enterica subspecies 1 serovar Typhimurium (S. Tm). We show that the virulent wild-type pathogen overcomes colonization resistance by inducing the host's inflammatory immune response and exploiting it for its purpose. In contrast, an avirulent Salmonella mutant defective in triggering inflammation was unable to overcome colonization resistance by itself. Colonization by this mutant was restored if inflammation was provided concomitantly, in mice with inflammatory bowel disease (genetic and inducible) or by co-infection with wild-type S. Tm. These findings reveal a previously unrecognized strategy by which pathogenic bacteria overcome colonization resistance: abusing the host's inflammatory immune response to gain an edge against the normal microbial community of the gut. This represents a first step towards unravelling the molecular mechanisms underlying this three-way interaction of host, microbiota, and pathogens. Inducing inflammation is key to the ability of the virulent pathogen Salmonella enterica serovar Typhimurium to outcompete the protective resident microbiota in a race to colonize the gut.