The microbiota mediates pathogen clearance from the gut lumen after non-typhoidal Salmonella diarrhea.
The microbiota mediates pathogen clearance from the gut lumen after non-typhoidal Salmonella diarrhea.
复制标题
DOI：
10.1371/journal.ppat.1001097
复制
发表时间：
2010-09-09
期刊：
影响因子：
6.7
通讯作者：
Hardt WD
中科院分区：
文献类型：
--
作者：
Endt K;Stecher B;Chaffron S;Slack E;Tchitchek N;Benecke A;Van Maele L;Sirard JC;Mueller AJ;Heikenwalder M;Macpherson AJ;Strugnell R;von Mering C;Hardt WD
许多肠道致病细菌以哺乳动物肠道为目标。人们对保护宿主免受感染的机制知之甚少。我们使用鼠伤寒沙门氏菌腹泻小鼠模型研究了分泌性抗体 (sIgA) 和微生物群的保护功能。这种病原体是全世界人类腹泻的常见原因。鼠伤寒沙门氏菌 (S. tm att, sseD) 在链霉素治疗的小鼠中引起自限性肠道感染。 40 天后，所有动物都克服了疾病，产生了 sIgA 反应，并且大多数动物已经清除了肠腔中的病原体。 sIgA 限制病原体进入粘膜表面，并在攻击性感染中保护其免受肠道炎症的影响。这种保护是 O 抗原特异性的，正如缺乏鼠伤寒沙门氏菌 O 抗原的病原体（wbaP、肠炎沙门氏菌）和 sIgA 缺陷小鼠（TCRβ−/−δ−/−、JH −/−、IgA−/−、pIgR−/−）所证明的那样。令人惊讶的是，sIgA 缺乏并不影响病原体从肠腔清除的动力学。相反，这是由微生物群介导的。使用“L-小鼠”证实了这一点，“L-小鼠”肠道菌群复杂性低，缺乏定植抗性并产生正常的 sIgA 反应，但无法从肠腔中清除 S.tm att。在这些小鼠中，病原体清除是通过转移正常的复杂微生物群来实现的。因此，除了定植抗性（完整微生物群对病原体的阻断）之外，微生物群还介导第二种新的保护功能，即病原体清除。在这里，正常微生物群从耗尽和成分紊乱的状态中重新生长，并逐渐清除肠腔中甚至非常高的病原体负荷，而肠腔是大多数“经典”免疫效应机制无法进入的部位。总之，sIgA 和微生物群具有互补的保护功能。微生物群赋予定植抵抗力并介导原发感染中的病原体清除，而如果宿主再次遇到相同的病原体，sIgA 可以防止疾病。这对于治疗鼠伤寒沙门氏菌腹泻和预防传播具有重要意义。许多病原体感染肠道。针对这些感染的保护是由粘膜免疫防御（包括分泌的 IgA）以及竞争性肠道微生物群介导的。然而，到目前为止，这两种不同防御机制的相对重要性仍不清楚。我们以非伤寒沙门氏菌 (NTS) 肠道感染为例解决了这个问题，这种感染可以在感染患者的粪便中长期传播。我们使用小鼠模型来揭示肠道微生物群和适应性免疫系统在对抗 NTS 感染方面具有不同但互补的功能。原发性沙门氏菌感染会破坏正常微生物群并引发沙门氏菌特异性 sIgA。当动物第二次感染 NTS 时，sIgA 可以预防疾病。然而，sIgA 对于从肠道清除病原体来说是可有可无的。相反，这是由微生物群介导的。通过重建其正常密度和组成，微生物群对于终止长期粪便沙门氏菌排泄是必要且充分的。这建立了一个新的范例：微生物群清除肠腔中的病原体，而 sIgA 可以在相同病原体再次感染时防止疾病。这对于 sIgA 反应的进化作用以及开发基于微生物群的疗法来治愈感染患者具有重要意义。
Many enteropathogenic bacteria target the mammalian gut. The mechanisms protecting the host from infection are poorly understood. We have studied the protective functions of secretory antibodies (sIgA) and the microbiota, using a mouse model for S. typhimurium diarrhea. This pathogen is a common cause of diarrhea in humans world-wide. S. typhimurium (S. tm att, sseD) causes a self-limiting gut infection in streptomycin-treated mice. After 40 days, all animals had overcome the disease, developed a sIgA response, and most had cleared the pathogen from the gut lumen. sIgA limited pathogen access to the mucosal surface and protected from gut inflammation in challenge infections. This protection was O-antigen specific, as demonstrated with pathogens lacking the S. typhimurium O-antigen (wbaP, S. enteritidis) and sIgA-deficient mice (TCRβ−/−δ−/−, JH −/−, IgA−/−, pIgR−/−). Surprisingly, sIgA-deficiency did not affect the kinetics of pathogen clearance from the gut lumen. Instead, this was mediated by the microbiota. This was confirmed using ‘L-mice’ which harbor a low complexity gut flora, lack colonization resistance and develop a normal sIgA response, but fail to clear S. tm att from the gut lumen. In these mice, pathogen clearance was achieved by transferring a normal complex microbiota. Thus, besides colonization resistance ( = pathogen blockage by an intact microbiota), the microbiota mediates a second, novel protective function, i.e. pathogen clearance. Here, the normal microbiota re-grows from a state of depletion and disturbed composition and gradually clears even very high pathogen loads from the gut lumen, a site inaccessible to most “classical” immune effector mechanisms. In conclusion, sIgA and microbiota serve complementary protective functions. The microbiota confers colonization resistance and mediates pathogen clearance in primary infections, while sIgA protects from disease if the host re-encounters the same pathogen. This has implications for curing S. typhimurium diarrhea and for preventing transmission. Numerous pathogens infect the gut. Protection against these infections is mediated by mucosal immune defenses including secreted IgA as well as by the competing intestinal microbiota. However, so far the relative importance of these two different defense mechanisms remains unclear. We addressed this question using the example of non-typhoidal Salmonella (NTS) gut infections which can be spread in stool of infected patients over long periods of time. We used a mouse model to reveal that the intestinal microbiota and the adaptive immune system hold different but complementary functions in fighting NTS infections. A primary Salmonella infection disrupts the normal microbiota and elicits Salmonella-specific sIgA. sIgA prevents disease when the animal is infected with NTS for a second time. However, sIgA was dispensable for pathogen clearance from the gut. Instead, this was mediated by the microbiota. By re-establishing its normal density and composition, the microbiota was necessary and sufficient for terminating long-term fecal Salmonella excretion. This establishes a novel paradigm: The microbiota clears the pathogen from the gut lumen, while sIgA protects from disease upon re-infection with the same pathogen. This has implications for the evolutionary role of sIgA responses as well as for developing microbiota-based therapies for curing infected patients.
登录
查看更多内容
影响因子：
3.3
作者：
CURTISS, R;KELLY, SM;HASSAN, JO
通讯作者：
HASSAN, JO
影响因子：
4.4
作者：
CHEN, JZ;TROUNSTINE, M;HUSZAR, D
通讯作者：
HUSZAR, D
影响因子：
3.6
作者：
Gunn, JS;Lim, KB;Miller, SI
通讯作者：
Miller, SI
影响因子：
11.8
作者：
Hohmann, EL
通讯作者：
Hohmann, EL
影响因子：
14.9
作者：
Cole JR;Wang Q;Cardenas E;Fish J;Chai B;Farris RJ;Kulam-Syed-Mohideen AS;McGarrell DM;Marsh T;Garrity GM;Tiedje JM
通讯作者：
Tiedje JM