Novel murine infection models provide deep insights into the "ménage à trois" of Campylobacter jejuni, microbiota and host innate immunity.
Novel murine infection models provide deep insights into the "ménage à trois" of Campylobacter jejuni, microbiota and host innate immunity.
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DOI：
10.1371/journal.pone.0020953
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Heimesaat MM
中科院分区：
文献类型：
--
作者：
Bereswill S;Fischer A;Plickert R;Haag LM;Otto B;Kühl AA;Dasti JI;Zautner AE;Muñoz M;Loddenkemper C;Gross U;Göbel UB;Heimesaat MM
虽然空肠弯曲杆菌感染在世界范围内有很高的流行率，并代表了一个重大的社会经济负担，它仍然没有很好地理解C。空肠引起肠道炎症。对C.空肠介导的肠道免疫病理学由于缺乏合适的脊椎动物模型而受到阻碍。特别地，小鼠显示出对该病原体的定殖抗性。为了克服这些限制，我们开发了一种新的C。使用无菌小鼠的空肠感染模型，其中通过抗生素治疗根除肠道植物群。这些动物可以永久地与完整的人类（hfa）或小鼠（mfa）微生物群相关联。经口感染C.空肠在gnotobiotic和hfa小鼠的胃肠道中定殖六周，而mfa小鼠在两天内清除病原体。稳定的C。空肠定植伴随促炎免疫应答，表现为hfa小鼠结肠粘膜中T和B淋巴细胞、调节性T细胞、中性粒细胞和凋亡细胞数量增加，以及TNF-α、IL-6和MCP-1浓度增加。对MyD 88 −/−、TRIF−/−、TLR 4 −/−和TLR 9 −/−小鼠的分析表明，TLR 4-和TLR 9-信号传导对于C.空肠感染有趣的是，C。与亲本菌株感染相比，甲酸代谢和感知缺陷的空肠突变菌株诱导较少的肠道免疫病理学。总之，小鼠肠道植物群对于抗C.空肠，并可通过用人类植物群重建知菌小鼠来克服。检测C.分别通过宿主TLR 4和TLR 9介导的空泡-LPS和-CpG-DNA在免疫病理学中起关键作用。最后，宿主的免疫反应与细菌的甲酸代谢和入侵适应性密切相关。我们的结论是，gnotobiotic和“人源化”小鼠代表了优秀的新的C。空肠感染和炎症模型，并提供深入了解C。空肠、微生物群和人类弯曲杆菌病的先天免疫。
Although Campylobacter jejuni-infections have a high prevalence worldwide and represent a significant socioeconomic burden, it is still not well understood how C. jejuni causes intestinal inflammation. Detailed investigation of C. jejuni-mediated intestinal immunopathology is hampered by the lack of appropriate vertebrate models. In particular, mice display colonization resistance against this pathogen. To overcome these limitations we developed a novel C. jejuni-infection model using gnotobiotic mice in which the intestinal flora was eradicated by antibiotic treatment. These animals could then be permanently associated with a complete human (hfa) or murine (mfa) microbiota. After peroral infection C. jejuni colonized the gastrointestinal tract of gnotobiotic and hfa mice for six weeks, whereas mfa mice cleared the pathogen within two days. Strikingly, stable C. jejuni colonization was accompanied by a pro-inflammatory immune response indicated by increased numbers of T- and B-lymphocytes, regulatory T-cells, neutrophils and apoptotic cells, as well as increased concentrations of TNF-α, IL-6, and MCP-1 in the colon mucosa of hfa mice. Analysis of MyD88−/−, TRIF−/−, TLR4−/−, and TLR9−/− mice revealed that TLR4- and TLR9-signaling was essential for immunopathology following C. jejuni-infection. Interestingly, C. jejuni-mutant strains deficient in formic acid metabolism and perception induced less intestinal immunopathology compared to the parental strain infection. In summary, the murine gut flora is essential for colonization resistance against C. jejuni and can be overcome by reconstitution of gnotobiotic mice with human flora. Detection of C. jejuni-LPS and -CpG-DNA by host TLR4 and TLR9, respectively, plays a key role in immunopathology. Finally, the host immune response is tightly coupled to bacterial formic acid metabolism and invasion fitness. We conclude that gnotobiotic and “humanized” mice represent excellent novel C. jejuni-infection and -inflammation models and provide deep insights into the immunological and molecular interplays between C. jejuni, microbiota and innate immunity in human campylobacteriosis.
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DOI：
10.1073/pnas.0502040102
发表时间：
2005-06-28
影响因子：
11.1
作者：
Andersen-Nissen, E;Smith, KD;Aderem, A
通讯作者：
Aderem, A
影响因子：
3.1
作者：
Rathinam, Vijay A. K.;Appledorn, Daniel M.;Mansfield, Linda S.
通讯作者：
Mansfield, Linda S.
影响因子：
3.1
作者：
JESUDASON, MV;HENTGES, DJ;PONGPECH, P
通讯作者：
PONGPECH, P
影响因子：
6.4
作者：
KORLATH, JA;OSTERHOLM, MT;ROBINSON, RA
通讯作者：
ROBINSON, RA
影响因子：
9.4
作者：
Poly, F;Threadgill, D;Stintzi, A
通讯作者：
Stintzi, A