FimH adhesin of type 1 fimbriae is a potent inducer of innate antimicrobial responses which requires TLR4 and type 1 interferon signalling.
FimH adhesin of type 1 fimbriae is a potent inducer of innate antimicrobial responses which requires TLR4 and type 1 interferon signalling.
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DOI：
10.1371/journal.ppat.1000233
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发表时间：
2008-12
期刊：
影响因子：
6.7
通讯作者：
Mackenzie R
中科院分区：
文献类型：
--
作者：
Ashkar AA;Mossman KL;Coombes BK;Gyles CL;Mackenzie R
细菌成分已被证明可通过Toll样受体（TLRs）诱导先天性抗病毒免疫。我们最近发现，1型菌毛的黏附素部分FimH可通过TLR4诱导先天性免疫系统。在此我们报道FimH在体外和体内均可诱导强烈的先天性抗菌反应。FimH在小鼠巨噬细胞和原代小鼠胚胎成纤维细胞（MEFs）中诱导出一种先天性抗病毒状态，这与干扰素 -β的产生相关。此外，FimH在野生型小鼠的细胞中诱导先天性抗病毒反应，但在MyD88 - / -、Trif - / -、干扰素 -α/β受体 - / - 或IRF3 - / - 小鼠的细胞中则不能。阴道给予FimH（而非脂多糖，LPS）可完全保护野生型小鼠，但不能保护MyD88 - / -、干扰素 -α/β受体 - / -、IRF3 - / - 或TLR4 - / - 小鼠免受后续生殖器单纯疱疹病毒2型（HSV - 2）的攻击。FimH诱导的先天性抗病毒免疫与干扰素 -β的产生相关，但与干扰素 -α或干扰素 -γ无关。为了检验在自然感染情况下FimH是否在先天性免疫诱导中起作用，我们在C57Bl/6（B6）小鼠和TLR4缺陷小鼠的尿路中检测了对野生型尿路致病性大肠杆菌（UPEC）和FimH缺失突变体的先天性免疫反应。表达FimH的UPEC在B6小鼠中诱导出强烈的多形核细胞反应，但在TLR4 - / - 小鼠中则不能，而缺乏FimH的突变细菌则无此作用。此外，TLR4的存在对于先天性控制和抵御UPEC至关重要。我们的结果表明，FimH是先天性抗菌反应的强效诱导剂，并且在黏膜表面通过TLR4的信号传导方式与LPS不同。我们的研究表明，FimH有可能被用作一种针对黏膜病原体的先天性杀菌剂。
先天性免疫系统是一种进化上保守的防御机制，可保护宿主免受病毒、细菌和真菌等微生物的感染。入侵的病原体可被一组进化上保守的受体识别，包括Toll样受体（TLRs），这些受体可在黏膜表面的上皮细胞表面找到。我们最近发现，尿路致病性大肠杆菌1型菌毛顶端的一种特异性黏附素FimH可直接与TLR4结合。在此，我们证明了这种相互作用的生物学意义。在自然感染的情况下，TLR4对FimH的识别对于宿主针对尿路致病性大肠杆菌产生先天性免疫反应非常重要。此外，我们还表明，纯化的FimH蛋白在组织培养和动物模型中均可诱导强烈的先天性抗病毒反应。这种反应主要由I型干扰素的产生所介导。我们的结果表明，FimH是开发用于抵御病原体感染的杀菌剂的极佳候选者。
Components of bacteria have been shown to induce innate antiviral immunity via Toll-like receptors (TLRs). We have recently shown that FimH, the adhesin portion of type 1 fimbria, can induce the innate immune system via TLR4. Here we report that FimH induces potent in vitro and in vivo innate antimicrobial responses. FimH induced an innate antiviral state in murine macrophage and primary MEFs which was correlated with IFN-β production. Moreover, FimH induced the innate antiviral responses in cells from wild type, but not from MyD88−/−, Trif−/−, IFN−α/βR−/− or IRF3−/− mice. Vaginal delivery of FimH, but not LPS, completely protected wild type, but not MyD88−/−, IFN-α/βR−/−, IRF3−/− or TLR4−/− mice from subsequent genital HSV-2 challenge. The FimH-induced innate antiviral immunity correlated with the production of IFN-β, but not IFN-α or IFN-γ. To examine whether FimH plays a role in innate immune induction in the context of a natural infection, the innate immune responses to wild type uropathogenic E. coli (UPEC) and a FimH null mutant were examined in the urinary tract of C57Bl/6 (B6) mice and TLR4-deficient mice. While UPEC expressing FimH induced a robust polymorphonuclear response in B6, but not TLR4−/− mice, mutant bacteria lacking FimH did not. In addition, the presence of TLR4 was essential for innate control of and protection against UPEC. Our results demonstrate that FimH is a potent inducer of innate antimicrobial responses and signals differently, from that of LPS, via TLR4 at mucosal surfaces. Our studies suggest that FimH can potentially be used as an innate microbicide against mucosal pathogens. The innate immune system is an evolutionarily conserved defence mechanism that protects the host from infection by microbes such as viruses, bacteria and fungi. Incoming pathogens are recognized by a set of evolutionary conserved receptors, including the Toll-like receptors (TLRs), that can be found on the surface of epithelial cells at the mucosal surface. We recently found that FimH, a specific adhesin located at the tip of type 1 fimbriae in uropathogenic E. coli, binds directly to TLR4. Here, we demonstrate the biological significance of this interaction. In the context of a natural infection, recognition of FimH by TLR4 is important for the host to mount an innate immune response against uropathogenic E. coli. Furthermore, we show that purified FimH protein induces a potent innate antiviral response, both in tissue culture and in animal models. This response is mediated predominantly by the production of type I interferon. Our results suggest that FimH is an excellent candidate for development as a microbicide against pathogen infection.
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影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
5.4
作者：
Ashkar, AA;Bauer, S;Rosenthal, KL
通讯作者：
Rosenthal, KL
影响因子：
5.2
作者：
Herbst, MM;Pyles, RB
通讯作者：
Pyles, RB
DOI：
10.1073/pnas.92.6.2081
发表时间：
1995-03-14
影响因子：
11.1
作者：
JONES, CH;PINKNER, JS;HULTGREN, SJ
通讯作者：
HULTGREN, SJ
影响因子：
5.4
作者：
Harandi, AM;Eriksson, K;Holmgren, J
通讯作者：
Holmgren, J