Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
Institute of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg-University Mainz, Germany.
Eur J Immunol. 2019 May;49(5):747-757. doi: 10.1002/eji.201848022. Epub 2019 Mar 10.
Infection with Clostridium difficile is one of the major causes of health care acquired diarrhea and colitis. Signaling though MyD88 downstream of TLRs is critical for initiating the early protective host response in mouse models of C. difficile infection (CDI). In the intestine, MyD88 is expressed in various tissues and cell types, such as the intestinal epithelium and mononuclear phagocytes (MNP), including DC or macrophages. Using a genetic gain-of-function system, we demonstrate here that restricting functional MyD88 signaling to the intestinal epithelium, but also to MNPs is sufficient to protect mice during acute CDI by upregulation of the intestinal barrier function and recruitment of neutrophils. Nevertheless, we also show that mice depleted for CD11c-expressing MNPs in the intestine display no major defects in mounting an effective inflammatory response, indicating that the absence of these cells is irrelevant for inducing host protection during acute infection. Together, our results highlight the importance of epithelial-specific MyD88 signaling and demonstrate that although functional MyD88 signaling in DC and macrophages alone is sufficient to correct the phenotype of MyD88-deficiency, these cells do not seem to be essential for host protection in MyD88-sufficient animals during acute infection with C. difficile.
艰难梭菌感染是医疗保健相关腹泻和结肠炎的主要原因之一。在艰难梭菌感染（CDI）的小鼠模型中，TLR 下游的 MyD88 信号转导对于启动早期保护性宿主反应至关重要。在肠道中，MyD88 在各种组织和细胞类型中表达，如肠上皮细胞和单核吞噬细胞（MNP），包括 DC 或巨噬细胞。在这里，我们使用遗传功能获得系统证明，限制功能性 MyD88 信号转导到肠上皮细胞，以及 MNPs，足以通过上调肠道屏障功能和招募中性粒细胞来保护小鼠免受急性 CDI 的侵害。然而，我们还表明，在肠道中耗尽表达 CD11c 的 MNPs 的小鼠在引发有效炎症反应方面没有主要缺陷，表明这些细胞的缺失对于在急性感染期间诱导宿主保护并不重要。总之，我们的结果强调了上皮特异性 MyD88 信号转导的重要性，并表明尽管 DC 和巨噬细胞中功能性 MyD88 信号转导足以纠正 MyD88 缺陷型的表型，但在急性艰难梭菌感染期间，这些细胞对于 MyD88 充足的动物的宿主保护似乎不是必需的。
