Center of Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
J Infect Dis. 2012 Nov;206(9):1415-23. doi: 10.1093/infdis/jis505. Epub 2012 Aug 16.
Pneumonia is frequently caused by gram-negative pathogens, among which Klebsiella pneumoniae prominently features. Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is important for an appropriate immune response during infection. TLR signaling can proceed via 2 distinct routes that are dependent on the adaptor proteins Myeloid differentiation primary response gene (88) (MyD88) and TIR-domain-containing adaptor-inducing interferon-β (TRIF). The aim of the study was to determine the relative contribution of MyD88 and TRIF signaling in resident and hematopoietic cells to host defense during pneumonia.
Bone marrow chimeras of MyD88 deficient/wild type and TRIF mutant/wild type mice were created and infected with K. pneumoniae via the airways.
MyD88 in both resident and hematopoietic cells contributed to survival and antibacterial defense in late-stage infection, whereas only TRIF in hematopoietic cells was protective. On the other hand, resident MyD88 and hematopoietic TRIF contributed to distant cellular injury. Resident MyD88 was pivotal for early chemokine release and neutrophil recruitment in the bronchoalveolar space.
MyD88- and TRIF-dependent signaling has a differential contribution to host defense in different cell types that changes from early- to late-stage gram-negative pneumonia.
肺炎常由革兰氏阴性病原体引起，其中肺炎克雷伯菌尤为突出。Toll 样受体（TLR）识别病原体相关分子模式对于感染期间适当的免疫反应很重要。TLR 信号转导可以通过 2 种不同的途径进行，这取决于衔接蛋白髓系分化初级反应基因 88（MyD88）和 TIR 结构域包含衔接子诱导干扰素-β（TRIF）。本研究旨在确定 MyD88 和 TRIF 信号在驻留细胞和造血细胞中的相对贡献，以在肺炎期间宿主防御。
创建了 MyD88 缺陷/野生型和 TRIF 突变/野生型骨髓嵌合体小鼠，并通过气道感染肺炎克雷伯菌。
驻留细胞和造血细胞中的 MyD88 均有助于晚期感染的存活和抗菌防御，而仅造血细胞中的 TRIF 具有保护作用。另一方面，驻留细胞的 MyD88 和造血细胞的 TRIF 有助于远距离细胞损伤。驻留细胞的 MyD88 对于早期趋化因子释放和中性粒细胞在支气管肺泡空间的募集至关重要。
MyD88 和 TRIF 依赖性信号转导对不同细胞类型的宿主防御有不同的贡献，这种贡献从革兰氏阴性肺炎的早期到晚期发生变化。
