Regulation Of Immunopathology In Bacterial And Parasitic

细菌和寄生虫免疫病理学的调节

• 批准号: 6809059
• 负责人: Alan Sher
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6809059
• 关键词: Helicobacter; Mycobacterium avium; Mycobacterium tuberculosis; bacterial disease; bactericidal immunity; genetically modified animals; helper T lymphocyte; host organism interaction; immunopathology; immunoregulation; inflammatory bowel diseases; interleukin 10; laboratory mouse; microorganism immunology; parasitic diseases; toll like receptor

To assess the role of Toll-like receptor (TLR) signaling in host resistance to Mycobacterium avium infection, mice deficient in the TLR adaptor molecule Myeloid Differentiation Factor 88 (MyD88), as well as TLR2-/- and TLR4-/- animals, were infected with a virulent strain of M. avium and bacterial burdens and immune responses compared with those in wild type (WT) animals. MyD88-/- mice failed to control acute and chronic M. avium growth and succumbed 9 - 14 wks post-infection. Infected TLR2-/- mice also showed increased susceptibility, but displayed longer survival and lower bacterial burdens than MyD88-/- animals, while TLR4-/- mice were indistinguishable from their WT counterparts. Histopathological examination of MyD88-/- mice revealed massive destruction of lung tissue not present in WT, TLR2-/- or TLR4-/- mice. In addition, in vivo TNF, IL-12p40 mRNA induction and IFN-gamma cytokine synthesis were impaired in the infected MyD88-/- mice but not in the other strains. These findings indicate that resistance to mycobacterial infection is regulated by multiple MyD88-dependent signals in addition to those previously attributed to TLR2 or TLR4 and that these undefined elements play a major role in determining bacterial induced pro-inflammatory as well as IFN-gamma responses. We have previously shown that specific pathogen-free IL-10-deficient (IL-10 KO) mice develop a Th1-cytokine associated colitis after experimental infection with the intestinal bacteria Helicobacter hepaticus. This year we demonstrated that H. hepaticus Ag (SHelAg)-specific CD4+ Th1 clones transfer disease to H. hepaticusinfected T cell-deficient RAG KO hosts. Importantly, uninfected recipients of the SHelAgspecific clones did not develop intestinal inflammation, and an unrelated control Th1 clone did not induce colitis upon transfer to infected RAG KO mice. The disease-inducing T cell clones recognized antigen(s) (Ag) specifically expressed by H. hepaticus and other murine Helicobacter species but failed to respond to Ag preparations from H. pylori, various non-Helicobacter bacteria, or with cecal bacterial lysate from uninfected mice. Characterization of the Ag specificity of one of the clones showed that it reacts uniquely with a 15-mer peptide epitope on the flagellar hook protein (FlgE) of H. hepaticus . Together, these results demonstrate that colitis can be induced by clonal T cell populations that are highly specific for target Ag on intestinal bacteria, suggesting that an aberrant T cell response directed against gut flora is sufficient to trigger IBD.

为了评估TOLL样受体（TLR）信号传导在宿主对分枝杆菌感染的抗性中的作用，小鼠缺乏TLR衔接子分子髓样分化因子88（MyD88）（MyD88），以及TLR2 - / - / - / - 和TLR4-/ - - 与这些毒素的抗菌株和分类（与抗抗原的菌株相比），并将其感染（ 动物。 MyD88 - / - 小鼠无法控制急性和慢性M.鸟类的生长，并在感染后9-14周屈服。感染的TLR2 - / - 小鼠也显示出易感性的增加，但比MyD88 - / - 动物显示出更长的生存率和更低的细菌负担，而TLR4 - / - 小鼠与WT对应物无法区分。 MyD88 - / - 小鼠的组织病理学检查显示，WT，TLR2 - / - 或TLR4 - / - 小鼠中不存在肺组织的大规模破坏。此外，在感染的MyD88 - / - 小鼠中，体内TNF，IL-12P40 mRNA诱导和IFN-gamma细胞因子合成受损，但在其他菌株中却没有。这些发现表明，除了先前归因于TLR2或TLR4的抗性分枝杆菌感染的耐药性受到多种MyD88依赖性信号的调节，并且这些未定义的元素在确定细菌诱导的促炎性促炎和IFN-GAMMA响应方面起着重要作用。 我们先前已经表明，在用肠道细菌螺旋杆菌实验感染后，特定的无病原体IL-10缺陷型（IL-10 KO）小鼠在实验感染肝杆菌后会形成Th1-偶然动物相关的结肠炎。今年，我们证明了H. H. H. H. H. H. hepaticus AG（Shebag）特异性CD4+ Th1克隆转移到H. H. H. H. H. H. toctic us感染的T细胞缺陷的RAG KO宿主。重要的是，Shehagspecific克隆的未感染的接受者没有出现肠炎，而无关的对照Th1克隆则不会在转移到感染的RAG KO小鼠中诱导结肠炎。诱发疾病的T细胞克隆识别肝炎和其他鼠螺旋杆菌特异性表达的抗原（S）（Ag），但未能对幽门螺杆菌，各种非螺旋细菌的Ag制剂反应，或者用来自单一感染的小鼠的Cecal细菌裂解物。其中一个克隆的Ag特异性的表征表明，它与H.肝的鞭毛钩蛋白（FLGE）上的15-Mer肽表位唯一反应。总之，这些结果表明，可以由针对肠道细菌的靶AG特异性的克隆T细胞群体诱导结肠炎，这表明针对肠菌群的异常T细胞反应足以触发IBD。