TLR4-and TLR2-Mediated B Cell Responses Control the Clearance of the Bacterial Pathogen, Leptospira interrogans
TLR4-and TLR2-Mediated B Cell Responses Control the Clearance of the Bacterial Pathogen, Leptospira interrogans
复制标题
DOI：
10.4049/jimmunol.0900506
复制
发表时间：
2009-08-15
影响因子：
4.4
通讯作者：
Werts, Catherine
中科院分区：
文献类型：
--
作者：
Chassin, Cecilia;Picardeau, Mathieu;Werts, Catherine
钩端螺旋体病是一种广泛流行的人畜共患病，由致病性问号钩端螺旋体引起，由无症状感染的啮齿动物传播。钩端螺旋体脂蛋白和脂多糖通过TLR2和TLR4刺激小鼠细胞。宿主防御机制尚不清楚，尽管TLR4已被证明参与清除钩端螺旋体。在这项研究中，我们发现双(TLR2和TLR4)基因敲除(DKO)小鼠在接种钩端螺旋体后迅速死于严重的肝肾衰竭。值得注意的是，在感染了螺旋体的DKO小鼠的肝脏和肾脏中检测到的严重的促炎反应似乎独立于TLRs的主要接头MyD88。用野生型和DKO小鼠构建的嵌合体小鼠的感染，以及几个缺乏T和/或B淋巴细胞的转基因小鼠的感染，通过早期产生特异性TLR4依赖的抗钩端螺旋体内毒素抗体，确定B细胞是负责清除钩端螺旋体的关键淋巴细胞亚群。我们还在肝脏和肾脏中发现了TLR2/TLR4介导的B和T淋巴细胞产生干扰素-γ的保护性组织区隔。相比之下，在感染钩端螺旋体的DKO小鼠中观察到的组织炎症进一步被描述为主要是由于肝脏中的B淋巴细胞和肾脏中的T细胞。总之，这些发现表明TLR2和TLR4在钩端螺旋体病的早期控制中起关键作用，但不直接触发致病性钩端螺旋体引起的炎症。免疫学杂志，2009,183：2669-2677。
Leptospirosis is a widespread zoonosis caused by pathogenic Leptospira interrogans that are transmitted by asymptomatic infected rodents. Leptospiral lipoproteins and LPS have been shown to stimulate murine cells via TLRs 2 and 4. Host defense mechanisms remain obscure, although TLR4 has been shown to be involved in clearing Leptospira. In this study, we show that double (TLR2 and TLR4) knockout (DKO) mice rapidly died from severe hepatic and renal failure following Leptospira inoculation. Strikingly, the severe proinflammatory response detected in the liver and kidney from Leplospira-infected DKO mice appears to be independent of MyD88, the main adaptor of TLRs. Infection of chimeric mice constructed with wild-type and DKO mice, and infection of several lines of transgenic mice devoid of T and/or B lymphocytes, identified B cells as the crucial lymphocyte subset responsible for the clearance of Leptospira, through the early production of specific TLR4-dependent anti-Leptospira IgMs elicited against the leptospiral LPS. We also found a protective tissue compartmentalized TLR2/TLR4-mediated production of IFN-gamma by B and T lymphocytes, in the liver and kidney, respectively. In contrast, the tissue inflammation observed in Leptospira-infected DKO mice was further characterized to be mostly due to B lymphocytes in the liver and T cells in the kidney. Altogether these findings demonstrate that TLR2 and TLR4 play a key role in the early control of leptospirosis, but do not directly trigger the inflammation induced by pathogenic Leptospira. The Journal of Immunology, 2009, 183: 2669-2677.