Weng Meiqian, Huntley Deke, Huang I-Fei, Foye-Jackson Ondulla, Wang Lijian, Sarkissian Aliese, Zhou Qingping, Walker W Allan, Cherayil Bobby J, Shi Hai Ning
Mucosal Immunology Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
J Immunol. 2007 Oct 1;179(7):4721-31. doi: 10.4049/jimmunol.179.7.4721.
The distribution of several pathogenic helminth infections coincides geographically with many devastating microbial diseases, including enteric bacterial infections. To dissect the mechanisms by which helminths modulate the host's response to enteric bacteria and bacteria-mediated intestinal inflammation, we have recently established a coinfection model and shown that coinfection with the helminth Heligmosomoides polygyrus exacerbates colitis induced by infection with the gram-negative bacterial pathogen Citrobacter rodentium. The disease severity of the coinfected mice was correlated with high Citrobacter loads in the gut, translocation of the bacteria into mucosal and systemic immune compartments, delayed bacterial clearance, and a significantly enhanced colonic TNF-alpha response. In the present study, using our in vivo coinfection model as well as in vitro approaches, we test the hypothesis that the phenotypic and functional alterations in macrophages induced by the helminth-driven T cell response may contribute to the observed alterations in the response to C. rodentium. We show that via a STAT6-dependent mechanism H. polygyrus coinfection results in a marked infiltration into the colonic lamina propria of F4/80+ cells that have the phenotype of alternatively activated macrophages. Functional analysis of these macrophages further shows that they are impaired in their killing of internalized bacteria. Yet, these cells produce an enhanced amount of TNF-alpha in response to C. rodentium infection. These results demonstrate that helminth infection can impair host protection against concurrent enteric bacterial infection and promote bacteria-induced intestinal injury through a mechanism that involves the induction of alternatively activated macrophages.
几种致病性蠕虫感染的分布在地理上与许多毁灭性的微生物疾病相吻合，包括肠道细菌感染。为了剖析蠕虫调节宿主对肠道细菌和细菌介导的肠道炎症反应的机制，我们最近建立了一种共感染模型，并表明感染蠕虫多房棘球绦虫会加剧由革兰氏阴性细菌病原体鼠柠檬酸杆菌感染引起的结肠炎。共感染小鼠的疾病严重程度与肠道中高载量的柠檬酸杆菌、细菌向粘膜和全身免疫区室的转移、细菌清除延迟以及结肠TNF-α反应显著增强相关。在本研究中，我们使用体内共感染模型以及体外方法，检验了以下假设：蠕虫驱动的T细胞反应诱导的巨噬细胞表型和功能改变可能导致对鼠柠檬酸杆菌反应的观察到的改变。我们表明，通过STAT6依赖的机制，多房棘球绦虫共感染导致具有交替激活巨噬细胞表型的F4/80+细胞显著浸润到结肠固有层。对这些巨噬细胞的功能分析进一步表明，它们杀灭内化细菌的能力受损。然而，这些细胞在对鼠柠檬酸杆菌感染的反应中产生了更多的TNF-α。这些结果表明，蠕虫感染可损害宿主对同时发生的肠道细菌感染的保护，并通过一种涉及诱导交替激活巨噬细胞的机制促进细菌诱导的肠道损伤。
