Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA.
Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA.
Cell Host Microbe. 2019 May 8;25(5):756-765.e5. doi: 10.1016/j.chom.2019.03.003. Epub 2019 Apr 16.
Clostridium difficile infection (CDI) is the number one hospital-acquired infection in the United States. CDI is more common and severe in inflammatory bowel disease patients. Here, we studied the mechanism by which prior colitis exacerbates CDI. Mice were given dextran sulfate sodium (DSS) colitis, recovered for 2 weeks, and then were infected with C. difficile. Mortality and CDI severity were increased in DSS-treated mice compared to controls. Severe CDI is dependent on CD4 T cells, which persist after colitis-associated inflammation subsides. Adoptive transfer of Th17 cells to naive mice is sufficient to increase CDI-associated mortality through elevated IL-17 production. Finally, in humans, the Th17 cytokines IL-6 and IL-23 associate with severe CDI, and patients with high serum IL-6 are 7.6 times more likely to die post infection. These findings establish a central role for Th17 cells in CDI pathogenesis following colitis and identify them as a potential target for preventing severe disease.
艰难梭菌感染（CDI）是美国头号医院获得性感染。炎症性肠病患者的 CDI 更常见且更严重。在这里，我们研究了先前结肠炎加重 CDI 的机制。给小鼠用葡聚糖硫酸钠（DSS）结肠炎，恢复 2 周，然后用艰难梭菌感染。与对照组相比，DSS 处理的小鼠死亡率和 CDI 严重程度增加。严重的 CDI 依赖于 CD4 T 细胞，这些细胞在结肠炎相关炎症消退后仍然存在。将 Th17 细胞过继转移给幼稚小鼠足以通过增加 IL-17 产生来增加与 CDI 相关的死亡率。最后，在人类中，Th17 细胞因子 IL-6 和 IL-23 与严重的 CDI 相关，血清中 IL-6 水平高的患者感染后死亡的可能性增加 7.6 倍。这些发现确立了 Th17 细胞在结肠炎后 CDI 发病机制中的核心作用，并将其确定为预防严重疾病的潜在目标。
