Infectious Diseases and Microbiology Unit, Institute of Child Health, University College London, London, United Kingdom.
PLoS One. 2013 Jul 29;8(7):e69846. doi: 10.1371/journal.pone.0069846. Print 2013.
Clostridium difficile infection (CDI) is the leading cause of hospital and community-acquired antibiotic-associated diarrhoea and currently represents a significant health burden. Although the role and contribution of C. difficile toxins to disease pathogenesis is being increasingly understood, at present other facets of C. difficile-host interactions, in particular, bacterial-driven effects on host immunity remain less studied. Using an ex-vivo model of infection, we report that the human gastrointestinal mucosa elicits a rapid and significant cytokine response to C. difficile. Marked increase in IFN-γ with modest increase in IL-22 and IL-17A was noted. Significant increase in IL-8 suggested potential for neutrophil influx while presence of IL-12, IL-23, IL-1β and IL-6 was indicative of a cytokine milieu that may modulate subsequent T cell immunity. Majority of C. difficile-driven effects on murine bone-marrow-derived dendritic cell (BMDC) activation were toxin-independent; the toxins were however responsible for BMDC inflammasome activation. In contrast, human monocyte-derived DCs (mDCs) released IL-1β even in the absence of toxins suggesting host-specific mediation. Infected DC-T cell crosstalk revealed the ability of R20291 and 630 WT strains to elicit a differential DC IL-12 family cytokine milieu which culminated in significantly greater Th1 immunity in response to R20291. Interestingly, both strains induced a similar Th17 response. Elicitation of mucosal IFN-γ/IL-17A and Th1/Th17 immunity to C. difficile indicates a central role for this dual cytokine axis in establishing antimicrobial immunity to CDI.
艰难梭菌感染（CDI）是医院和社区获得性抗生素相关性腹泻的主要原因，目前代表着重大的健康负担。尽管艰难梭菌毒素在疾病发病机制中的作用和贡献越来越被理解，但目前其他方面的艰难梭菌-宿主相互作用，特别是细菌对宿主免疫的影响，研究得较少。我们使用体外感染模型报告说，人类胃肠道黏膜对艰难梭菌产生快速而显著的细胞因子反应。观察到 IFN-γ 显著增加，IL-22 和 IL-17A 适度增加。IL-8 的显著增加表明可能有中性粒细胞流入，而 IL-12、IL-23、IL-1β 和 IL-6 的存在表明可能调节随后 T 细胞免疫的细胞因子环境。大多数艰难梭菌对骨髓来源树突状细胞（BMDC）激活的影响与毒素无关；然而，毒素负责 BMDC 炎症小体的激活。相比之下，人单核细胞来源的 DC（mDC）即使没有毒素也会释放 IL-1β，这表明存在宿主特异性介导。感染的 DC-T 细胞串扰揭示了 R20291 和 630 WT 株有能力引发不同的 DC IL-12 家族细胞因子环境，这导致对 R20291 产生更强的 Th1 免疫反应。有趣的是，两种菌株都诱导了相似的 Th17 反应。艰难梭菌诱导黏膜 IFN-γ/IL-17A 和 Th1/Th17 免疫表明，这种双重细胞因子轴在建立针对 CDI 的抗微生物免疫中起着核心作用。
