Reid-Yu Sarah A, Tuinema Brian R, Small Cherrie N, Xing Lydia, Coombes Brian K
Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, Ontario, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, Ontario, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada; Farncombe Family Digestive Health Research Institute, Hamilton, Ontario, Canada.
PLoS Pathog. 2015 Feb 2;11(2):e1004648. doi: 10.1371/journal.ppat.1004648. eCollection 2015 Feb.
Chemokines have been shown to be effective bactericidal molecules against a variety of bacteria and fungi in vitro. These direct antimicrobial effects are independent of their chemotactic activities involving immunological receptors. However, the direct biological role that these proteins may play in host defense, particularly against intestinal pathogens, is poorly understood. Here, we show that CXCL9, an ELR- chemokine, exhibits direct antimicrobial activity against Citrobacter rodentium, an attaching/effacing pathogen that infects the gut mucosa. Inhibition of this antimicrobial activity in vivo using anti-CXCL9 antibodies increases host susceptibility to C. rodentium infection with pronounced bacterial penetration into crypts, increased bacterial load, and worsened tissue pathology. Using Rag1(-/-) mice and CXCR3(-/-) mice, we demonstrate that the role for CXCL9 in protecting the gut mucosa is independent of an adaptive response or its immunological receptor, CXCR3. Finally, we provide evidence that phagocytes function in tandem with NK cells for robust CXCL9 responses to C. rodentium. These findings identify a novel role for the immune cell-derived CXCL9 chemokine in directing a protective antimicrobial response in the intestinal mucosa.
趋化因子已被证明在体外是针对多种细菌和真菌的有效杀菌分子。这些直接的抗菌作用独立于其涉及免疫受体的趋化活性。然而，这些蛋白质在宿主防御中，特别是针对肠道病原体可能发挥的直接生物学作用，目前了解甚少。在这里，我们表明CXCL9，一种ELR-趋化因子，对啮齿柠檬酸杆菌具有直接抗菌活性，啮齿柠檬酸杆菌是一种感染肠道黏膜的黏附/脱落病原体。使用抗CXCL9抗体在体内抑制这种抗菌活性会增加宿主对啮齿柠檬酸杆菌感染的易感性，细菌明显侵入隐窝，细菌载量增加，组织病理学恶化。使用Rag1(-/-)小鼠和CXCR3(-/-)小鼠，我们证明CXCL9在保护肠道黏膜中的作用独立于适应性反应或其免疫受体CXCR3。最后，我们提供证据表明吞噬细胞与自然杀伤细胞协同作用，对啮齿柠檬酸杆菌产生强大的CXCL9反应。这些发现确定了免疫细胞衍生的CXCL9趋化因子在指导肠道黏膜保护性抗菌反应中的新作用。
