CXCL9 contributes to antimicrobial protection of the gut during citrobacter rodentium infection independent of chemokine-receptor signaling.
CXCL9 contributes to antimicrobial protection of the gut during citrobacter rodentium infection independent of chemokine-receptor signaling.
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DOI：
10.1371/journal.ppat.1004648
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发表时间：
2015-02
期刊：
影响因子：
6.7
通讯作者：
Coombes BK
中科院分区：
文献类型：
--
作者：
Reid-Yu SA;Tuinema BR;Small CN;Xing L;Coombes BK
趋化因子已被证明是有效的杀菌分子对各种细菌和真菌在体外。这些直接的抗微生物作用不依赖于它们涉及免疫受体的趋化活性。然而，这些蛋白质在宿主防御中可能发挥的直接生物学作用，特别是对肠道病原体的作用，知之甚少。在这里，我们表明，CXCL9，ELR-趋化因子，表现出直接的抗微生物活性，对柠檬酸杆菌啮齿类，附着/消失的病原体，感染肠粘膜。使用抗CXCL9抗体在体内抑制这种抗微生物活性增加宿主对C.啮齿动物感染，细菌明显渗入隐窝，细菌负荷增加，组织病理学恶化。使用Rag1-/-小鼠和CXCR3-/-小鼠，我们证明了CXCL9在保护肠粘膜中的作用独立于适应性反应或其免疫受体CXCR3。最后，我们提供的证据表明，吞噬细胞的功能与NK细胞的强大的CXCL9对C。啮齿动物。这些发现确定了免疫细胞衍生的CXCL9趋化因子在指导肠粘膜中的保护性抗菌反应中的新作用。宿主防御肽是对病原体的先天免疫应答的重要组成部分，特别是在粘膜表面。一些趋化因子，以前已知它们能够将免疫细胞募集到炎症部位，已经被鉴定为在体外对多种病原体具有直接的抗微生物活性。尽管如此，目前尚不清楚趋化因子是否在保护肠粘膜免受肠道病原体侵害方面发挥作用，而不依赖于其免疫受体。使用野生型小鼠和基因敲除的肠道病原体感染的小鼠模型，我们表明趋化因子CXCL9对病原体感染具有直接的抗微生物活性。这种抗微生物活性防止细菌侵入肠隐窝，从而保护宿主免受免疫病理学的影响。这种CXCL9依赖性抗微生物活性的中和增加了宿主对感染的易感性，导致细菌渗透到肠隐窝中并增加组织病理学。这些数据支持了趋化因子在粘膜表面宿主防御中的受体非依赖性作用的重要性，并可能为感染提供替代治疗策略，特别是对于对常规抗生素具有抗性的生物体。
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. Host defense peptides are an essential part of the innate immune response to pathogens, particularly at mucosal surfaces. Some chemokines, previously known for their ability to recruit immune cells to a site of inflammation, have been identified to have direct antimicrobial activity in vitro against a variety of pathogens. Despite this, it was unknown whether chemokines play a role in protecting the gut mucosa against enteric pathogens, independent of their immunological receptors. Using a mouse model of enteric pathogen infection with both wild type mice and genetic knockouts, we showed that the chemokine CXCL9 has direct antimicrobial activity against pathogen infection. This antimicrobial activity prevented the invasion of bacteria into intestinal crypts, thus protecting the host from immunopathology. Neutralization of this CXCL9-dependent antimicrobial activity increased host susceptibility to infection, leading to bacterial penetration into intestinal crypts and increased tissue pathology. These data support the importance of a receptor-independent role for chemokines in host defense at mucosal surfaces and may offer alternative treatment strategies for infections, particularly in regards to organisms that are resistant to conventional antibiotics.
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影响因子：
6.7
作者：
Kang YJ;Otsuka M;van den Berg A;Hong L;Huang Z;Wu X;Zhang DW;Vallance BA;Tobias PS;Han J
通讯作者：
Han J
影响因子：
3.7
作者：
Lamers RP;Cavallari JF;Burrows LL
通讯作者：
Burrows LL
影响因子：
32.4
作者：
Groom JR;Richmond J;Murooka TT;Sorensen EW;Sung JH;Bankert K;von Andrian UH;Moon JJ;Mempel TR;Luster AD
通讯作者：
Luster AD
DOI：
10.1084/jem.187.12.2009
发表时间：
1998-06-15
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cole KE;Strick CA;Paradis TJ;Ogborne KT;Loetscher M;Gladue RP;Lin W;Boyd JG;Moser B;Wood DE;Sahagan BG;Neote K
通讯作者：
Neote K
影响因子：
2.4
作者：
Assi K;Bergstrom K;Vallance B;Owen D;Salh B
通讯作者：
Salh B