Department of Medicine, University of Virginia, Charlottesville, VA, USA.
PLoS Pathog. 2010 Nov 18;6(11):e1001199. doi: 10.1371/journal.ppat.1001199.
Chemokines have been found to exert direct, defensin-like antimicrobial activity in vitro, suggesting that, in addition to orchestrating cellular accumulation and activation, chemokines may contribute directly to the innate host response against infection. No observations have been made, however, demonstrating direct chemokine-mediated promotion of host defense in vivo. Here, we show that the murine interferon-inducible CXC chemokines CXCL9, CXCL10, and CXCL11 each exert direct antimicrobial effects in vitro against Bacillus anthracis Sterne strain spores and bacilli including disruptions in spore germination and marked reductions in spore and bacilli viability as assessed using CFU determination and a fluorometric assay of metabolic activity. Similar chemokine-mediated antimicrobial activity was also observed against fully virulent Ames strain spores and encapsulated bacilli. Moreover, antibody-mediated neutralization of these CXC chemokines in vivo was found to significantly increase host susceptibility to pulmonary B. anthracis infection in a murine model of inhalational anthrax with disease progression characterized by systemic bacterial dissemination, toxemia, and host death. Neutralization of the shared chemokine receptor CXCR3, responsible for mediating cellular recruitment in response to CXCL9, CXCL10, and CXCL11, was not found to increase host susceptibility to inhalational anthrax. Taken together, our data demonstrate a novel, receptor-independent antimicrobial role for the interferon-inducible CXC chemokines in pulmonary innate immunity in vivo. These data also support an immunomodulatory approach for effectively treating and/or preventing pulmonary B. anthracis infection, as well as infections caused by pathogenic and potentially, multi-drug resistant bacteria including other spore-forming organisms.
趋化因子已被发现具有体外直接的防御素样抗菌活性，这表明趋化因子除了协调细胞的聚集和激活外，还可能直接有助于宿主对感染的先天反应。然而，尚未观察到趋化因子在体内直接介导促进宿主防御的作用。在这里，我们表明，鼠源干扰素诱导的 CXC 趋化因子 CXCL9、CXCL10 和 CXCL11 各自对炭疽芽胞杆菌 Sterne 株孢子和杆菌具有体外直接的抗菌作用，包括孢子萌发中断和孢子和杆菌活力明显降低，如 CFU 测定和代谢活性的荧光测定所评估的那样。对完全毒力的 Ames 株孢子和囊封杆菌也观察到类似的趋化因子介导的抗菌活性。此外，体内中和这些 CXC 趋化因子的抗体被发现显著增加了宿主对吸入性炭疽的易感性，在吸入性炭疽的小鼠模型中，疾病进展的特征是全身细菌传播、毒血症和宿主死亡。负责介导细胞募集以响应 CXCL9、CXCL10 和 CXCL11 的共享趋化因子受体 CXCR3 的中和并未增加宿主对吸入性炭疽的易感性。总之，我们的数据表明，干扰素诱导的 CXC 趋化因子在体内肺先天免疫中具有新型的、受体非依赖的抗菌作用。这些数据还支持一种免疫调节方法，可有效治疗和/或预防肺部炭疽感染，以及由致病性和潜在的、多药耐药细菌引起的感染，包括其他形成孢子的生物体。
