Department of Immunology and Infectious Diseases, Montana State University, Bozeman, MT 59717-3610, USA.
Am J Pathol. 2012 Jul;181(1):196-210. doi: 10.1016/j.ajpath.2012.03.018. Epub 2012 May 26.
The importance of the priming of the lung environment by past infections is being increasingly recognized. Exposure to any given antigen can either improve or worsen the outcome of subsequent lung infections, depending on the immunological history of the host. Thus, an ability to impart transient alterations in the lung environment in anticipation of future insult could provide an important novel therapy for emerging infectious diseases. In this study, we show that nasal administration of virus-like particles (VLPs) before, or immediately after, lethal challenge with methicillin-resistant Staphylococcus aureus (MRSA) of mice i) ensures complete recovery from lung infection and near absolute clearance of bacteria within 12 hours of challenge, ii) reduces host response-induced lung tissue damage, iii) promotes recruitment and efficient bacterial clearance by neutrophils and CD11c(+) cells, and iv) protects macrophages from MRSA-induced necrosis. VLP-mediated protection against MRSA relied on innate immunity. Complete recovery occurred in VLP-dosed mice with severe combined immunodeficiency, but not in wild-type mice depleted of either Ly6G(+) or CD11c(+) cells. Early IL-13 production associated with VLP-induced CD11c(+) cells was essential for VLP-induced protection. These results indicate that VLP-induced alteration of the lung environment protects the host from lethal MRSA pneumonia by enhancing phagocyte recruitment and killing and by reducing inflammation-induced tissue damage via IL-13-dependent mechanisms.
肺部环境的预激活在过去的感染中变得越来越重要。宿主的免疫史决定了暴露于任何特定抗原既可以改善也可以恶化随后的肺部感染的结果。因此，赋予宿主对未来损伤产生短暂改变肺部环境的能力可能为新发传染病提供一种重要的新型治疗方法。在这项研究中，我们表明，在对耐甲氧西林金黄色葡萄球菌（MRSA）进行致死性攻击之前或之后立即经鼻给予病毒样颗粒（VLPs），i）可确保从肺部感染中完全恢复，并且在挑战后 12 小时内几乎完全清除细菌，ii）减少宿主反应引起的肺组织损伤，iii）促进中性粒细胞和 CD11c（+）细胞的募集和有效细菌清除，以及 iv）保护巨噬细胞免受 MRSA 诱导的坏死。VLP 介导的针对 MRSA 的保护依赖于先天免疫。在严重联合免疫缺陷小鼠中，VLP 给药完全恢复，但在 Ly6G（+）或 CD11c（+）细胞耗尽的野生型小鼠中则没有。与 VLP 诱导的 CD11c（+）细胞相关的早期 IL-13 产生对于 VLP 诱导的保护至关重要。这些结果表明，VLP 诱导的肺部环境改变通过增强吞噬细胞的募集和杀伤，并通过 IL-13 依赖性机制减少炎症引起的组织损伤，从而保护宿主免受致命性 MRSA 肺炎的侵害。
