Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-5900.
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-5900
J Immunol. 2019 Apr 1;202(7):2027-2034. doi: 10.4049/jimmunol.1801471. Epub 2019 Feb 11.
Methicillin-resistant has emerged as a significant contributor to morbidity and mortality associated with influenza infection. In this study, we show in a mouse model that preceding influenza infection promotes resistance to killing by antibiotics. This resistance coincides with influenza-induced accumulation of inflammatory monocytes in the lung. CCR type 2 (CCR2) is responsible for pulmonary monocyte recruitment after influenza infection. We found that antibiotic-treated Ccr2-deficient (Ccr2) mice exhibit significantly improved bacterial control and survival from influenza and methicillin-resistant coinfection, despite a delay in viral clearance. Mechanistically, our results from in vivo studies indicate that influenza-induced monocytes serve as reservoirs for intracellular survival, thereby promoting bacterial resistance to antibiotic treatment. Blocking CCR2 with a small molecular inhibitor (PF-04178903), in conjunction with antibiotic treatment, enhanced lung bacterial clearance and significantly improved animal survival. Collectively, our study demonstrates that inflammatory monocytes constitute an important and hitherto underappreciated mechanism of the conflicting immune requirements for viral and bacterial clearance by hosts, which subsequently leads to exacerbated outcomes of influenza and coinfection.
耐甲氧西林金黄色葡萄球菌已成为与流感感染相关发病率和死亡率的重要因素。在本研究中，我们在小鼠模型中表明，流感感染前会促进抗生素杀伤的耐药性。这种耐药性与流感诱导的肺部炎症性单核细胞积累相一致。CCR 型 2（CCR2）负责流感感染后的肺部单核细胞募集。我们发现，尽管病毒清除延迟，但用抗生素治疗的 Ccr2 缺陷（Ccr2）小鼠表现出明显更好的细菌控制和对流感和耐甲氧西林金黄色葡萄球菌合并感染的生存能力。从机制上讲，我们的体内研究结果表明，流感诱导的单核细胞是细胞内金黄色葡萄球菌存活的储存库，从而促进了细菌对抗生素治疗的耐药性。用小分子抑制剂（PF-04178903）阻断 CCR2，结合抗生素治疗，可增强肺部细菌清除率，并显著提高动物存活率。总的来说，我们的研究表明，炎症性单核细胞构成了宿主清除病毒和细菌的冲突免疫需求的一个重要且迄今为止未被充分认识的机制，这随后导致流感和耐甲氧西林金黄色葡萄球菌合并感染的结果恶化。
