Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America.
PLoS One. 2012;7(9):e41879. doi: 10.1371/journal.pone.0041879. Epub 2012 Sep 4.
Secondary bacterial pneumonias are a frequent complication of influenza and other respiratory viral infections, but the mechanisms underlying viral-induced susceptibility to bacterial infections are poorly understood. In particular, it is unclear whether the host's response against the viral infection, independent of the injury caused by the virus, results in impairment of antibacterial host defense. Here, we sought to determine whether the induction of an "antiviral" immune state using various viral recognition receptor ligands was sufficient to result in decreased ability to combat common bacterial pathogens of the lung. Using a mouse model, animals were administered polyinosine-polycytidylic acid (poly I:C) or Toll-like 7 ligand (imiquimod or gardiquimod) intranasally, followed by intratracheal challenge with Streptococcus pneumoniae. We found that animals pre-exposed to poly I:C displayed impaired bacterial clearance and increased mortality. Poly I:C-exposed animals also had decreased ability to clear methicillin-resistant Staphylococcus aureus. Furthermore, we showed that activation of Toll-like receptor (TLR)3 and Retinoic acid inducible gene (RIG-I)/Cardif pathways, which recognize viral nucleic acids in the form of dsRNA, both contribute to poly I:C mediated impairment of bacterial clearance. Finally, we determined that poly I:C administration resulted in significant induction of type I interferons (IFNs), whereas the elimination of type I IFN signaling improved clearance and survival following secondary bacterial pneumonia. Collectively, these results indicate that in the lung, poly I:C administration is sufficient to impair pulmonary host defense against clinically important gram-positive bacterial pathogens, which appears to be mediated by type I IFNs.
继发性细菌性肺炎是流感和其他呼吸道病毒感染的常见并发症，但病毒诱导对细菌感染易感性的机制还不清楚。特别是，目前尚不清楚宿主对病毒感染的反应，是否独立于病毒造成的损伤，会导致抗菌宿主防御功能受损。在这里，我们试图确定使用各种病毒识别受体配体诱导“抗病毒”免疫状态是否足以导致对抗肺部常见细菌病原体的能力下降。我们使用小鼠模型，经鼻腔给予聚肌苷酸-聚胞苷酸（poly I:C）或 Toll 样受体 7 配体（咪喹莫特或加地喹莫特），然后经气管内滴注肺炎链球菌进行挑战。结果发现，预先用 poly I:C 处理的动物清除细菌的能力受损，死亡率增加。poly I:C 暴露的动物清除耐甲氧西林金黄色葡萄球菌的能力也下降。此外，我们还表明，Toll 样受体（TLR）3 和视黄酸诱导基因（RIG-I）/Cardif 途径的激活，以双链 RNA 的形式识别病毒核酸，都有助于 poly I:C 介导的细菌清除受损。最后，我们确定 poly I:C 给药导致 I 型干扰素（IFN）的显著诱导，而消除 I 型 IFN 信号转导可改善继发性细菌性肺炎后的清除率和存活率。总之，这些结果表明，在肺部，poly I:C 给药足以损害肺部宿主防御对临床重要的革兰氏阳性细菌病原体的防御能力，这似乎是由 I 型 IFNs 介导的。
