Cathelicidins Have Direct Antiviral Activity against Respiratory Syncytial Virus In Vitro and Protective Function In Vivo in Mice and Humans.
Cathelicidins Have Direct Antiviral Activity against Respiratory Syncytial Virus In Vitro and Protective Function In Vivo in Mice and Humans.
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DOI：
10.4049/jimmunol.1502478
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发表时间：
2016-03-15
期刊：
影响因子：
--
通讯作者：
Davidson DJ
中科院分区：
文献类型：
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作者：
Currie SM;Gwyer Findlay E;McFarlane AJ;Fitch PM;Böttcher B;Colegrave N;Paras A;Jozwik A;Chiu C;Schwarze J;Davidson DJ
呼吸道合胞病毒（RSV）是婴儿呼吸道感染的主要原因，导致显著的发病率和死亡率。目前没有疫苗或具体有效的治疗方法。迫切需要更全面地了解宿主对RSV的有效反应的关键组成部分以及新的预防和治疗干预措施。Cathelicidins是宿主防御肽，在发炎的肺中表达，在宿主对感染的先天防御中具有关键的杀微生物和调节作用。在这篇文章中，我们证明了人cathelicidin LL-37介导的RSV的抗病毒作用，诱导直接损害病毒包膜，破坏病毒颗粒和减少病毒结合，感染，人上皮细胞在体外。此外，外源施用的LL-37在肺部RSV感染的鼠模型中在体内对RSV介导的疾病具有保护作用，当与病毒同时施用时显示出最大功效。此外，由感染诱导的内源性鼠cathelicidin在RSV感染后体内对疾病的保护中具有重要作用。最后，在健康成人RSV感染模型中，较高的LL-37鼻内水平与保护作用相关。这些数据使我们提出，cathelicidins是宿主防御RSV肺部感染的关键，非冗余组分，作为第一接触点抗病毒屏障，并在最大限度地减少疾病后果的严重程度方面具有额外的后期作用。因此，cathelicidins代表了针对RSV感染的预防策略的诱导型靶标，并且可以为用于已建立感染的新型治疗类似物的设计提供信息。
Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infection in infants, causing significant morbidity and mortality. No vaccine or specific, effective treatment is currently available. A more complete understanding of the key components of effective host response to RSV and novel preventative and therapeutic interventions are urgently required. Cathelicidins are host defense peptides, expressed in the inflamed lung, with key microbicidal and modulatory roles in innate host defense against infection. In this article, we demonstrate that the human cathelicidin LL-37 mediates an antiviral effect on RSV by inducing direct damage to the viral envelope, disrupting viral particles and decreasing virus binding to, and infection of, human epithelial cells in vitro. In addition, exogenously applied LL-37 is protective against RSV-mediated disease in vivo, in a murine model of pulmonary RSV infection, demonstrating maximal efficacy when applied concomitantly with virus. Furthermore, endogenous murine cathelicidin, induced by infection, has a fundamental role in protection against disease in vivo postinfection with RSV. Finally, higher nasal levels of LL-37 are associated with protection in a healthy human adult RSV infection model. These data lead us to propose that cathelicidins are a key, nonredundant component of host defense against pulmonary infection with RSV, functioning as a first point of contact antiviral shield and having additional later-phase roles in minimizing the severity of disease outcome. Consequently, cathelicidins represent an inducible target for preventative strategies against RSV infection and may inform the design of novel therapeutic analogs for use in established infection.