PLOS Pathogens：我國學者揭示奧司他韋聯合西羅莫司治療重症流感新機制

近日，國際期刊PLOS Pathogens《公共科學圖書館-病原體》發表了首都醫科大學中日友好醫院王辰、曹彬教授團隊合作的題為Delayed Oseltamivir Plus Sirolimus Treatment Attenuates H1N1 Virus-induced Severe Lung Injury Correlated with Repressed NLRP3 Inflammasome Activation and Inflammatory Cell Infiltration的研究論文，(延遲奧司他韋聯合西羅莫司用藥通過抑制NLRP3炎性小體活化和炎症細胞浸潤減輕重症H1N1病毒感染引起的肺損傷)。研究首次發現聯合用藥減輕肺損傷的關鍵信號通路及作用機制，為西羅莫司在臨床重症流感患者中的應用提供理論和實驗依據。

甲型流感病毒是引起大規模流感爆發的主要病原體，對全世界公共衛生構成嚴重威脅。研究團隊前期發現流感病毒可誘發包括胸腺萎縮在內的全身多器官免疫損傷，肺臟多種天然免疫細胞可誘發急性肺損傷和急性呼吸窘迫綜合征，是造成疾病重症的主要原因之一。

機體的過度免疫應答，包括免疫細胞浸潤和細胞因子風暴，可導致肺免疫病理損傷。抗病毒藥物聯合免疫調節劑，不僅抑制病毒複製，而且減少宿主過度免疫應答造成的肺損傷，是臨床重症流感患者的主要治療途徑。糖皮質激素雖然是臨床治療常用免疫調節劑，但最新證據表明糖皮質激素可能會增加病毒載量，增加繼發細菌和真菌等病原微生物感染的風險，從而增加流感患者死亡風險率。因此，尋找其他靶點的免疫調節劑將為臨床重症流感提供一種新的治療策略。

該研究發現在模擬臨床重症感染的甲型H1N1流感小鼠模型中，mTOR過度活化並介導肺免疫病理損傷。mTOR上調NF-κB活性，增加ROS含量，降低自噬水平，激活NLRP3炎症小體，增加促炎細胞因子分泌，加重肺損傷。西羅莫司，是一種mTOR抑製劑，不僅能阻斷病毒複製所需的宿主通路，而且可調節病毒誘導的免疫反應。奧司他韋延遲給葯，聯合西羅莫司用藥可降低病毒滴度、抑制mTOR-NLRP3炎症小體-IL-1β軸、減少多種細胞因子表達、降低炎症細胞浸潤，從而減輕肺免疫病理損傷。

圖. 奧司他韋聯合西羅莫司抗病毒作用機制

該研究首次發現聯合用藥減輕肺損傷的關鍵信號通路及作用機制，為西羅莫司在臨床重症流感患者中的應用提供理論和實驗依據，開拓了「老葯新用」新機制。研究提示西羅莫司作為免疫調節劑，輔助奧司他韋延遲用藥可減輕重症流感感染誘導的肺臟免疫病理損傷，為臨床治療重症流感提供新的思路和治療方法。

ABSTRACT

Severe influenza A virus infection causes high mortality and morbidity worldwide due to delayed antiviral treatment and inducing overwhelming immune responses, which contribute to immunopathological lung injury. Sirolimus, an inhibitor of mammalian target of rapamycin (mTOR), was effective in improving clinical outcomes in patients with severe H1N1 infection; however, the mechanisms by which it attenuates acute lung injury have not been elucidated. Here, delayed oseltamivir treatment was used to mimic clinical settings on lethal influenza A (H1N1) pdm09 virus (pH1N1) infection mice model. We revealed that delayed oseltamivir plus sirolimus treatment protects mice against lethal pH1N1 infection by attenuating severe lung damage. Mechanistically, the combined treatment reduced viral titer and pH1N1-induced mTOR activation. Subsequently, it suppressed the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated secretion of interleukin (IL)-1β and IL-18. It was noted that decreased NLRP3 inflammasome activation was associated with inhibited nuclear factor (NF)-κB activation, reduced reactive oxygen species production and increased autophagy. Additionally, the combined treatment reduced the expression of other proinflammatory cytokines and chemokines, and decreased inflammatory cell infiltration in lung tissue and bronchioalveolar lavage fluid. Consistently, it inhibited the mTOR-NF-κB-NLRP3 inflammasome-IL-1β axis in a lung epithelial cell line. These results demonstrated that combined treatment with sirolimus and oseltamivir attenuates pH1N1-induced severe lung injury, which is correlated with suppressed mTOR-NLRP3-IL-1β axis and reduced viral titer. Therefore, treatment with sirolimus as an adjuvant along with oseltamivir may be a promising immunomodulatory strategy for managing severe influenza.

1.Xuehong Jia , Bo Liu , Linlin Bao , Qi Lv, Fengdi Li, Hui Li, Yunqing An,Xulong Zhang , Bin Cao , Chen Wang.Delayed oseltamivir plus sirolimus treatment attenuates H1N1 virus-induced severe lung injury correlated with repressed NLRP3 inflammasome activation and inflammatory cell infiltration. PLOS Pathogens. November 13, 2018.

https://doi.org/10.1371/journal.ppat.1007428

2.國家自然科學基金委員會：資助成果 | 我國學者揭示奧司他韋聯合西羅莫司治療重症流感新機制。

本期編輯：Annabella

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