呼吸疾病國家重點實驗室在人感染H5N6禽流感治療研究取得新進展

導 讀

H5N6亞型禽流感病毒一般只在鳥類中感染並傳播，但2014年以來，H5N6禽病毒在我國出現跨越種間屏障感染人事件。據世界衛生組織統計，迄今為止19例實驗室確診H5N6感染人病例，其中6人死亡，病死率約為32%。在2015年初，廣州醫科大學附屬第一醫院在全球首次成功救治了人感染H5N6患者。近日，呼吸疾病國家重點實驗室在在小鼠動物模型中對廣州H5N6人感染分離株病毒的致病性、體內複製特點、炎症反應進行了系統的研究。提示抗禽流感免疫球蛋白可用於救治H5N6感染者，降低死亡率。相關研究以「Patient-derived avianinfluenza A (H5N6) virus is highly pathogenic in mice but can be effectivelytreated by anti-influenza polyclonal antibodies」為題在線發表於國際學術期刊 Emerging Microbes & Infections上。

獼猴抗禽流感廣譜免疫球蛋白對H5N6流感病毒感染小鼠的治療效果

研究背景

甲型流感病毒依據病毒表面的血細胞凝集素(HA)和神經氨酸酶(NA)分為不同亞型，其中HA有18個亞型，NA有9個亞型。通常人類只感染甲流H1N1亞型、H3N2亞型和乙型流感病毒。H5N6亞型禽流感病毒一般只在鳥類中感染並傳播，但2014年以來，H5N6禽病毒在我國出現跨越種間屏障感染人事件。據世界衛生組織統計，迄今為止19例實驗室確診H5N6感染人病例，其中6人死亡，病死率約為32%。2015年初，廣州醫科大學附屬第一醫院在全球首次成功救治了人感染H5N6患者。

結果速覽

研究表明：

（1）H5N6人體分離株在小鼠具備高致病力，對小鼠的半數致死劑量僅為5 pfu，遠高於報道的H5N1及H7N9禽流感病毒人感染分離株在小鼠的致病力。小鼠感染H5N6病毒後，病毒在多臟器快速複製併產生細胞因子風暴，導致小鼠迅速死亡。

Fig. 1 Infection of the patient-derived H5N6/GZ14 isolate in mice

Fig. 2 Pro-inflammatory cytokines and chemokines in the lungsof H5N6/GZ14-infected mice

（2）研究人員使用實驗室製備的獼猴抗禽流感廣譜免疫球蛋白治療，能夠完全保護感染了致死劑量H5N6病毒的小鼠。該研究提示抗禽流感免疫球蛋白可用於救治H5N6感染者，降低死亡率。

Fig. 3 Coomassie Blue staining after SDS-PAGE and the antibodytiter of immunized rhesus macaque sera and purified IgG.

Fig. 4 Efficacy of anti-influenza polyclonal antibodies for treating H5N6/GZ14-infected mice

結 語

本研究得到廣州海關（原廣東出入境檢驗檢疫局）生物安全三級實驗室的大力協助，國家自然科學基金、科技部H7N9應急專項、廣州市健康醫療協同創新重大專項基金的經費支持。潘蔚綺副研究員和謝浩俊博士為該論文的共同第一作者，陳凌研究員和黃吉城研究員為該論文的共同通訊作者。

ABSTRACT

Highly pathogenic avian influenza A (H5N6) virus has been circulating in poultry since 2013 and causes sporadicinfections and fatalities in humans. Due to the re-occurrence and continuous evolution of this virus subtype, there is an urgent need to better understandthe pathogenicity of the H5N6 virus and to identify effective preventative and therapeutic strategies. We established a mouse model to evaluate the virulence of H5N6 A/Guangzhou/39715/2014 (H5N6/GZ14), which was isolated from an infected patient. BALB/c mice were inoculated intranasally with H5N6/GZ14 and monitored for morbidity, mortality, cytokine production, lung injury, viral replication, and viral dissemination to other organs. H5N6/GZ14 is highly pathogenic and can kill 50% of mice at a very low infectious dose of 5 plaque-forming units (pfu) Infection with H5N6/GZ14 showed rapid disease progression, viral replication to high titers in the lung, a strongly induced pro-inflammatory cytokine response, and severe lung injury. Moreover, infectious H5N6/GZ14 could be detected in the heart and brain of the infected mice. We also demonstrated that anti-influenzapolyclonal antibodies generated by immunizing rhesus macaques could protect mice from lethal infection. Our results provide insights into the pathogenicity of the H5N6 human isolate.

參考文獻：

1. .Pan W, Xie H1, Li X, Guan W, Chen P,Zhang B, Zhang M1, Dong J, Wang Q, Li Z, Li S, Yang Z, Li C, Zhong N, Huang J,Chen LPatient-derived avian influenzaA (H5N6) virus is highly pathogenic in mice but can be effectively treated byanti-influenza polyclonal antibodies.Emerg Microbes Infect. 2018 Jun13;7(1):107.

2. 呼吸疾病國家重點實驗室：實驗室人感染H5N6禽流感治療研究取得進展

本期編輯：Annabella

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