呼吸疾病國(guó)家重點(diǎn)實(shí)驗(yàn)室在人感染H5N6禽流感治療研究取得新進(jìn)展
導(dǎo)讀
H5N6亞型禽流感病毒一般只在鳥(niǎo)類中感染并傳播，但2014年以來(lái)，H5N6禽病毒在我國(guó)出現(xiàn)跨越種間屏障感染人事件。據(jù)世界衛(wèi)生組織統(tǒng)計(jì)，迄今為止19例實(shí)驗(yàn)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(yī)科大學(xué)附屬第一醫(yī)院在全球首次成功救治了人感染H5N6患者。近日，呼吸疾病國(guó)家重點(diǎn)實(shí)驗(yàn)室在在小鼠動(dòng)物模型中對(duì)廣州H5N6人感染分離株病毒的致病性、體內(nèi)復(fù)制特點(diǎn)、炎癥反應(yīng)進(jìn)行了系統(tǒng)的研究。提示抗禽流感免疫球蛋白可用于救治H5N6感染者，降低死亡率。相關(guān)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(fā)表于國(guó)際學(xué)術(shù)期刊 Emerging Microbes & Infections上。
獼猴抗禽流感廣譜免疫球蛋白對(duì)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(jù)病毒表面的血細(xì)胞凝集素(HA)和神經(jīng)氨酸酶(NA)分為不同亞型，其中HA有18個(gè)亞型，NA有9個(gè)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(niǎo)類中感染并傳播，但2014年以來(lái)，H5N6禽病毒在我國(guó)出現(xiàn)跨越種間屏障感染人事件。據(jù)世界衛(wèi)生組織統(tǒng)計(jì)，迄今為止19例實(shí)驗(yàn)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(yī)科大學(xué)附屬第一醫(yī)院在全球首次成功救治了人感染H5N6患者。
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結(jié)果速覽
研究表明：
（1）H5N6人體分離株在小鼠具備高致病力，對(duì)小鼠的半數(shù)致死劑量?jī)H為5 pfu，遠(yuǎn)高于報(bào)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病毒后，病毒在多臟器快速?gòu)?fù)制并產(chǎn)生細(xì)胞因子風(fēng)暴，導(dǎo)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 lungs of H5N6/GZ14-infected mice
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（2）研究人員使用實(shí)驗(yàn)室制備的獼猴抗禽流感廣譜免疫球蛋白治療，能夠完全保護(hù)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于救治H5N6感染者，降低死亡率。
Fig. 3 Coomassie Blue staining after SDS-PAGE and the antibody titer of immunized rhesus macaque sera and purified IgG.
Fig. 4 Efficacy of anti-influenza polyclonal antibodies for treating H5N6/GZ14-infected mice
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結(jié)語(yǔ)
本研究得到廣州海關(guān)（原廣東出入境檢驗(yàn)檢疫局）生物安全三級(jí)實(shí)驗(yàn)室的大力協(xié)助，國(guó)家自然科學(xué)基金、科技部H7N9應(yīng)急專項(xiàng)、廣州市健康醫(yī)療協(xié)同創(chuàng)新重大專項(xiàng)基金的經(jīng)費(fèi)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。
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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.
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參考文獻(xiàn)：
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 L Patient-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.
doi: 10.1038/s41426-018-0113-2.
2. 呼吸疾病國(guó)家重點(diǎn)實(shí)驗(yàn)室：實(shí)驗(yàn)室人感染H5N6禽流感治療研究取得進(jìn)展
內(nèi)容來(lái)源：病毒學(xué)界
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