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2018年33卷6期

Influenza is one of the oldest infectious diseases affecting humans. Every influenza pandemic in history has ended with disastrous outcomes regarding public health and the social economy. November 1, 2018, marked the first “World Flu Day” that was formally launched at the Asian-Pacific Centenary Spanish 1918-Flu Symposium in Shenzhen, China. The campaign was initiated and developed by Dr. George F. Gao in collaboration with other world’s leading influenza specialists. The “World Flu Day” initiative aimed to raise public awareness about influenza, to accelerate scientific innovation and international cooperation on influenza surveillance, and to push for stronger global support on influenza prevention and control. The sculpture entitled “Quarere Veritatem” in the cover represents an influenza virus.

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PERSPECTIVE

On the Centenary of the Spanish Flu: Being Prepared for the Next Pandemic

Liu William J., Bi Yuhai, Wang Dayan, Gao George F.

2018, 33(6): 463 doi: 10.1007/s12250-018-0079-1

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Influenza is one of the oldest infectious diseases affecting humans. Every influenza pandemic in history has ended with disastrous outcomes regarding public health and the social economy. This year marks the 100th anniversary of the Spanish flu (H1N1) outbreak of 1918, which is recognized as the most lethal natural event in recent history. In spite of limited travel and transportation at that time, the Spanish flu pandemic of 1918 reached peak activity on multiple continents simultaneously within several months after its emergence in late 1917 from different hypothesized origins, such as US military camps, the state of Kansas, or the troop staging and hospital camp in étaples, France (Patterson and Pyle 1991; Oxford et al. 2005; Shanks 2016). However, in some islands of the Pacific region, such as in New Caledonia, the pandemic’s lethal effects lasted for over 3 years, until July 1921 (Shanks et al. 2018). The pandemic flu is estimated to have infected more than 500 million people, causing between 50 and 100 million deaths globally (Patterson and Pyle 1991; Guan et al. 2010). The evidence suggests that most pandemicrelated deaths were not caused by the direct pathological effects of the influenza virus, but rather by the lethal effects of secondary bacterial pneumonia (Chien et al. 2009).

The Era of Immune Checkpoint Therapy: From Cancer to Viral Infection—A Mini Comment on the 2018 Medicine Nobel Prize

Liu Jia, Pan Wen, Yang Dongliang

2018, 33(6): 467 doi: 10.1007/s12250-018-0077-3

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The 2018 Medicine Nobel Prize was awarded jointly to two immunologists, James P. Allison at the University of Texas MD Anderson Cancer Center in Houston and Tasuku Honjo at Kyoto University in Japan, who pioneered a new way to treat cancers (Ledford et al. 2018). Both Laureates have shown how so called "immune checkpoints" on T cells can be used to manipulate the immune responses so that T cells can efficiently attack cancer cells. Using the immune system to fight cancers has been investigated for more than a 100 years. Recent advances in cancer immunotherapy, particularly immune checkpoint blockade therapy have dramatically changed the therapeutic strategy against advanced cancers. Through inhibiting negative immune regulation, these approaches have demonstrated improved overall survival for patients with advanced cancers. Importantly, for some of the patients treated with such strategies, their tumors seem to totally disappear.
REVIEW

Reverse Genetics for Peste des Petits Ruminants Virus: Current Status and Lessons to Learn from Other Non-segmented Negative-Sense RNA Viruses

Niyokwishimira Alfred, Dou Yongxi, Qian Bang, Meera Prajapati, Zhang Zhidong

2018, 33(6): 472 doi: 10.1007/s12250-018-0066-6

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Peste des petits ruminants (PPR) is a highly contagious transboundary animal disease with a severe socio-economic impact on the livestock industry, particularly in poor countries where it is endemic. Full understanding of PPR virus (PPRV) pathobiology and molecular biology is critical for effective control and eradication of the disease. To achieve these goals, establishment of stable reverse genetics systems for PPRV would play a key role. Unfortunately, this powerful technology remains less accessible and poorly documented for PPRV. In this review, we discussed the current status of PPRV reverse genetics as well as the recent innovations and advances in the reverse genetics of other non-segmented negative-sense RNA viruses that could be applicable to PPRV. These strategies may contribute to the improvement of existing techniques and/or the development of new reverse genetics systems for PPRV.
Research Article

Genetic Evidence of Middle East Respiratory Syndrome Coronavirus (MERS-Cov) and Widespread Seroprevalence among Camels in Kenya

Ommeh Sheila, Zhang Wei, Zohaib Ali, Chen Jing, Zhang Huajun, Hu Ben, Ge Xing-Yi, Yang Xing-Lou, Masika Moses, Obanda Vincent, Luo Yun, Li Shan, Waruhiu Cecilia, Li Bei, Zhu Yan, Ouma Desterio, Odendo Vincent, Wang Lin-Fa, Anderson Danielle E., Lichoti Jacqueline, Mungube Erick, Gakuya Francis, Zhou Peng, Ngeiywa Kisa-Juma, Yan Bing, Agwanda Bernard, Shi Zheng-Li

2018, 33(6): 484 doi: 10.1007/s12250-018-0076-4

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We describe the first genome isolation of Middle East respiratory syndrome coronavirus (MERS-CoV) in Kenya. This fatal zoonotic pathogen was first described in the Kingdom of Saudi Arabia in 2012. Epidemiological and molecular evidence revealed zoonotic transmission from camels to humans and between humans. Currently, MERS-CoV is classified by the WHO as having high pandemic potential requiring greater surveillance. Previous studies of MERS-CoV in Kenya mainly focused on site-specific and archived camel and human serum samples for antibodies. We conducted active nationwide cross-sectional surveillance of camels and humans in Kenya, targeting both nasal swabs and plasma samples from 1,163 camels and 486 humans collected from January 2016 to June 2018. A total of 792 camel plasma samples were positive by ELISA. Seroprevalence increased with age, and the highest prevalence was observed in adult camels (82.37%, 95% confidence interval (CI) 79.50–84.91). More female camels were significantly seropositive (74.28%, 95% CI 71.14–77.19) than male camels (Porf4b in African viruses. None of the human plasma screened contained neutralizing antibodies against MERS-CoV. This study confirms the geographically widespread occurrence of MERS-CoV in Kenyan camels. Further one-health surveillance approaches in camels, wildlife, and human populations are needed.

人乳头瘤E7蛋白对浆细胞样树突状细胞体外成熟和功能的影响

韩睿, 宋寅敬, 孙思源, 周强, 陈贤祯, 郑俏丽, 程浩

2018, 33(6): 493 doi: 10.1007/s12250-018-0069-3

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人乳头瘤病毒(HPV)治疗的主要难点在于持续存在和复发。既往的报告中已有关于HPV E7蛋白负载的树突细胞作为细胞疫苗的评估。浆细胞样树突状细胞(pDC)在免疫系统中起着连接天然免疫和获得性免疫的重要作用,但它们在HPV E7负载中的作用尚不清楚。为了研究HPV 6b,11和16E7蛋白的负载是否影响pDC的活性,我们用HPV E7蛋白刺激人外周血分离的pDC和小鼠骨髓来源的pDC。在HPV 6b / 11 E7蛋白刺激后,pDC中CD40,CD80,CD86和MHC II的表达显著上调。 I型干扰素和IL-6的分泌和基因表达均被HPV 6b / 11 E7蛋白上调,且相对HPV 16 E7蛋白更为显著。HPV 6b / 11 E7蛋白刺激pDC后,TLR信号通路和JNK / p38 MAP激酶信号通路的主要因子的表达均升高。我们的研究结果表明,HPV E7蛋白可以促进pDC的分化和成熟,并激活TLR和MAPK通路,诱导宿主的天然免疫反应。该研究结果可能有助于探索用HPV E7负载pDC靶向HPV感染的新型免疫疗法。

人类免疫缺陷病毒-1 gp120和乙肝表面抗原诱导的初级免疫应答差异决定了抗体回忆反应不同

袁丽, 陈文江, 王甲业, 李妍, 田丹, 王明霞, 于昊彤, 许颖出, 李迪, 庄敏, 凌虹

2018, 33(6): 502 doi: 10.1007/s12250-018-0074-6

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开发一种1型人类免疫缺陷病毒 (HIV-1)包膜糖蛋白(Env)相关并且能免疫诱导产生有效的抗感染保护抗体的疫苗是一项巨大的挑战。最近,我们比较了HIV-1 Env gp120和乙肝病毒表面抗原(HBsAg)的抗体产生模式,以了解如何提高基于Env的免疫原的保护效力。我们前期的研究表明HIV Env和HBsAg表现出不同的抗体诱导机制,并且T细胞在再次免疫应答中起着重要作用。本研究中,为阐明初级免疫反应在免疫记忆反应形成和抗体产生中的作用,我们用HIV-1 Env gp120和HBsAg抗原免疫C57BL/6小鼠,检测免疫小鼠初次免疫和加强免疫后滤泡辅助性T细胞(Tfh)和生发中心(GCs)的发育,以及免疫的记忆反应形成。我们发现在引流淋巴结中,与HBsAg相比,gp120免疫诱导产生更多Tfh细胞和细胞程序性死亡(PD) 1+ T细胞,B细胞表面表达更多的主要组织相容性复合体II分子,而活化B细胞水平相当,但HBsAg免疫诱导较弱的GC反应和记忆B细胞,伴随着更慢的抗体回忆反应和更弱的免疫记忆反应。以上结果提示,在初级免疫反应中诱导产生更多PD-1+ T细胞,可能是HIV-1 Env引起的抗体回忆反应迟缓的主要原因。

乙型脑炎病毒NS1′蛋白抑制I型干扰素β的产生

周登元, 贾凡, 李秋燕, 张路平, 陈政, 赵子恺, 崔敏, 宋云峰, 陈焕春, 曹胜波, 叶静

2018, 33(6): 515 doi: 10.1007/s12250-018-0067-5

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乙型脑炎病毒主要由蚊子传播,是引起亚洲病毒性脑炎的主要原因。NS1'是NS1蛋白C-末端延伸的52个氨基酸,由-1核糖体移码产生,并且仅存在于黄病毒日本乙型脑炎血清群中。以前的研究表明,NS1'在毒力中起着至关重要的作用,但其机制尚不清楚。在本研究中,我们构建了NS1'缺失(rG66A)的乙脑病毒并发现rG66A病毒在野生型小鼠中的毒力低于其亲本病毒(pSA14)。然而,在IFNAR敲除小鼠模型中观察到由两种病毒引起的死亡率类似。此外,我们发现rG66A病毒比pSA14诱导更强的I型干扰素应答,并且JEV NS1'能够显著抑制IFN-β和IFN刺激基因的产生。总之,我们的研究结果表明,NS1'在阻断I型IFN产生中发挥重要作用,可以帮助JEV逃避宿主的抗病毒免疫并利于病毒复制。

猪繁殖与呼吸综合征病毒免疫与感染情况下猪γ干扰素产生淋巴细胞的表型特征研究

李向东, 裴增扬, 白怡琳, 王立华, 史纪暑, 田克恭

2018, 33(6): 524 doi: 10.1007/s12250-018-0073-7

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猪繁殖与呼吸综合征是一种重要的动物疫病,细胞免疫介导的I型干扰素对猪繁殖与呼吸综合征病毒感染起到重要的保护作用。不同类型的免疫细胞包括辅助性T 细胞、杀伤性T细胞、记忆性T细胞、γδ T细胞在病毒感染过程中均可产生I型干扰素,但上述细胞在感染过程中的表型特征尚不清楚。本试验采用流式细胞术对免疫和感染猪繁殖与呼吸综合征病毒的不同淋巴细胞进行表型分析,发现辅助性T细胞是感染后产生γ干扰素的主要细胞亚群,病毒感染后的辅助性T细胞和记忆性T细胞亚群数量均上升,但二者在产生γ干扰素的机制不尽相同。本研究揭示了γ干扰素在猪繁殖与呼吸综合征病毒感染过程中的保护作用,并提供了评价疫苗引起细胞免疫的试验方法。

H9N2禽流感病毒聚合酶B2基因D253N突变增强病毒在哺乳类动物中的致病性

张劲丰, 苏荣, 简小云, 安宏亮, 江荣斌, 莫家斌

2018, 33(6): 531 doi: 10.1007/s12250-018-0072-8

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聚合酶B2基因(Polymerase basic 2, PB2)突变为禽流感病毒适应哺乳类宿主的重要标志,许多与PB2基因627位点、核定位序列(Nuclear localization sequence, NLS)相关的突变已被发现,这些突变均增加了禽流感病毒(建议加上:在哺乳类动物中)的复制能力。然而,关于PB2基因其余位点突变的研究却仍然较少。本研究对H9N2禽流感病毒PB2基因D253N突变的作用进行了探索,发现该突变可致PB2蛋白中间结构域的氨基酸残基发生变化。在人源细胞中,该突变可显著增加病毒的聚合酶活性和复制效率,然而在小鼠呼吸道感染模型中,未发现该突变能引起病毒复制效率明显提高。本研究提示PB2中间结构域的D253N突变与627位点及NLS区域的突变相似,均可增强禽流感病毒在人源细胞中的复制能力。

2',3'-双脱氧鸟苷体外抗乙型肝炎病毒活性

张评浒, 翟硕, 苌锦红, 郭巨涛

2018, 33(6): 538 doi: 10.1007/s12250-018-0065-7

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2',3'-双脱氧鸟苷(DoG)在体内鸭乙肝模型中已被证实具有抑制鸭乙肝病毒(DHBV)的作用。本研究对DoG体外抗人和动物DNA肝炎病毒的作用进行了探讨。本研究结果表明DoG在体外肝细胞模型中能剂量依赖性地抑制HBV、DHBV以及旱獭肝炎病毒(WHV)的复制,相对应的半数有效浓度分别为0.3 ± 0.05, 6.82 ± 0.25, and 23.0 ± 1.5 μmol/L。与其它肝炎病毒DNA聚合酶抑制剂相似,DoG不能改变细胞内病毒RNA的含量,但能诱导产生已被证实经RNase H剪切pgRNA而形成的且长度短于全长病毒pgRNA的RNA新片段。此外,应用瞬时转染检测系统也证实DoG对HBV野生型、3TC抗性突变rtA181V和ADV抗性突变rtN236T都具有相似的抗病毒活性。本研究结果表明核苷类似物DoG可能具有抗HBV活性的潜在价值。

蝎毒多肽Smp76通过调节一型干扰素反应从而抑制病毒感染

冀正林, 李方方, 夏治强, 郭星辰, 高敏君, 孙芳, 成玉婷, 吴英亮, 李文鑫, Ali Syed Abid, 曹志贱

2018, 33(6): 545 doi: 10.1007/s12250-018-0068-4

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登革病毒和寨卡病毒在许多发展中国家传播,每年感染数百万人,对人类健康和经济造成严重危害。然而,现在几乎没有有效针对这两种病毒的疫苗和治疗方法。因此,新的抗病毒剂的研发迫在眉睫。我们在大肠杆菌BL21(DE3)系统中成功表达并纯化了蝎毒多肽Smp76。Smp76可以浓度依赖的方式有效抑制登革病毒和寨卡病毒。更重要的是,Smp76不直接失活病毒,而是通过上调一型干扰素来发挥抗病毒作用。这与传统的抗菌肽不同。Smp76作为一种新的抗病毒剂,具有调节一型干扰素应答的独特机制,证明了抗菌肽具有免疫调节的作用。
LETTER

扩增子测序研究病毒宿主内多样性的准确性评估

倪铭, 陈晨, 刘翟

2018, 33(6): 557 doi: 10.1007/s12250-018-0052-z

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RNA病毒由于有很高的复制突变率,在宿主体内常以具有多样性的群体形式存在。最近,多个研究组通过研究病毒宿主内多样性,解读了病毒的宿主内微进化过程以及病毒-宿主相互作用。研究病毒宿主内多样性的常用技术手段之一为扩增子测序,即首先对样本中的病毒进行特异性扩增,再对扩增子进行深度测序。但是,扩增子测序在病毒扩增和测序过程中可能引入错误,所以需要对该技术的敏感性和特异性进行评估。本研究通过构建模型样本,定量评价了扩增子测序发现病毒宿主内单核苷酸突变(intrahost single nucleotide variation, iSNV)的假阳性和假阴性、iSNV突变等位基因频率(mutated allele frequency, MuAF)的准确性,以及MuAF在不同扩增子之间的偏性。在我们对模型样本的测试中,样本病毒载量较高时(Ct值为25,或约1 × 105拷贝/微升),采用MuAF > 0.3%的阈值可使iSNV发现的假阴性率为零,假阳性率小于0.001。对于病毒载量很小的样本(Ct值为35,或约100拷贝/微升),采取更高的MuAF > 0.7%的阈值可获得类似的准确性。总的来说,在对临床和现场样本进行病毒宿主内多样性研究时,扩增子测序可提供足够高的准确性和敏感度,是一种有效可行的技术方案。

水貂圆环病毒可以感染水貂、狐狸和貉

杨艳玲, 程悦宁, 李楠, 程世鹏, 郭利, 周玉成, 张海威, 张新圆, 任林柱

2018, 33(6): 561 doi: 10.1007/s12250-018-0059-5

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本研究针对中国的水貂、狐狸、貉子等毛皮动物临床腹泻病例进行水貂圆环病毒的检测。结果发现,中国部分水貂、狐狸、貉子养殖场的水貂圆环病毒的感染率较高,其中,狐狸对水貂圆环病毒最为敏感,然后是水貂和貉子。其次,分离得到的三株水貂圆环病毒MiCV-LN、Fox CV-JL和Raccoon CV-HLJ与NCBI公布的水貂圆环病毒MiCV-DL13株具有极高的同源性,相似率达99 %。另外,水貂圆环病毒与其它病原的共感染可能对疾病的发生具有促进作用,其中水貂圆环病毒与大肠杆菌的共感染率为9 %(7/78),而水貂圆环病毒、大肠杆菌和水貂肠炎细小病毒的三重感染率为1.3 %(1/78)。本研究首次发现水貂圆环病毒也可感染狐狸与貉子。