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2018 Vol.33(5)

Nipah virus (NiV), a zoonotic paramyxovirus belonging to the genus Henipavirus, is classified as a Biosafety Level-4 pathogen based on its high pathogenicity in humans and the lack of available vaccines or therapeutics. Since its initial emergence in 1998 in Malaysia, this virus has been reported in Asia, Africa, and the South Pacific Ocean. NiV has a wide range of hosts, from its natural reservoir Pteropid bats to humans, horses, dogs, cats, cows, and pigs. NiV spreads from bats to humans through two main pathways, intermediate hosts (pigs and horses) and food-borne transmission via date palm sap contaminated with the saliva or urine of fruit bats. In this issue, Sun et al. reviewed the recent studies on the geographical and phylogenetic properties, transmission, and protein structure and function of NiV. The cover image is provided courtesy of Bangyao Sun and Di Liu. (See Page 385-393 for details).

EDITORIAL

Professor Hu Zhihong: The New President of the Society for Invertebrate Pathology

Basil Arif, Jiali Si, Zheng-Li Shi

2018, 33(5): 383 doi: 10.1007/s12250-018-0060-z

Received: 27 September 2018 Accepted: 30 September 2018 Published: 23 October 2018
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REVIEW

Phylogeography, Transmission, and Viral Proteins of Nipah Virus

Bangyao Sun, Lijia Jia, Bilin Liang, Quanjiao Chen, Di Liu

2018, 33(5): 385 doi: 10.1007/s12250-018-0050-1

Received: 14 June 2018 Accepted: 05 September 2018 Published: 11 October 2018
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Nipah virus (NiV), a zoonotic paramyxovirus belonging to the genus Henipavirus, is classified as a Biosafety Level-4 pathogen based on its high pathogenicity in humans and the lack of available vaccines or therapeutics. Since its initial emergence in 1998 in Malaysia, this virus has become a great threat to domestic animals and humans. Sporadic outbreaks and person-to-person transmission over the past two decades have resulted in hundreds of human fatalities. Epidemiological surveys have shown that NiV is distributed in Asia, Africa, and the South Pacific Ocean, and is transmitted by its natural reservoir, Pteropid bats. Numerous efforts have been made to analyze viral protein function and structure to develop feasible strategies for drug design. Increasing surveillance and preventative measures for the viral infectious disease are urgently needed.
Research Article

The Distribution of Different Clades of Seneca Valley Viruses in Guangdong Province, China

Pan Chen, Fan Yang, Weijun Cao, Huanan Liu, Keshan Zhang, Xiangtao Liu, Zhiwen Xu, Zixiang Zhu, Haixue Zheng

2018, 33(5): 394 doi: 10.1007/s12250-018-0056-8

Received: 15 May 2018 Accepted: 03 September 2018 Published: 16 October 2018
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Seneca Valley virus (SVV), a newly determined etiological agent of vesicular disease in swine, causes porcine idiopathic disease and occasional acute death in piglets. Recently, an increased number of SVV infection cases have been reported in the United States (US) and China, resulting in significant economic losses to the swine industry. The first identification of SVV in China was reported in Guangdong Province, a major swine producing province. The cases of SVV were continuously reported in Guangdong in 2015 and 2016. However, the spread of SVV in Guangdong in 2017 remains unknown. In this study, we determined two new SVV strains, CH-GD-2017-1 and CH-GD-2017-2, from Guangdong. The genetic analysis suggested that the two Guangdong strains showed different characteristics to previous Guangdong strains. They showed lower nucleotide similarity with strains isolated in 2015 and 2016, and were more similar to the US strains. Phylogenetic analyses indicated that the new strains were clustered in a different clade with previous Guangdong strains. We found 28 mutated amino acids in the new strains, compared with the first Guangdong strain, SVV CH-01-2015. In the geographic analysis, we found that the US and China reported more SVV cases than other countries, and most of the SVV cases were reported in east and central China—of which, Guangdong Province is one of the major epidemic regions. In conclusion, our findings indicate that SVV continued to spread in Guangdong Province in 2017, and two different clades of SVVs have emerged in this region.

Detection of EBV and HHV6 in the Brain Tissue of Patients with Rasmussen's Encephalitis

Dong Liu, Xin Wang, Yisong Wang, Peigang Wang, Dongying Fan, Sichang Chen, Yuguang Guan, Tianfu Li, Jing An, Guoming Luan

2018, 33(5): 402 doi: 10.1007/s12250-018-0063-9

Received: 24 June 2018 Accepted: 10 October 2018 Published: 29 October 2018
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Rasmussen's encephalitis (RE) is a rare pediatric neurological disorder, and the exact etiology is not clear. Viral infection may be involved in the pathogenesis of RE, but conflicting results have reported. In this study, we evaluated the expression of both Epstein-Barr virus (EBV) and human herpes virus (HHV) 6 antigens in brain sections from 30 patients with RE and 16 control individuals by immunohistochemistry. In the RE group, EBV and HHV6 antigens were detected in 56.7% (17/ 30) and 50% (15/30) of individuals, respectively. In contrast, no detectable EBV and HHV6 antigen expression was found in brain tissues of the control group. The co-expression of EBV and HHV6 was detected in 20.0% (6/30) of individuals. In particular, a 4-year-old boy had a typical clinical course, including a medical history of viral encephalitis, intractable epilepsy, and hemispheric atrophy. The co-expression of EBV and HHV6 was detected in neurons and astrocytes in the brain tissue, accompanied by a high frequency of CD8+ T cells. Our results suggest that EBV and HHV6 infection and the activation of CD8+ T cells are involved in the pathogenesis of RE.

Countrywide Survey for MERS-Coronavirus Antibodies in Dromedaries and Humans in Pakistan

Ali Zohaib, Muhammad Saqib, Muhammad Ammar Athar, Jing Chen, Awais-ur-Rahman Sial, Saeed Khan, Zeeshan Taj, Halima Sadia, Usman Tahir, Muhammad Haleem Tayyab, Muhammad Asif Qureshi, Muhammad Khalid Mansoor, Muhammad Ahsan Naeem, Bing-Jie Hu, Bilal Ahmed Khan, Ikram Din Ujjan, Bei Li, Wei Zhang, Yun Luo, Yan Zhu, Cecilia Waruhiu, Iahtasham Khan, Xing-Lou Yang, Muhammad Sohail Sajid, Victor Max Corman, Bing Yan, Zheng-Li Shi

2018, 33(5): 410 doi: 10.1007/s12250-018-0051-0

Received: 26 July 2018 Accepted: 03 September 2018 Published: 11 October 2018
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Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a zoonotic pathogen capable of causing severe respiratory disease in humans. Although dromedary camels are considered as a major reservoir host, the MERS-CoV infection dynamics in camels are not fully understood. Through surveillance in Pakistan, nasal (n=776) and serum (n=1050) samples were collected from camels between November 2015 and February 2018. Samples were collected from animal markets, free-roaming herds and abattoirs. An in-house ELISA was developed to detect IgG against MERS-CoV. A total of 794 camels were found seropositive for MERS-CoV. Prevalence increased with the age and the highest seroprevalence was recorded in camels aged > 10 years (81.37%) followed by those aged 3.1-10 years (78.65%) and ≤ 3 years (58.19%). Higher prevalence was observed in female (78.13%) as compared to male (70.70%). Of the camel nasal swabs, 22 were found to be positive by RT-qPCR though with high Ct values. Moreover, 2,409 human serum samples were also collected from four provinces of Pakistan during 2016-2017. Among the sampled population, 840 humans were camel herders. Although we found a high rate of MERS-CoV antibody positive dromedaries (75.62%) in Pakistan, no neutralizing antibodies were detected in humans with and without contact to camels.

Histone Deacetylase 3 Inhibitor Suppresses Hepatitis C Virus Replication by Regulating Apo-A1 and LEAP-1 Expression

Yuan Zhou, Qian Wang, Qi Yang, Jielin Tang, Chonghui Xu, Dongwei Gai, Xinwen Chen, Jizheng Chen

2018, 33(5): 418 doi: 10.1007/s12250-018-0057-7

Received: 27 July 2018 Accepted: 24 August 2018 Published: 17 October 2018
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Histone deacetylase (HDAC) inhibitors show clinical promise for the treatment of cancers, including hepatocellular carcinoma (HCC). In this study, we investigated the effect of HDAC inhibitor treatment on hepatitis C virus (HCV) replication in Huh7 human liver cells and in a mouse model of HCV infection. Viral replication was markedly suppressed by the HDAC3 inhibitor at concentrations below 1 mmol/L, with no cellular toxicity. This was accompanied by upregulation of liver-expressed antimicrobial peptide 1(LEAP-1) and downregulation of apolipoprotein-A1 (Apo-A1), as determined by microarray and quantitative RT-PCR analyses. Moreover, HDAC3 was found to modulate the binding of CCAAT-enhancer-binding protein α(C/EBPα), hypoxia-inducible factor 1α (HIF1α), and signal transducer and activator of transcription 3 (STAT3) to the LEAP-1 promoter. HDAC3 inhibitor treatment also blocked HCV replication in a mouse model of HCV infection. These results indicate that epigenetic therapy with HDAC3 inhibitor may be a potential treatment for diseases associated with HCV infection such as HCC.

Identification of Nonstructural Protein 8 as the N-Terminus of the RNADependent RNA Polymerase of Porcine Reproductive and Respiratory Syndrome Virus

Yuanyuan Liu, Yunhao Hu, Yue Chai, Liping Liu, Jiangwei Song, Shaochuan Zhou, Jia Su, Lei Zhou, Xinna Ge, Xin Guo, Jun Han, Hanchun Yang

2018, 33(5): 429 doi: 10.1007/s12250-018-0054-x

Received: 09 July 2018 Accepted: 30 August 2018 Published: 23 October 2018
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Porcine reproductive and respiratory syndrome virus (PRRSV) is a member within the family Arteriviridae of the order Nidovirales. Replication of this positive-stranded RNA virus within the host cell involves expression of viral replicase proteins encoded by two ORFs, namely ORF1a and ORF1b. In particular, translation of ORF1b depends on a -1-ribosomal frameshift strategy. Thus, nonstructural protein 9 (nsp9), the first protein within ORF1b that specifies the function of the viral RNA-dependent RNA polymerase, is expressed as the C-terminal extension of nsp8, a small nsp that is encoded by ORF1a. However, it has remained unclear whether the mature form of nsp9 in virus-infected cells still retains nsp8, addressing which is clearly critical to understand the biological function of nsp9. By taking advantage of specific antibodies to both nsp8 and nsp9, we report the following findings. (1) In infected cells, PRRSV nsp9 was identified as a major product with a size between 72 and 95 kDa (72-95 KDa form), which exhibited the similar mobility on the gel to the in vitro expressed nsp8-9ORF1b, but not the ORF1b-coded portion (nsp9ORF1b). (2) The antibodies to nsp8, but not to nsp7 or nsp10, could detect a major product that had the similar mobility to the 72-95 KDa form of nsp9. Moreover, nsp9 could be co-immunoprecipitated by antibodies to nsp8, and vice versa. (3) Neither nsp4 nor nsp2 PLP2 was able to cleave nsp8- nsp9 in vitro. Together, our studies provide experimental evidence to suggest that nsp8 is an N-terminal extension of nsp9. Our findings here paves way for further charactering the biological function of PRRSV nsp9.

CypA Regulates AIP4-Mediated M1 Ubiquitination of Influenza A Virus

Madina Mahesutihan, Weinan Zheng, Liang Cui, Yun Li, Pengtao Jiao, Wenxian Yang, Wei Liu, Jing Li, Wenhui Fan, Limin Yang, Wenjun Liu, Lei Sun

2018, 33(5): 440 doi: 10.1007/s12250-018-0058-6

Received: 16 July 2018 Accepted: 13 September 2018 Published: 16 October 2018
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Cyclophilin A (CypA) is a peptidyl-prolyl cis/trans isomerase that interacts with the matrix protein (M1) of influenza A virus (IAV) and restricts virus replication by regulating the ubiquitin–proteasome-mediated degradation of M1. However, the mechanism by which CypA regulates M1 ubiquitination remains unknown. In this study, we reported that E3 ubiquitin ligase AIP4 promoted K48-linked ubiquitination of M1 at K102 and K104, and accelerated ubiquitin–proteasome-mediated degradation of M1. The recombinant IAV with mutant M1 (K102R/K104R) could not be rescued, suggesting that the ubiquitination of M1 at K102/K104 was essential for IAV replication. Furthermore, CypA inhibited AIP4-mediated M1 ubiquitination by impairing the interaction between AIP4 and M1. More importantly, both the mutations of M1 (K102R/ K104R) and CypA inhibited the nuclear export of M1, indicating that CypA regulates the cellular localization of M1 via inhibition of AIP4-mediated M1 ubiquitination at K102 and K104, which results in the reduced replication of IAV. Collectively, our findings reveal a novel ubiquitination-based mechanism by which CypA regulates the replication of IAV.
LETTERS

Characterization of Avian-like Influenza A (H4N6) Virus Isolated from Caspian Seal in 2012

Marina Gulyaeva, Ivan Sobolev, Kirill Sharshov, Olga Kurskaya, Alexander Alekseev, Lidia Shestopalova, Anna Kovner, Yuhai Bi, Weifeng Shi, Michael Shchelkanov, Alexander Shestopalov

2018, 33(5): 449 doi: 10.1007/s12250-018-0053-y

Received: 24 July 2018 Accepted: 03 September 2018 Published: 17 October 2018
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Marine mammals are widely distributed and can be found almost in all coastal waters and coastlines around the world. The interface areas between marine and terrestrial environments provide natural habitats for aquatic and semiaquatic mammals as well as for reservoir species of avian influenza viruses (AIV) (Runstadler et al. 2013). Previous studies showed that wild aquatic birds, the natural reservoir of AIV, are able to transmit the virus to various mammals, including seals, swine, horses, muskrats, and humans (Webster et al. 1992; Reperant et al. 2009; Gulyaeva et al. 2017). Close contacts between sea mammals and wild birds on breeding-grounds could promote both interspecies transmission of AIV and virus establishment in a new host (Fereidouni et al. 2014). Various AIV subtypes (A/seal/ Massachusetts/80(H7N7), A/Seal/MA/133/82(H4N5), A/Seal/MA/3807/91(H4N6), A/Seal/MA/3911/92(H3N3), A/harbour seal/Mass/1/2011(H3N8) and A/harbor seal/NL/ PV14-221_ThS/2015(H10N7) etc.) have been isolated from different species of marine mammals during the last 30 years. AIV isolated from marine mammals and wild birds are closely related, which suggests that wild birds are the major source of AIV infection (Fereidouni et al. 2014; Bodewes et al. 2015). In addition, AIV can cross species barrier and replicate well in experimental mammals without prior adaptation (Driskell et al. 2012).

Significant Spike-Specific IgG and Neutralizing Antibodies in Mice Induced by a Novel Chimeric Virus-Like Particle Vaccine Candidate for Middle East Respiratory Syndrome Coronavirus

Jiaming Lan, Yao Deng, Jingdong Song, Baoying Huang, Wenling Wang, Wenjie Tan

2018, 33(5): 453 doi: 10.1007/s12250-018-0064-8

Received: 28 August 2018 Accepted: 11 October 2018 Published: 29 October 2018
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Middle East respiratory syndrome coronavirus (MERS-CoV) is a major health concern to the general population, with no available licensed therapeutic or vaccine. Virus-like particles (VLPs) comprise viral structural proteins, which represent a safe and highly immunogenic vaccine delivery platform able to induce potent adaptive immune responses. The study aimed to develop immunogenic chimeric VLPs (cVLPs) against MERS-CoV infection via co-expression of modified Spike (S) of MERS-CoV and M1 of H5N1 in a baculoviral expression system. The results indicated that chimeric MERS VLPs were morphologically similar to native MERS-CoV. Whereafter six-to-eight-week-old female BALB/c mice were intramuscularly injected with 1 μg of cVLPs of MERS-S. ELISA and pseudovirus neutralization assay showed high titers of S protein-specific IgG and neutralizing antibodies were induced by the cVLPs. Hence, the cVLPs are promising prophylactic vaccine candidates against MERS-CoV infections.
PERSPECTIVE

Common Infections May Lead to Alzheimer's Disease

Yuyan Wang, Ling Ding, Qing Zhu, Minfeng Shu, Qiliang Cai

2018, 33(5): 456 doi: 10.1007/s12250-018-0049-7

Received: 27 July 2018 Accepted: 24 August 2018 Published: 17 September 2018
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Recent study by Joel Dudley and colleagues published in Neuron on July 11, demonstrated that both HHV-6A and HHV-7 could be key causal contributors to Alzheimer’s disease (AD). However, among various biological and technical issues, we review how complicate to demonstrate the link of HHV-6A and HHV-7 infection with AD in current situation, and highlight the potential open research directions of follow-up studies in the future.

Targeting cIAPs, a New Option for Functional Cure of Chronic Hepatitis B Infection?

Hongyan Liu, Jinlin Hou, Xiaoyong Zhang

2018, 33(5): 459 doi: 10.1007/s12250-018-0062-x

Received: 09 August 2018 Accepted: 30 September 2018 Published: 29 October 2018
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Hepatitis B virus (HBV) infection remains a great public health problem worldwide. Here, we discuss the rationality and possibility of cellular inhibitor of apoptosis proteins (cIAPs) as a therapeutic target for HBV functional cure, and introduce the ongoing Phase I clinical study of cIAPs antagonists APG-1387 for chronic hepatitis B treatment.