Publications by authors named "Weifeng Shi"

137 Publications

Intratumoral Virotherapy with Wild-Type Newcastle Disease Virus in Carcinoma Krebs-2 Cancer Model.

Viruses 2021 Mar 25;13(4). Epub 2021 Mar 25.

FRC of Fundamental and Translational Medicine, Eurasian Institute of Zoonotic Infections, Timakova Street 2, 630117 Novosibirsk, Russia.

The results of experimental and clinical trials of the agents based on oncolytic Newcastle disease virus (NDV) strains provided hope for the development of virotherapy as a promising method for treating human tumors. However, the mechanism of the antitumor effect of NDV and realization of its cytotoxic potential in a cancer cell remains to be elucidated. In the current work, we have studied the antitumor effect of NDV in a syngeneic model of mouse Krebs-2 carcinoma treated with intratumoral injections of a wild-type strain NDV/Altai/pigeon/770/2011. Virological methods were used for preparation of a virus-containing sample. Colorimetric MTS assay was used to assess the viability of Krebs-2 tumor cells infected with a viral strain in vitro. In vivo virotherapy was performed in eight-week-old male BALB/c mice treated with serial intratumoral injections of NDV in an experimental model of Krebs-2 solid carcinoma. Changes in the tumor nodes of Krebs-2 carcinoma after virotherapy were visualized by MRI and immunohistological staining. Light microscopy examination, immunohistochemical and morphometric analyses have shown that intratumoral viral injections contribute to the inhibition of tumor growth, appearance of necrosis-like changes in the tumor tissue and the antiangiogenic effect of the virus. It has been established that a course of intratumoral virotherapy with NDV/Altai/pigeon/770/2011 strain in a mouse Krebs-2 carcinoma resulted in increased destructive changes in the tumor tissue, in the volume density of necrotic foci and numerical density of endothelial cells expressing CD34 and VEGFR. These results indicate that intratumoral NDV injection reduces tumor progression of an aggressive tumor.
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http://dx.doi.org/10.3390/v13040552DOI Listing
March 2021

Retrospective meta-transcriptomic identification of severe dengue in a traveller returning from Africa to Sweden, 1990.

One Health 2021 Jun 22;12:100217. Epub 2021 Jan 22.

Public Health Agency of Sweden, Nobels väg 18, SE-171 82 Solna, Sweden.

Pathogens associated with haemorrhagic fever commonly have zoonotic origins. The first documented imported case of likely viral severe haemorrhagic fever in Sweden occurred in 1990. Despite extensive study, no aetiological agent was identified. Following retrospective investigation with total RNA-sequencing of samples collected between 7 and 36 days from onset of symptoms we identified dengue virus 3 (DENV-3) and a human pegivirus (HPgV). We conclude that the patient likely suffered from haemorrhagic symptoms due to an atypical severe and undiagnosed dengue infection.
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http://dx.doi.org/10.1016/j.onehlt.2021.100217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851179PMC
June 2021

Bioinformatics resources for SARS-CoV-2 discovery and surveillance.

Brief Bioinform 2021 03;22(2):631-641

Shandong First Medical University, China.

In early January 2020, the novel coronavirus (SARS-CoV-2) responsible for a pneumonia outbreak in Wuhan, China, was identified using next-generation sequencing (NGS) and readily available bioinformatics pipelines. In addition to virus discovery, these NGS technologies and bioinformatics resources are currently being employed for ongoing genomic surveillance of SARS-CoV-2 worldwide, tracking its spread, evolution and patterns of variation on a global scale. In this review, we summarize the bioinformatics resources used for the discovery and surveillance of SARS-CoV-2. We also discuss the advantages and disadvantages of these bioinformatics resources and highlight areas where additional technical developments are urgently needed. Solutions to these problems will be beneficial not only to the prevention and control of the current COVID-19 pandemic but also to infectious disease outbreaks of the future.
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http://dx.doi.org/10.1093/bib/bbaa386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929396PMC
March 2021

Ubiquitin E3 Ligase c-Cbl Is a Host Negative Regulator of Nef Protein of HIV-1.

Front Microbiol 2020 19;11:597972. Epub 2020 Nov 19.

The Second Affiliated Hospital of Soochow University, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, China.

Nef is an accessory protein encoded by human immunodeficiency virus type-1 (HIV-1) and plays important roles in regulating HIV-1 infection and viral replication. Interestingly, HIV-1 Nef can promote degradation of numerous host proteins to disrupt cellular antiviral immune response. However, how HIV-1 Nef is degraded by host factors remains largely unexplored. Here, we identified c-Cbl as a host ubiquitin E3 ligase of HIV-1 Nef. We found that c-Cbl interacts with Nef and reduces protein levels of HIV-1 Nef. Further studies demonstrated that c-Cbl promoted Lys48-linked polyubiquitination of HIV-1 Nef, thus attenuating protein stability of HIV-1 Nef. Importantly, cellular c-Cbl ubiquitinated and degraded Nef proteins produced by HIV-1 NL4-3 virions, and ultimately attenuated HIV-1 virulence for infection of THP1 cells. This study reveals a ubiquitination and proteasome-dependent degradation mechanism of HIV-1 Nef protein, and could provide potential strategies for fighting against HIV-1.
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http://dx.doi.org/10.3389/fmicb.2020.597972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710902PMC
November 2020

Total infectomes of 162 SARS-CoV-2 cases using meta-transcriptomic sequencing.

J Infect 2021 Jan 8;82(1):e44-e48. Epub 2020 Dec 8.

Key Laboratory of Etiology and Epidemiology of Emerging Infectious Diseases in Universities of Shandong, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271000, China; The First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital), Jinan 250014, China; School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian 271000, China. Electronic address:

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http://dx.doi.org/10.1016/j.jinf.2020.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722261PMC
January 2021

Anti-ST2 Nanoparticle Alleviates Lung Inflammation by Targeting ILC2s-CD4T Response.

Int J Nanomedicine 2020 3;15:9745-9758. Epub 2020 Dec 3.

Department of Laboratory Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, People's Republic of China.

Background: Asthma has been regarded as an inflammatory disease, and group 2 innate lymphoid cells (ILC2s) are implicated in asthma pathogenesis. However, no strategy is available to block ILC2s function. Efficiency is also limited due to the use of systemic or subcutaneous routes of administration. The purpose of this study was to investigate the effects of nanoparticles targeting suppression of tumorigenicity 2 (ST2), which is the ILC2 receptor, to alleviate lung inflammation in the murine model of asthma.

Methods: The ultra-small SPIO nanoparticles were firstly synthesized, OVA-induced mice were administered by anti-ST2-conjugated nanoparticles. The inflammatory degree of the lung was investigated by H&E. The percentages of ILC2s and CD4T cells in bronchoalveolar lavage fluid (BALF) and lung tissue were determined by FACS. Th2-cytokine and OVA-IgE levels were detected by real-time PCR and ELISA, respectively.

Results: Treatment with anti-ST2-conjugated nanoparticles significantly alleviated airway inflammation, IL-33 and IL-13 levels and the percentage of CD4T cells. The percentage of ILC2s was increased, whereas the levels of IL-13 and IL-5 expressed by ILC2s were reduced.

Conclusion: In the present study, we demonstrated that anti-ST2-conjugated nanoparticles can efficiently control lung inflammation in OVA-induced mice by reducing the ability of ILC2s to produce IL-5 and IL-13, thereby reducing CD4+T cells. Our study also demonstrated that the nanoparticle delivery system could improve the performance of anti-ST2, which may be used as a strategic tool to expand the current drug market.
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http://dx.doi.org/10.2147/IJN.S268282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721292PMC
December 2020

Dominant subtype switch in avian influenza viruses during 2016-2019 in China.

Nat Commun 2020 11 20;11(1):5909. Epub 2020 Nov 20.

Key Laboratory of Etiology and Epidemiology of Emerging Infectious Diseases in Universities of Shandong, Shandong First Medical University & Shandong Academy of Medical Sciences, 271016, Taian, China.

We have surveyed avian influenza virus (AIV) genomes from live poultry markets within China since 2014. Here we present a total of 16,091 samples that were collected from May 2016 to February 2019 in 23 provinces and municipalities in China. We identify 2048 AIV-positive samples and perform next generation sequencing. AIV-positive rates (12.73%) from samples had decreased substantially since 2016, compared to that during 2014-2016 (26.90%). Additionally, H9N2 has replaced H5N6 and H7N9 as the dominant AIV subtype in both chickens and ducks. Notably, novel reassortants and variants continually emerged and disseminated in avian populations, including H7N3, H9N9, H9N6 and H5N6 variants. Importantly, almost all of the H9 AIVs and many H7N9 and H6N2 strains prefer human-type receptors, posing an increased risk for human infections. In summary, our nation-wide surveillance highlights substantial changes in the circulation of AIVs since 2016, which greatly impacts the prevention and control of AIVs in China and worldwide.
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http://dx.doi.org/10.1038/s41467-020-19671-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679419PMC
November 2020

Uncovering two phases of early intercontinental COVID-19 transmission dynamics.

J Travel Med 2020 12;27(8)

WorldPop, School of Geography and Environmental Science, University of Southampton, Southampton, UK.

Background: The COVID-19 pandemic has posed an ongoing global crisis, but how the virus spread across the world remains poorly understood. This is of vital importance for informing current and future pandemic response strategies.

Methods: We performed two independent analyses, travel network-based epidemiological modelling and Bayesian phylogeographic inference, to investigate the intercontinental spread of COVID-19.

Results: Both approaches revealed two distinct phases of COVID-19 spread by the end of March 2020. In the first phase, COVID-19 largely circulated in China during mid-to-late January 2020 and was interrupted by containment measures in China. In the second and predominant phase extending from late February to mid-March, unrestricted movements between countries outside of China facilitated intercontinental spread, with Europe as a major source. Phylogenetic analyses also revealed that the dominant strains circulating in the USA were introduced from Europe. However, stringent restrictions on international travel across the world since late March have substantially reduced intercontinental transmission.

Conclusions: Our analyses highlight that heterogeneities in international travel have shaped the spatiotemporal characteristics of the pandemic. Unrestricted travel caused a large number of COVID-19 exportations from Europe to other continents between late February and mid-March, which facilitated the COVID-19 pandemic. Targeted restrictions on international travel from countries with widespread community transmission, together with improved capacity in testing, genetic sequencing and contact tracing, can inform timely strategies for mitigating and containing ongoing and future waves of COVID-19 pandemic.
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http://dx.doi.org/10.1093/jtm/taaa200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665593PMC
December 2020

Broad host range of SARS-CoV-2 and the molecular basis for SARS-CoV-2 binding to cat ACE2.

Cell Discov 2020 29;6:68. Epub 2020 Sep 29.

CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101 China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the recent pandemic COVID-19, is reported to have originated from bats, with its intermediate host unknown to date. Here, we screened 26 animal counterparts of the human ACE2 (hACE2), the receptor for SARS-CoV-2 and SARS-CoV, and found that the ACE2s from various species, including pets, domestic animals and multiple wild animals, could bind to SARS-CoV-2 receptor binding domain (RBD) and facilitate the transduction of SARS-CoV-2 pseudovirus. Comparing to SARS-CoV-2, SARS-CoV seems to have a slightly wider range in choosing its receptor. We further resolved the cryo-electron microscopy (cryo-EM) structure of the cat ACE2 (cACE2) in complex with the SARS-CoV-2 RBD at a resolution of 3 Å, revealing similar binding mode as hACE2 to the SARS-CoV-2 RBD. These results shed light on pursuing the intermediate host of SARS-CoV-2 and highlight the necessity of monitoring susceptible hosts to prevent further outbreaks.
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http://dx.doi.org/10.1038/s41421-020-00210-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526519PMC
September 2020

Rapid humoral immune responses are required for recovery from haemorrhagic fever with renal syndrome patients.

Emerg Microbes Infect 2020 Dec;9(1):2303-2314

Key Laboratory of Etiology and Epidemiology of Emerging Infectious Diseases in Universities of Shandong, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, People's Republic of China.

Haemorrhagic fever with renal syndrome (HFRS) following Hantaan virus (HTNV) infection displays variable clinical signs. Humoral responses elicited during HTNV infections are considered important, however, this process remains poorly understood. Herein, we have investigated the phenotype, temporal dynamics, and characteristics of B-cell receptor (BCR) repertoire in an HFRS cohort. The serological profiles were characterized by a lowered expression level of nucleoprotein (NP)-specific antibody in severe cases. Importantly, B-cell subsets were activated and proliferated within the first two weeks of symptom onset and moderate cases reacted more rapidly. BCR analysis in the recovery phase revealed a dramatic increase in the immunoglobulin gene diversity which was more significantly progressed in moderate infections. In severe cases, B-cell-related transcription was lower with inflammatory sets overactivated. Taken together, these data suggest the clinical signs and disease recovery in HFRS patients were positively impacted by rapid and efficacious humoral responses.
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http://dx.doi.org/10.1080/22221751.2020.1830717DOI Listing
December 2020

Emerging HxNy Influenza A Viruses.

Cold Spring Harb Perspect Med 2020 Sep 14. Epub 2020 Sep 14.

National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing 102206, China.

The continuous emergence and reemergence of diverse subtypes of influenza A viruses, which are known as "HxNy" and are mediated through the reassortment of viral genomes, account for seasonal epidemics, occasional pandemics, and zoonotic outbreaks. We summarize and discuss the characteristics of historic human pandemic HxNy viruses and diverse subtypes of HxNy among wild birds, mammals, and live poultry markets. In addition, we summarize the key molecular features of emerging infectious HxNy influenza viruses from the perspectives of the receptor binding of Hx, the inhibitor-binding specificities and drug-resistance features of Ny, and the matching of the gene segments. Our work enhances our understanding of the potential threats of novel reassortant influenza viruses to public health and provides recommendations for effective prevention, control, and research of this pathogen.
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http://dx.doi.org/10.1101/cshperspect.a038406DOI Listing
September 2020

Genomic characterization of SARS-CoV-2 identified in a reemerging COVID-19 outbreak in Beijing's Xinfadi market in 2020.

Biosaf Health 2020 Dec 2;2(4):202-205. Epub 2020 Sep 2.

NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China.

After 56 days without coronavirus disease 2019 (COVID-19) cases, reemergent cases were reported in Beijing, China on June 11, 2020. Here, we report the genetic characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequenced from the clinical specimens of 4 human cases and 2 environmental samples. The nucleotide similarity among six SARS-CoV-2 genomes ranged from 99.98% to 99.99%. Compared with the reference strain of SARS-CoV-2 (GenBank No. NC_045512), all six genome sequences shared the same substitutions at nt241 (C → T), nt3037 (C → T), nt14408 (C → T), nt23403 (A → G), nt28881 (G → A), nt28882 (G → A), and nt28883 (G → C), which are the characteristic nucleotide substitutions of L-lineage European branch I. This was also proved by the maximum likelihood phylogenetic tree based on the full-length genome of SARS-CoV-2. They also have a unique shared nucleotide substitution, nt6026 (C → T), which is the characteristic nucleotide substitution of SARS-CoV-2 in Beijing's Xinfadi outbreak. It is noteworthy that there is an amino acid D614G mutation caused by nt23403 substitution in all six genomes, which may enhance the virus's infectivity in humans and help it become the leading strain of the virus to spread around the world today. It is necessary to continuously monitor the genetic variation of SARS-CoV-2, focusing on the influence of key mutation sites of SARS-CoV-2 on viral transmission, clinical manifestations, severity, and course of disease.
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http://dx.doi.org/10.1016/j.bsheal.2020.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467064PMC
December 2020

Characterization of Influenza A and B Viruses Circulating in Southern China During the 2017-2018 Season.

Front Microbiol 2020 29;11:1079. Epub 2020 May 29.

Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.

The trivalent seasonal influenza vaccine was the only approved and available vaccine during the 2016-2018 influenza seasons. It did not include the B/Yamagata strain. In this study, we report an acute respiratory disease outbreak associated with influenza B/Yamagata infections in Guangzhou, Southern China (January through March, 2018). Among the 9914 patients, 2241 (22.6%) were positive for the influenza B virus, with only 312 (3.1%) positive for the influenza A virus. The influenza B/Yamagata lineage dominated during this period in Southern China. The highest incidence of influenza A virus infection occurred in the children aged 5-14 years. In contrast, populations across all age groups were susceptible to the influenza B virus. Phylogenetic, mutations, and 3D structure analyses of hemagglutinin (HA) genes were performed to assess the vaccine-virus relatedness. The recommended A/H1N1 vaccine strain (A/Michigan/45/2015) during both 2017-2018 and 2018-2019 was antigen-specific for these circulating isolates (clade 6B.1) in Spring 2018. An outbreak of influenza B/Yamagata (clade 3) infections in 2018 occurred during the absence of the corresponding vaccine during 2016-2018. The recommended influenza B/Yamagata vaccine strain (B/Phuket/3073/2013) for the following season (2018-2019) was antigen-specific. Although there were only a few influenza B/Victoria infections in Spring 2018, five amino acid mutations were identified in the HA antigenic sites of the 19 B/Victoria isolates (clade 1A), when compared with the 2016-2018 B/Victoria vaccine strain. The number was larger than expected and suggested that the influenza B HA gene may be more variable than previously thought. One of the mutations (K180N) was noted to likely alter the epitope and to potentially affect the viral antigenicity. Seven mutations were also identified in the HA antigenic sites of 2018-2020 B/Victoria vaccine strain, of which some or all may reduce immunogenicity and the protective efficacy of the vaccine, perhaps leading to more outbreaks in subsequent seasons. The combined epidemiological, phylogenetic, mutations, and 3D structural analyses of the HA genes of influenza strains reported here contribute to the understanding and evaluation of how HA mutations affect vaccine efficacy, as well as to providing important data for screening and selecting more specific, appropriate, and effective influenza vaccine candidate strains.
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http://dx.doi.org/10.3389/fmicb.2020.01079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272714PMC
May 2020

A Novel Bat Coronavirus Closely Related to SARS-CoV-2 Contains Natural Insertions at the S1/S2 Cleavage Site of the Spike Protein.

Curr Biol 2020 06 11;30(11):2196-2203.e3. Epub 2020 May 11.

Key Laboratory of Etiology and Epidemiology of Emerging Infectious Diseases in Universities of Shandong, Shandong First Medical University, and Shandong Academy of Medical Sciences, Taian 271000, China; The First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital), Ji'nan 250014, China. Electronic address:

The unprecedented pandemic of pneumonia caused by a novel coronavirus, SARS-CoV-2, in China and beyond has had major public health impacts on a global scale [1, 2]. Although bats are regarded as the most likely natural hosts for SARS-CoV-2 [3], the origins of the virus remain unclear. Here, we report a novel bat-derived coronavirus, denoted RmYN02, identified from a metagenomic analysis of samples from 227 bats collected from Yunnan Province in China between May and October 2019. Notably, RmYN02 shares 93.3% nucleotide identity with SARS-CoV-2 at the scale of the complete virus genome and 97.2% identity in the 1ab gene, in which it is the closest relative of SARS-CoV-2 reported to date. In contrast, RmYN02 showed low sequence identity (61.3%) to SARS-CoV-2 in the receptor-binding domain (RBD) and might not bind to angiotensin-converting enzyme 2 (ACE2). Critically, and in a similar manner to SARS-CoV-2, RmYN02 was characterized by the insertion of multiple amino acids at the junction site of the S1 and S2 subunits of the spike (S) protein. This provides strong evidence that such insertion events can occur naturally in animal betacoronaviruses.
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http://dx.doi.org/10.1016/j.cub.2020.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211627PMC
June 2020

A Novel Hepe-Like Virus from Farmed Giant Freshwater Prawn .

Viruses 2020 03 17;12(3). Epub 2020 Mar 17.

Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, China.

The family Hepeviridae includes several positive-stranded RNA viruses, which infect a wide range of mammalian species, chicken, and trout. However, few hepatitis E viruses (HEVs) have been characterized from invertebrates. In this study, a hepevirus, tentatively named Crustacea hepe-like virus 1 (CHEV1), from the economically important crustacean, the giant freshwater prawn , was characterized. The complete genome consisted of 7750 nucleotides and had a similar structure to known hepatitis E virus genomes. Phylogenetic analyses suggested it might be a novel hepe-like virus within the family Hepeviridae. To our knowledge, this is the first hepe-like virus characterized from crustaceans.
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http://dx.doi.org/10.3390/v12030323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150978PMC
March 2020

Assessing the role of live poultry trade in community-structured transmission of avian influenza in China.

Proc Natl Acad Sci U S A 2020 03 2;117(11):5949-5954. Epub 2020 Mar 2.

State Key Laboratory of Remote Sensing Science, College of Global Change and Earth System Science, Beijing Normal University, 100875 Beijing, China;

The live poultry trade is thought to play an important role in the spread and maintenance of highly pathogenic avian influenza A viruses (HP AIVs) in Asia. Despite an abundance of small-scale observational studies, the role of the poultry trade in disseminating AIV over large geographic areas is still unclear, especially for developing countries with complex poultry production systems. Here we combine virus genomes and reconstructed poultry transportation data to measure and compare the spatial spread in China of three key subtypes of AIV: H5N1, H7N9, and H5N6. Although it is difficult to disentangle the contribution of confounding factors, such as bird migration and spatial distance, we find evidence that the dissemination of these subtypes among domestic poultry is geographically continuous and likely associated with the intensity of the live poultry trade in China. Using two independent data sources and network analysis methods, we report a regional-scale community structure in China that might explain the spread of AIV subtypes in the country. The identification of this structure has the potential to inform more targeted strategies for the prevention and control of AIV in China.
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http://dx.doi.org/10.1073/pnas.1906954117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084072PMC
March 2020

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.

Lancet 2020 02 30;395(10224):565-574. Epub 2020 Jan 30.

NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China; Central Theater, People's Liberation Army General Hospital, Wuhan, China; Center for Biosafety Mega-Science, Chinese Academy of Sciences, Beijing, China. Electronic address:

Background: In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed.

Methods: We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus.

Findings: The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues.

Interpretation: 2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation.

Funding: National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.
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http://dx.doi.org/10.1016/S0140-6736(20)30251-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159086PMC
February 2020

A Novel Coronavirus from Patients with Pneumonia in China, 2019.

N Engl J Med 2020 02 24;382(8):727-733. Epub 2020 Jan 24.

From the NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (N.Z., W.W., J.S., X.Z., B.H., R.L., P.N., X.M., D.W., W.X., G.W., G.F.G., W.T.), and the Department of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University (X.L.) - both in Beijing; Wuhan Jinyintan Hospital (D.Z.), the Division for Viral Disease Detection, Hubei Provincial Center for Disease Control and Prevention (B.Y., F.Z.), and the Center for Biosafety Mega-Science, Chinese Academy of Sciences (W.T.) - all in Wuhan; and the Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China (W.S.).

In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.).
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http://dx.doi.org/10.1056/NEJMoa2001017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092803PMC
February 2020

MALDI-TOF MS for the rapid identification and drug susceptibility testing of filamentous fungi.

Exp Ther Med 2019 Dec 22;18(6):4865-4873. Epub 2019 Oct 22.

Department of Clinical Laboratory, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, P.R. China.

The present study aimed to evaluate the applicability of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for identifying filamentous fungi and assessing the activities of common antifungal drugs against different kinds of filamentous fungi that are commonly encountered in a clinical setting. A total of 123 strains of filamentous fungi (24 species) were submitted for identification by MALDI-TOF MS, and the findings were compared with those obtained by conventional methods. The discrepancies were further investigated by internal transcribed spacer (ITS) sequence analysis. Then, 79 strains were randomly selected for further testing by the minimum inhibitory concentration Etest method. MALDI-TOF MS correctly identified 114 (92.70%) of the 123 filamentous fungi and failed to identify six isolates (4.9%). By contrast, the conventional identification methods made 113 (91.9%) correct identifications. In addition, 15 isolates of filamentous fungi were further identified by ribosomal DNA-ITS sequencing. In the antifungal susceptibility test, voriconazole showed the strongest antifungal activity among the tested drugs against a broad range of filamentous fungi. Caspofungin showed a better antifungal activity than fluconazole, itraconazole, and amphotericin B. MALDI-TOF MS offers a cost/time-saving, high-throughput and accurate working protocol for identifying filamentous fungi. Voriconazole could still serve as the first-line drug for treating serious infections caused by filamentous fungi, while caspofungin may be another treatment option for fungal infections.
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http://dx.doi.org/10.3892/etm.2019.8118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895777PMC
December 2019

Avian Influenza A Viruses among Occupationally Exposed Populations, China, 2014-2016.

Emerg Infect Dis 2019 12;25(12):2215-2225

To determine the seroprevalence and seroconversion of avian influenza virus (AIV) antibodies in poultry workers, we conducted a seroepidemiologic study in 7 areas of China during December 2014-April 2016. We used viral isolation and reverse transcription PCR to detect AIVs in specimens from live poultry markets. We analyzed 2,124 serum samples obtained from 1,407 poultry workers by using hemagglutination inhibition and microneutralization assays. We noted seroprevalence of AIV antibodies for subtypes H9N2, H7N9, H6N1, H5N1-SC29, H5N6, H5N1-SH199, and H6N6. In serum from participants with longitudinal samples, we noted seroconversion, with >4-fold rise in titers, for H9N2, H7N9, H6N1, H5N1-SC29, H6N6, H5N6, and H5N1-SH199 subtypes. We found no evidence of H10N8 subtype. The distribution of AIV antibodies provided evidence of asymptomatic infection. We found that AIV antibody prevalence in live poultry markets correlated with increased risk for H7N9 and H9N2 infection among poultry workers.
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http://dx.doi.org/10.3201/eid2512.190261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874249PMC
December 2019

Host-range shift of H3N8 canine influenza virus: a phylodynamic analysis of its origin and adaptation from equine to canine host.

Vet Res 2019 Oct 30;50(1):87. Epub 2019 Oct 30.

Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, Engineering Laboratory of Animal Immunity of Jiangsu Province, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China.

Prior to the emergence of H3N8 canine influenza virus (CIV) and the latest avian-origin H3N2 CIV, there was no evidence of a circulating canine-specific influenza virus. Molecular and epidemiological evidence suggest that H3N8 CIV emerged from H3N8 equine influenza virus (EIV). This host-range shift of EIV from equine to canine hosts and its subsequent establishment as an enzootic CIV is unique because this host-range shift was from one mammalian host to another. To further understand this host-range shift, we conducted a comprehensive phylodynamic analysis using all the available whole-genome sequences of H3N8 CIV. We found that (1) the emergence of H3N8 CIV from H3N8 EIV occurred in approximately 2002; (2) this interspecies transmission was by a reassortant virus of the circulating Florida-1 clade H3N8 EIV; (3) once in the canine species, H3N8 CIV spread efficiently and remained an enzootic virus; (4) H3N8 CIV evolved and diverged into multiple clades or sublineages, with intra and inter-lineage reassortment. Our results provide a framework to understand the molecular basis of host-range shifts of influenza viruses and that dogs are potential "mixing vessels" for the establishment of novel influenza viruses.
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http://dx.doi.org/10.1186/s13567-019-0707-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822366PMC
October 2019

Tamdy Virus in Ixodid Ticks Infesting Bactrian Camels, Xinjiang, China, 2018.

Emerg Infect Dis 2019 11;25(11):2136-2138

We isolated Tamdy virus (TAMV; strain XJ01/TAMV/China/2018) from Hyalomma asiaticum ticks infesting Bactrian camels in Xinjiang, China, in 2018. The genome of the strain showed high nucleotide similarity with previously described TAMV strains from Asia. Our study highlights the potential threat of TAMV to public health in China.
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http://dx.doi.org/10.3201/eid2511.190512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810205PMC
November 2019

A neonatal murine model of coxsackievirus A4 infection for evaluation of vaccines and antiviral drugs.

Emerg Microbes Infect 2019 ;8(1):1445-1455

Key Laboratory of Etiology and Epidemiology of Emerging Infectious Diseases in Universities of Shandong, Shandong First Medical University & Shandong Academy of Medical Sciences , Taian , People's Republic of China.

Coxsackievirus A4 (CVA4) infection can cause hand, foot and mouth disease (HFMD), an epidemic illness affecting neonatal and paediatric cohorts, which can develop to severe neurological disease with high mortality. In this study, we established the first ICR mouse model of CVA4 infection for the evaluation of inactivated vaccines and antiviral drug screening. The CVA4 YT226R strain was selected to infect the neonatal mice and three infectious factors were optimized to establish the infection model. The 3-day-old neonatal mice exhibited clinical symptoms such as hind limb paralysis and death. The severe inflammatory reactions were closely related to the abnormal expression of the acute phase response proinflammatory cytokine IL-6 and an imbalance in the IFN-γ/IL-4 ratio. Importantly, the inactivated CVA4 whole-virus vaccine induced humoral immune responses in adult females and the maternal antibodies afforded mice complete protection against lethal dose challenges of homologous or heterologous CVA4 strains. Both IFN-α2a and antiserum inhibited the replication of CVA4 and increased the survival rates of neonatal mice during the early stages of infection. This neonatal murine model of CVA4 infection will be useful for the development of prophylactic and therapeutic vaccines and for screening of antiviral drugs targeting CVA4 to decrease morbidity and mortality.
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http://dx.doi.org/10.1080/22221751.2019.1673135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792045PMC
February 2020

Amino acid substitutions in antigenic region B of hemagglutinin play a critical role in the antigenic drift of subclade 2.3.4.4 highly pathogenic H5NX influenza viruses.

Transbound Emerg Dis 2020 Jan 28;67(1):263-275. Epub 2019 Sep 28.

Key Laboratory of Animal Infectious Diseases, Ministry of Agriculture, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.

As one of the important control strategies for highly pathogenic avian influenza (HPAI) in China, vaccination has been implemented compulsively in poultry flocks since 2004. However, the emergence and dominance of the circulating antigenic variants require the update of vaccines periodically. In order to investigate the key molecular sites responsible for the antigenic drift, a total of 13 amino acid positions divergent between clade 2.3.4 H5 viruses and their descendent subclade 2.3.4.4 variants in or around the recognized antigenic epitopes A-E were initially identified through inspecting a comprehensive HA sequence alignment of the H5 subtype HPAI viruses. Subsequently, a panel of single-site or multi-site HA mutants was constructed by reverse genetics with two H5N1 viruses of S (clade 2.3.4) and QD1 (subclade 2.3.4.4) as the HA backbone to study their antigenic variations, respectively. The hemagglutination-inhibition assay revealed an evident impact of mutations at sites 88, 156, 205, 208, 239 and 289 to the HA antigenicity and highlighted that the amino acid substitutions located in the antigenic region B, especially the combined mutations at sites 205 and 208, were the major antigenic determinant which was also consistent with results from flow cytometry and antigenic mapping. Our findings provided more insights into the molecular mechanism of antigenic drift of the H5 subtype HPAI virus, which would be helpful for the selection of vaccine candidates and accordingly for the prevention and control of this devastating viral agent.
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http://dx.doi.org/10.1111/tbed.13347DOI Listing
January 2020

Micro-RNA 205-5p is Involved in the Progression of Gastric Cancer and Targets Phosphatase and Tensin Homolog (PTEN) in SGC-7901 Human Gastric Cancer Cells.

Med Sci Monit 2019 Aug 24;25:6367-6377. Epub 2019 Aug 24.

Department of Clinical Laboratory, The First People's Hospital of Changzhou, Changzhou, Jiangsu, China (mainland).

BACKGROUND This study aimed to investigate the role of micro-RNA 205-5p (miR-205-5p) in the progression of gastric cancer, and the target of miR-205-5p in human gastric cancer cells in vitro. MATERIAL AND METHODS Expression of miR-205-5p and PTEN in gastric cancer tissue samples and adjacent normal gastric tissue from 35 patients was studied using immunohistochemistry and in situ hybridization. SGC-7901 human gastric cancer cells included a normal control (NC) group, a group transfected with empty vector (Vector), a group treated with miR-205-5p inhibitor (miR-inhibitor), and a group treated with miR-205-5p inhibitor and small interfering PTEN mRNA (miR-inhibitor+si-PTEN). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) measured miR-205-5p expression, cell proliferation was measured by MTT assay, cell apoptosis by flow cytometry, transwell and wound healing assays measured cell migration, and transmission electron microscopy (TEM) showed ultrastructural changes in SGC-7901 cells. PTEN, AKT and p-AKT protein expression were measured using Western blot. The correlation between miR-205-5p and PTEN was analyzed using a dual-luciferase reporter assay. RESULTS Increased expression of miR-205-5p and PTEN in gastric cancer tissues were correlated with tumor stage. In SGC-7901 cells, miR-205-5p mRNA expression in the miR-inhibitor and miR-inhibitor+si-PTEN groups was significantly lower than that in the NC group (P<0.001). In the miR-inhibitor group, cell proliferation was significantly decreased, and apoptosis was significantly increased (P<0.001). CONCLUSIONS In gastric cancer, increased expression of miR-205-5p was associated with tumor stage, and in SGC-7901 cells PTEN was a target gene for miR-205-5p.
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http://dx.doi.org/10.12659/MSM.915970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724565PMC
August 2019

Co-circulation and persistence of multiple A/H3N2 influenza variants in China.

Emerg Microbes Infect 2019 ;8(1):1157-1167

a Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention , Beijing , People's Republic of China.

The spread of influenza A/H3N2 variants possessing the hemagglutinin 121 K mutation and the unexpectedly high incidence of influenza in the 2017-2018 northern hemisphere influenza season have raised serious concerns about the next pandemic. We summarized the national surveillance data of seasonal influenza in China and identified marked differences in influenza epidemics between northern and southern China, particularly the predominating subtype and the presence of an additional summer peak in southern China. Notably, a minor spring peak of influenza caused by a different virus subtype was also observed. We also revealed that the 3C.2a lineage was dominant from the summer of 2015 to the end of the 2015-2016 peak season in China, after which the 3C.2a2 lineage predominated despite the importation and co-circulation of the 121 K variants of 3C.2a1 and 3C.2a3 lineages at the global level. Finally, an analysis based on genetic distances revealed a delay in A/H3N2 vaccine strain update. Overall, our results highlight the complicated circulation pattern of seasonal influenza in China and the necessity for a timely vaccine strain update worldwide.
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http://dx.doi.org/10.1080/22221751.2019.1648183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713139PMC
December 2019

Intra-host Ebola viral adaption during human infection.

Biosaf Health 2019 Jun 20;1(1):14-24. Epub 2019 Feb 20.

NHC Key Laboratory of Biosafety National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China.

The onsite next generation sequencing (NGS) of Ebola virus (EBOV) genomes during the 2013-2016 Ebola epidemic in Western Africa provides an opportunity to trace the origin, transmission, and evolution of this virus. Herein, we have diagnosed a cohort of EBOV patients in Sierra Leone in 2015, during the late phase of the outbreak. The surviving EBOV patients had a recovery process characterized by decreasing viremia, fever, and biochemical parameters. EBOV genomes sequenced through the longitudinal blood samples of these patients showed dynamic intra-host substitutions of the virus during acute infection, including the previously described short stretches of 13 serial T>C mutations. Remarkably, within individual patients, samples collected during the early phase of infection possessed Ts at these nucleotide sites, whereas they were replaced by Cs in samples collected in the later phase, suggesting that these short stretches of T>C mutations could emerge independently. In addition, up to a total of 35 nucleotide sites spanning the EBOV genome were mutated coincidently. Our study showed the dynamic intra-host adaptation of EBOV during patient recovery and gave more insight into the complex EBOV-host interactions.
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http://dx.doi.org/10.1016/j.bsheal.2019.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347341PMC
June 2019

Effects of Acetylshikonin on the Infection and Replication of Coxsackievirus A16 in Vitro and in Vivo.

J Nat Prod 2019 05 7;82(5):1089-1097. Epub 2019 May 7.

Key Laboratory of Etiology and Epidemiology of Emerging Infectious Diseases in Universities of Shandong , Taishan Medical College , Taian , Shandong 271000 , People's Republic of China.

Coxsackievirus A16 (CVA16) is one of the most prevalent enteroviral pathogens associated with hand, foot, and mouth disease. In the present study, we have investigated (1) whether the bioactive compound acetylshikonin (AS) inhibits CVA16 infection in vitro and in vivo and (2) the potential antiviral mechanism(s). The results suggest that AS is nontoxic at concentrations of up to 5 μmol/L and could directly inactivate virus particles at relatively low concentrations (0.08 μmol/L), thereby rendering CVA16 incapable of cellular entry. Correspondingly, the expression of viral RNA in vitro was also reduced 100-fold ( P < 0.05) when compared to infected, untreated controls. Results from a CVA16-infected neonatal mouse model indicate that, in comparison to the virus-infected, untreated group, body weights of the mice in the virus-infected, compound-treated group increased more steadily with less severe clinical symptoms. In addition, viral loads in internal organs significantly decreased in treated animals, concomitantly with both reduced pathology and diminished expression of the proinflammatory cytokines IFN-γ and IL-6. In conclusion, AS exerted an inhibitory effect on CVA16 infection in vitro and in vivo. Our study provides a basis for further investigations of AS-type compounds to develop therapeutics to mitigate CVA-associated disease in children.
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http://dx.doi.org/10.1021/acs.jnatprod.8b00735DOI Listing
May 2019

Long noncoding RNAs: Novel regulators of virus-host interactions.

Rev Med Virol 2019 07 23;29(4):e2046. Epub 2019 Apr 23.

Key Laboratory of Etiology and Epidemiology of Emerging Infectious Diseases in Universities of Shandong Province, Taishan Medical University, Taian, China.

Long noncoding RNAs (lncRNAs) represent a key class of cellular regulators, involved in the modulation and control of multiple biological processes. Distinct classes of lncRNAs are now known to be induced by host cytokines following viral infections. Current evidence demonstrates that lncRNAs play essential roles at the host-pathogen interface regulating viral infections by either innate immune responses at various levels including activation of pathogen recognition receptors or by epigenetic, transcriptional, and posttranscriptional effects. We review the newly described mechanisms underlying the interactions between lncRNAs, cytokines, and metabolites differentially expressed following viral infections; we highlight the regulatory networks of host antiviral responses and emphasize the need for interdisciplinary research between lncRNA biology and immunology to deepen understanding of viral pathogenesis.
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http://dx.doi.org/10.1002/rmv.2046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169114PMC
July 2019