14 results on '"Huanan LIU"'
Search Results
2. A QP509L/QP383R-Deleted African Swine Fever Virus Is Highly Attenuated in Swine but Does Not Confer Protection against Parental Virus Challenge
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Li Dan, Zhengwang Shi, Haixue Zheng, Li Pan, Yi Ru, Panxue Wu, Wenping Yang, Tao Feng, Xiaolan Qi, and Huanan Liu
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QP383R ,Swine ,Virulence Factors ,Immunology ,Cellular Response to Infection ,Virulence ,Viremia ,Antibodies, Viral ,Virus Replication ,Microbiology ,African swine fever virus ,Virus ,Viral Proteins ,Virology ,medicine ,Animals ,African Swine Fever ,Cells, Cultured ,Disease Resistance ,Sequence Deletion ,porcine alveolar macrophages ,Attenuated vaccine ,biology ,Gene Expression Profiling ,Macrophages ,QP509L ,Outbreak ,medicine.disease ,biology.organism_classification ,African Swine Fever Virus ,Titer ,Gene Expression Regulation ,Mutagenesis ,Infectious disease (medical specialty) ,Insect Science ,Host-Pathogen Interactions ,Immunization ,Transcriptome - Abstract
African swine fever (ASF), a devastating infectious disease in swine, severely threatens the global pig farming industry. Disease control has been hampered by the unavailability of vaccines. Here, we report that deletion of the QP509L and QP383R genes (ASFV-ΔQP509L/QP383R) from the highly virulent ASF virus (ASFV) CN/GS/2018 strain results in complete viral attenuation in swine. Animals inoculated with ASFV-ΔQP509L/QP383R at a 104 50% hemadsorbing dose (HAD50) remained clinically normal during the 17-day observational period. All ASFV-ΔQP509L/QP383R-infected animals had low viremia titers and developed a low-level p30-specific antibody response. However, ASFV-ΔQP509L/QP383R did not induce protection against challenge with the virulent parental ASFV CN/GS/2018 isolate. RNA-sequencing analysis revealed that innate immune-related genes (Ifnb, Traf2, Cxcl10, Isg15, Rantes, and Mx1) were significantly lower in ASFV-ΔQP509L/QP383R-infected than in ASFV-infected porcine alveolar macrophages. In addition, ASFV-ΔQP509L/QP383R-infected pigs had low levels of interferon-β (IFN-β) based on enzyme-linked immunosorbent assay (ELISA). These data suggest that deletion of ASFV QP509L/383R reduces virulence but does not induce protection against lethal ASFV challenge. IMPORTANCE African swine fever (ASF) is endemic to several parts of the word, with outbreaks of the disease devastating the swine farming industry; currently, no commercially available vaccine exists. Here, we report that deletion of the previously uncharacterized QP509L and QP383R viral genes completely attenuates virulence in the ASF virus (ASFV) CN/GS/2018 isolate. However, ASFV-ΔQP509L/QP383R-infected animals were not protected from developing an ASF infection after challenge with the virulent parental virus. ASFV-ΔQP509L/QP383R induced lower levels of innate immune-related genes and IFN-β than the parental virus. Our results increase our knowledge of developing an effective and live ASF attenuated vaccine.
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- 2022
3. Genetic Determinants of Altered Virulence of Type O Foot-and-Mouth Disease Virus
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Zixiang Zhu, Wei Ting, Zheng Min, Keshan Zhang, Fan Yang, Ye Jin, Haixue Zheng, Jijun He, Jianhong Guo, Huanan Liu, Xiangtao Liu, and Weijun Cao
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Serotype ,Untranslated region ,Swine ,viruses ,Immunology ,Virulence ,host range ,Biology ,Viral Nonstructural Proteins ,medicine.disease_cause ,Virus Replication ,Microbiology ,Virus ,Host Specificity ,FMDV ,Leucine ,Virology ,Cricetinae ,genetic determinant ,Endopeptidases ,medicine ,Animals ,Spotlight ,chemistry.chemical_classification ,Mutation ,foot-and-mouth disease virus ,biology.organism_classification ,Amino acid ,chemistry ,Insect Science ,Foot-and-Mouth Disease ,Pathogenesis and Immunity ,Cattle ,Foot-and-mouth disease virus ,5' Untranslated Regions ,S fragment ,Gene Deletion - Abstract
FMD is probably the most important livestock disease in the world due to the severe economic consequences caused. The alteration of several viral genes may give the virus selective advantage to maintain its prevalence in nature. Here, we identified that a 70-nucleotide deletion in the S fragment combined with a single leucine insertion in the leader protein (Lpro) is a novel determinant of restricted growth on bovine cells, which significantly contributes to the altered virulence of serotype O FMDV in cattle. A synergistic and additive effect of the 70-nucleotide deletion in the S fragment and the single leucine insertion in Lpro on the virulence and host specificity of the virus was determined. These results will benefit efforts to understand the vial pathogenicity mechanism and molecular characteristics of FMDV., Under different circumstances, the alteration of several viral genes may give an evolutionary advantage to the virus to maintain its prevalence in nature. In this study, a 70-nucleotide deletion in the small fragment (S fragment) of the viral 5′-untranslated region (5′-UTR) together with one amino acid insertion in the leader protein (Lpro) that naturally occurred in several serotype O foot-and-mouth disease virus (FMDV) strains in China was identified. The properties of two field serotype O FMDV strains, with or without the 70-nucleotide deletion in the S fragment and the amino acid insertion in Lpro, were compared in vitro and in vivo. Clinical manifestations of FMD were clearly observed in cattle and pigs infected by the virus without the mutations. However, the virus with the mentioned mutations caused FMD outcomes only in pigs, not in cattle. To determine the role of the 70-nucleotide deletion in the S fragment and the single amino acid insertion in Lpro in the pathogenicity and host range of FMDV, four recombinant viruses, with complete genomes and a 70-nucleotide deletion in the S fragment, a single amino acid insertion in Lpro, or both mutations, were constructed and rescued. It showed that deletion of 70 nucleotides in the S fragment or insertion of one amino acid (leucine) at position 10 of Lpro partly decreased the viral pathogenicity of Mya-98 lineage virus in cattle and pigs. However, the virus with dual mutations caused clinical disease only in pigs, not in cattle. This suggested that the S fragment and Lpro are significantly associated with the virulence and host specificity of FMDV. The naturally occurring dual mutation in the S fragment and Lpro is a novel determinant of viral pathogenicity and host range for serotype O FMDV. IMPORTANCE FMD is probably the most important livestock disease in the world due to the severe economic consequences caused. The alteration of several viral genes may give the virus selective advantage to maintain its prevalence in nature. Here, we identified that a 70-nucleotide deletion in the S fragment combined with a single leucine insertion in the leader protein (Lpro) is a novel determinant of restricted growth on bovine cells, which significantly contributes to the altered virulence of serotype O FMDV in cattle. A synergistic and additive effect of the 70-nucleotide deletion in the S fragment and the single leucine insertion in Lpro on the virulence and host specificity of the virus was determined. These results will benefit efforts to understand the vial pathogenicity mechanism and molecular characteristics of FMDV.
- Published
- 2020
4. The glycine locating at random coil of picornaviruses VP3 enhances viral pathogenicity by targeting p53 to promote apoptosis and autophagy
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Zhou Xiaoli, Xiangtao Liu, Zheng Haixue, Dang Wen, Ruoqing Mao, Tian Hong, Sun Dehui, Qing-Feng Wu, Xinwen Ma, Zhang Keshan, Fan Yang, Huanan Liu, Xuan Guo, and Zixiang Zhu
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Mutation ,Picornavirus ,viruses ,Autophagy ,virus diseases ,biochemical phenomena, metabolism, and nutrition ,Biology ,Coxsackievirus ,medicine.disease_cause ,biology.organism_classification ,Virus ,Cell biology ,Viral replication ,Apoptosis ,medicine ,Phosphorylation - Abstract
Picornaviruses, comprising important and widespread pathogens of humans and animals, have evolved to control apoptosis and autophagy for their replication and spread. However, the underlying mechanism of the association between apoptosis/autophage and viral pathogenicity remains unclear. In the present study, VP3 of picornaviruses was demonstrated to induce apoptosis and autophagy. Foot-and-mouth disease virus (FMDV), which served as a research model here, can strongly induce both apoptosis and autophagy in the skin lesions. By directly interacting with p53, FMDV-VP3 facilitates its phosphorylation and translocation, resulting in Bcl-2 family-mediated apoptosis and LC3-dependent autophagy. The single residue Gly129 of FMDV-VP3 plays a crucial role in apoptosis and autophagy induction and the interaction with p53. Consistently, the comparison of rescued FMDV with mutated Gly129 and parental virus showed that the Gly129 is indispensable for viral replication and pathogenicity. More importantly, the Gly129 locates at a bend region of random coil structure, the mutation of Gly to Ala remarkably shrunk the volume of viral cavity. Coincidentally, the Gly is conserved in the similarly location of other picornaviruses, including poliovirus (PV), enterovirus 71 (EV71), coxsackievirus (CV) and seneca valley virus (SVA). This study demonstrates that picornaviruses induce apoptosis and autophagy to facilitate its pathogenicity and the Gly is functional site, providing novel insights into picornavirus biology.
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- 2019
5. The Pseudoknot Region of the 5′ Untranslated Region Is a Determinant of Viral Tropism and Virulence of Foot-and-Mouth Disease Virus
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Tian Hong, Huanan Liu, Weijun Cao, Keshan Zhang, Fan Yang, Jianhong Guo, Dang Wen, Haixue Zheng, Jijun He, Xiangtao Liu, and Zixiang Zhu
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Untranslated region ,Five prime untranslated region ,Swine ,animal diseases ,viruses ,Immunology ,host range ,Virulence ,Genome, Viral ,Viral Nonstructural Proteins ,Recombinant virus ,Microbiology ,Virus ,Cell Line ,03 medical and health sciences ,Cricetinae ,Virology ,pathogenicity ,pseudoknots ,Animals ,Tropism ,Sequence Deletion ,030304 developmental biology ,0303 health sciences ,Base Sequence ,biology ,foot-and-mouth disease virus ,030306 microbiology ,virus diseases ,biology.organism_classification ,Viral Tropism ,Foot-and-Mouth Disease ,Insect Science ,Tissue tropism ,Pathogenesis and Immunity ,Cattle ,Foot-and-mouth disease virus ,5' Untranslated Regions - Abstract
This study demonstrates that the deletion in the PK region occurred naturally in the FMDV genome. The isolated O/ME-SA/PanAsia lineage FMDV with an 86-nt deletion in the PK region showed a pig-adapted characteristic that could cause clinical signs in swine but not bovines. Compared to the wild-type FMDV strain, which possesses full infection capacity in both swine and bovines, the recombinant virus with the 86-nt deletion in the PK region is deficient in causing disease in bovines. Deletion of the previously reported 43 nt in the PK region also led to significantly decreased pathogenicity of FMDV in bovines. This study indicates that the PK region is a novel determinant of the tropism and virulence of FMDV., Foot-and-mouth disease virus (FMDV) is the causative agent of foot-and-mouth disease. It is characterized by genetic instability and different antigenic properties. The nonstructural protein 3A is a primary determinant of the tropism and virulence of Cathay topotype FMDVs. However, several other determinants are also speculated to be involved in viral tropism and virulence. Deletion of 43 nucleotides (nt) in the pseudoknot (PK) region of the 5′ untranslated region (UTR) has been found to coexist with the identified 3A deletion in Cathay topotype FMDV genomes. In this study, we isolated an O/ME-SA/PanAsia lineage FMDV strain, O/GD/CHA/2015, that includes an 86-nt deletion in the PK region and shows a porcinophilic phenotype. To investigate the potential role of the PK region in viral pathogenicity, we generated a recombinant FMDV strain with an incomplete PK region and compared its virulence and pathogenesis to the intact FMDV strain in swine and bovines. Deletion of the 86 nt in the PKs had no major effects on the pathogenicity of the virus in swine but significantly attenuated its ability to infect bovine cells and cattle, indicating that the PK region is a newly discovered determinant of viral tropism and virulence. The role of the 43-nt deletion existing in the Cathay topotype FMDV was also investigated by evaluating the infection properties of genetically engineered viruses. Consistently, the 43-nt deletion in the PK region significantly decreased the pathogenicity of the virus in bovines. Overall, our findings suggest that the PK region deletion occurred naturally in the FMDV genome and that the PK region is highly associated with viral host range and functions as a novel determinant for FMDV pathogenesis. IMPORTANCE This study demonstrates that the deletion in the PK region occurred naturally in the FMDV genome. The isolated O/ME-SA/PanAsia lineage FMDV with an 86-nt deletion in the PK region showed a pig-adapted characteristic that could cause clinical signs in swine but not bovines. Compared to the wild-type FMDV strain, which possesses full infection capacity in both swine and bovines, the recombinant virus with the 86-nt deletion in the PK region is deficient in causing disease in bovines. Deletion of the previously reported 43 nt in the PK region also led to significantly decreased pathogenicity of FMDV in bovines. This study indicates that the PK region is a novel determinant of the tropism and virulence of FMDV.
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- 2019
6. Foot-and-mouth disease virus structural protein VP3 degrades Janus kinase 1 to inhibit IFN-γ signal transduction pathways
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Shu Li, Zixiang Zhu, Huanan Liu, Xiangtao Liu, Weijun Cao, Fan Yang, Li Dan, Hong-Bing Shu, Jin Wei, and Haixue Zheng
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0301 basic medicine ,animal diseases ,viruses ,030106 microbiology ,Virus ,Interferon-gamma ,03 medical and health sciences ,chemistry.chemical_compound ,Cricetulus ,Genes, Reporter ,Report ,Animals ,Humans ,STAT1 ,Phosphorylation ,Luciferases ,Molecular Biology ,Janus kinase 2 ,biology ,Janus kinase 1 ,virus diseases ,Tyrosine phosphorylation ,Janus Kinase 1 ,Cell Biology ,Janus Kinase 2 ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,Virology ,HEK293 Cells ,STAT1 Transcription Factor ,030104 developmental biology ,Gene Expression Regulation ,chemistry ,Host-Pathogen Interactions ,Proteolysis ,biology.protein ,Tyrosine ,Capsid Proteins ,Protein Multimerization ,Foot-and-mouth disease virus ,Signal transduction ,Lysosomes ,Protein Binding ,Signal Transduction ,Developmental Biology - Abstract
Foot-and-mouth disease is a highly contagious viral disease of cloven-hoofed animals that is caused by foot-and-mouth disease virus (FMDV). To replicate efficiently in vivo, FMDV has evolved methods to circumvent host antiviral defense mechanisms, including those induced by interferons (IFNs). Previous research has focused on the effect of FMDV L(pro) and 3C(pro) on type I IFNs. In this study, FMDV VP3 was found to inhibit type II IFN signaling pathways. The overexpression of FMDV VP3 inhibited the IFN-γ-triggered phosphorylation of STAT1 at Tyr701 and the subsequent expression of downstream genes. Mechanistically, FMDV VP3 interacted with JAK1/2 and inhibited the tyrosine phosphorylation, dimerization and nuclear accumulation of STAT1. FMDV VP3 also disrupted the assembly of the JAK1 complex and degraded JAK1 but not JAK2 via a lysosomal pathway. Taken together, the results reveal a novel mechanism used by which FMDV VP3 counteracts the type II IFN signaling pathways.
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- 2016
7. The Distribution of Different Clades of Seneca Valley Viruses in Guangdong Province, China
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Pan Chen, Huanan Liu, Fan Yang, Xiangtao Liu, Zixiang Zhu, Haixue Zheng, Weijun Cao, Zhiwen Xu, and Zhang Keshan
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0301 basic medicine ,Veterinary medicine ,China ,Swine ,Immunology ,Distribution (economics) ,Genome, Viral ,Picornaviridae ,Biology ,Genetic analysis ,03 medical and health sciences ,Swine Vesicular Disease ,Phylogenetics ,Virology ,Animals ,Clade ,Swine vesicular disease ,Phylogeny ,Phylogenetic tree ,business.industry ,Strain (biology) ,food and beverages ,virus diseases ,030104 developmental biology ,Molecular Medicine ,business ,Research Article - Abstract
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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12250-018-0056-8) contains supplementary material, which is available to authorized users.
- Published
- 2018
8. Immunogenicity and protective efficacy of an inactivated cell culture-derived Seneca Valley virus vaccine in pigs
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Keshan Zhang, Zixiang Zhu, Hong Tian, Haixue Zheng, Fan Yang, Xiangtao Liu, Weijun Cao, and Huanan Liu
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0301 basic medicine ,Swine ,Picornaviridae ,Antibodies, Viral ,Virus ,Cell Line ,03 medical and health sciences ,Immunogenicity, Vaccine ,Immunity ,Medicine ,Binary ethylenimine ,Animals ,Neutralizing antibody ,Swine Diseases ,Picornaviridae Infections ,General Veterinary ,General Immunology and Microbiology ,biology ,business.industry ,Immunogenicity ,Public Health, Environmental and Occupational Health ,Viral Vaccines ,Virology ,Antibodies, Neutralizing ,Vaccination ,Titer ,030104 developmental biology ,Infectious Diseases ,Vaccines, Inactivated ,Inactivated vaccine ,biology.protein ,Molecular Medicine ,Immunization ,business - Abstract
Seneca Valley virus (SVV) infection in pigs is associated with porcine idiopathic vesicular disease (PIVD). Outbreaks of SVV infection in pig herds have been reported in several Asia and Americas countries. Recently, a series of outbreaks of SVV infection occurred in China, Canada, Thailand and the United States. However, no available vaccines have been developed to limit the transmission of SVV. The SVV CH-FJ-2017 from Fujian province in China is a representative of the epidemic strains, and shows 98.5-99.9% capsid protein amino acid identity with the recent SVV strains. In the present study, we developed a SVV CH-FJ-2017 inactivated vaccine. The SVV was produced by cultivation of BHK-21 cells in roller bottles, inactivated with binary ethylenimine, and mixed with oil adjuvant (Montanide ISA). The immunogenicity of the inactivated vaccine in pigs was evaluated by neutralizing test, and the immunized pigs were challenged with SVV CH-FJ-2017. The results showed that animals receiving one dose of the inactivated vaccine (2 μg/dose) with oil adjuvant developed high neutralizing antibody titers and showed no clinical signs after virus challenge comparing with the non-vaccinated animals, indicating a good protective efficacy of the produced vaccine against SVV infection. This is the first reported SVV vaccine that can be used for control of SVV infection in pigs.
- Published
- 2017
9. Foot-and-mouth disease virus infection inhibits LGP2 protein expression to exaggerate inflammatory response and promote viral replication
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Xiangle Zhang, Haixue Zheng, Chuntian Li, Hong Tian, Guoqing Wang, Xiangtao Liu, Li Dan, Huanan Liu, Xiaoli Du, Fan Yang, Shi Zhengwang, Zixiang Zhu, Keshan Zhang, Huanhuan Feng, and Weijun Cao
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0301 basic medicine ,Cancer Research ,Swine ,viruses ,animal diseases ,Immunology ,Disease ,Biology ,Virus Replication ,Virus ,Gene Expression Regulation, Enzymologic ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Viral Proteins ,Immunity ,Cricetinae ,Animals ,Humans ,Regulation of gene expression ,HEK 293 cells ,LGP2 ,virus diseases ,Cell Biology ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,Virology ,Immunity, Innate ,030104 developmental biology ,HEK293 Cells ,Viral replication ,Foot-and-Mouth Disease Virus ,Foot-and-Mouth Disease ,RNA, Viral ,Original Article ,Foot-and-mouth disease virus ,RNA Helicases - Abstract
The role of the innate immune protein LGP2 (laboratory of genetics and physiology 2) in FMDV-infected cells remains unknown. Here, we demonstrate the antiviral role of LGP2 during FMDV infection. FMDV infection triggered LGP2 mRNA expression but reduced protein expression. Overexpression of LGP2 suppressed FMDV replication, and the inflammatory response was significantly inhibited by LGP2 in virus-infected cells. The N-terminal DExDc and the C-terminal regulatory domain regions of LGP2 were essential for LGP2-mediated antiviral activity against FMDV. Disruption of RNA recognition by LGP2 is suggested to abolish completely LGP2-mediated antiviral activity against FMDV. FMDV leader protein (Lpro), as well as the 3Cpro and 2B proteins were determined to possess the ability to induce reduction of LGP2 protein expression. 2B-induced reduction of LGP2 was independent of cleavage of eukaryotic translation initiation factor 4 gamma; and the proteasomes, lysosomes or caspase-dependent pathways were not involved in this process. The C-terminal amino acids of 101–154 were essential for 2B-induced reduction of LGP2 and upregulation of inflammatory response. Direct interaction was demonstrated between LGP2 and 2B. Our results describe the antiviral role of LGP2 against FMDV and a novel antagonistic mechanism of FMDV that is mediated by 2B protein.
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- 2016
10. The VP1 S154D mutation of type Asia1 foot-and-mouth disease virus enhances viral replication and pathogenicity
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Li Dan, Keshan Zhang, Huanan Liu, Fan Yang, Ye Jin, Haixue Zheng, Kaiqi Lian, Xiangtao Liu, Zixiang Zhu, Jianhong Guo, and Weijun Cao
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0301 basic medicine ,Microbiology (medical) ,Integrins ,Swine ,viruses ,Integrin ,Amino Acid Motifs ,Biology ,Virus Replication ,Microbiology ,Epitope ,Virus ,law.invention ,Cell Line ,03 medical and health sciences ,Mice ,law ,Genetics ,Animals ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,virus diseases ,biochemical phenomena, metabolism, and nutrition ,Viral Load ,biology.organism_classification ,Virology ,Molecular biology ,Reverse genetics ,030104 developmental biology ,Infectious Diseases ,Capsid ,Viral replication ,Foot-and-Mouth Disease Virus ,Foot-and-Mouth Disease ,Mutation ,biology.protein ,Recombinant DNA ,Capsid Proteins ,Foot-and-mouth disease virus - Abstract
One of the proteins encoded by the foot-and-mouth disease virus (FMDV), the VP1 protein, a capsid protein, plays an important role in integrin receptor attachment and humoral immunity-mediated host responses. The integrin receptor recognition motif and an important antigenic epitope exist within the G-H loop, which is comprised of amino acids 134-160 of the VP1 protein. FMDV strain, Asia1/HN/CHA/06, isolated from a pig, was passaged four times in suckling mice and sequenced. Sequencing analyses showed that there was a mutation of the integrin receptor recognition motif Arg-Gly-Asp/Arg-Asp-Asp (RGD/RDD, VP1 143-145) and a VP1 154 serine/Asp (VP1 S154D) mutation in the G-H loop of the VP1 protein. The influence of the RGD/RDD mutation on Asia1 FMDV disease phenotype has been previously studied. In this study, to determine the influence of the VP1 S154D mutation on FMDV Asia1 replication and pathogenicity, two recombinant FMDVs with different residues only at the VP1 154 site were rescued by reverse genetics techniques and their infectious potential in host cells and pathogenicity in pigs were compared. Our data indicates that the VP1 S154D mutation increases the replication level of FMDV Asia1/HN/CHA/06 in BHK-21, IB-RS-2, and PK-15 cells and enhances pathogenicity in pigs. Through the transient transfection-infection assay to compare integrin receptor usage of two recombinant viruses, the result shows that the VP1 S154D mutation markedly increases the ability of type Asia1 FMDV to use the integrin receptors αυβ6 and αυβ8 from pig. This study identifies a key research target for illuminating the role of residues located at G-H loop in FMDV pathogenicity.
- Published
- 2015
11. The VP3 structural protein of foot-and-mouth disease virus inhibits the IFN-β signaling pathway
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Li Dan, Zixiang Zhu, Hong-Bing Shu, Xiangtao Liu, Shu Li, Fan Yang, Cao-Qi Lei, Wenping Yang, Kaiqi Lian, Haixue Zheng, and Huanan Liu
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0301 basic medicine ,Gene Expression Regulation, Viral ,Immunoprecipitation ,Swine ,animal diseases ,viruses ,Protein domain ,Biochemistry ,Virus ,Cell Line ,03 medical and health sciences ,Protein Domains ,Genetics ,Animals ,Humans ,RNA, Messenger ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,Aphthovirus ,Messenger RNA ,Innate immune system ,030102 biochemistry & molecular biology ,biology ,virus diseases ,Interferon-beta ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,Immunity, Innate ,Cell biology ,030104 developmental biology ,Foot-and-Mouth Disease Virus ,Capsid Proteins ,Foot-and-mouth disease virus ,Signal transduction ,Biotechnology ,Protein Binding ,Signal Transduction - Abstract
Foot-and-mouth disease is a frequently occurring disease of cloven-hoofed animals that is caused by infection with the foot-and-mouth virus (FMDV). FMDV circumvents the type-I IFN response by expressing proteins that antagonize cellular innate immunity, such as leader protease and 3C protease. We identified the FMDV structural protein VP3 as a negative regulator of the virus-triggered IFN-β signaling pathway. Expression of FMDV VP3 inhibited the Sendai virus-triggered activation of IFN regulatory factor-3 and the expression of retinoic acid-inducible gene-I/melanoma differentiation-associated protein-5. Transient transfection and coimmunoprecipitation confirmed that the structural protein VP3 interacts with virus-induced signaling adapter (VISA), which is dependent on the C-terminal aa 111-220 of VP3. In addition, we found that FMDV VP3 inhibits the expression of VISA by disrupting its mRNA. Taken together, our findings reveal a novel strategy used by the structural VP3 protein of FMDV to evade host innate immunity.-Li, D., Yang, W., Yang, F., Liu, H., Zhu, Z., Lian, K., Lei, C., Li, S., Liu, X., Zheng, H., Shu, H. The VP3 structural protein of foot-and-mouth disease virus inhibits the IFN-β signaling pathway.
- Published
- 2015
12. Foot-and-mouth disease virus non-structural protein 3A inhibits the interferon-β signaling pathway
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Xiangtao Liu, Fan Yang, Huanan Liu, Li Dan, Shu Li, Hong-Bing Shu, Haixue Zheng, Cao-Qi Lei, Zhisheng Xu, and Zixiang Zhu
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0301 basic medicine ,Gene Expression Regulation, Viral ,Interferon-Induced Helicase, IFIH1 ,animal diseases ,viruses ,Sus scrofa ,Gene Expression ,Biology ,Viral Nonstructural Proteins ,Virus ,Article ,03 medical and health sciences ,Protein Interaction Mapping ,Gene silencing ,Animals ,Humans ,Protein Interaction Domains and Motifs ,Gene Silencing ,Receptors, Immunologic ,Adaptor Proteins, Signal Transducing ,Multidisciplinary ,Innate immune system ,Signal transducing adaptor protein ,virus diseases ,MDA5 ,Interferon-beta ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,Virology ,030104 developmental biology ,HEK293 Cells ,Foot-and-Mouth Disease Virus ,Host-Pathogen Interactions ,DEAD Box Protein 58 ,Signal transduction ,Foot-and-mouth disease virus ,IRF3 ,Signal Transduction - Abstract
Foot-and-mouth disease virus (FMDV) is the etiological agent of FMD, which affects cloven-hoofed animals. The pathophysiology of FMDV has not been fully understood and the evasion of host innate immune system is still unclear. Here, the FMDV non-structural protein 3A was identified as a negative regulator of virus-triggered IFN-β signaling pathway. Overexpression of the FMDV 3A inhibited Sendai virus-triggered activation of IRF3 and the expressions of RIG-I/MDA5. Transient transfection and co-immunoprecipitation experiments suggested that FMDV 3A interacts with RIG-I, MDA5 and VISA, which is dependent on the N-terminal 51 amino acids of 3A. Furthermore, 3A also inhibited the expressions of RIG-I, MDA5 and VISA by disrupting their mRNA levels. These results demonstrated that 3A inhibits the RLR-mediated IFN-β induction and uncovered a novel mechanism by which the FMDV 3A protein evades the host innate immune system.
- Published
- 2015
13. The rescue and evaluation of FLAG and HIS epitope-tagged Asia 1 type foot-and-mouth disease viruses
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Zixiang Zhu, Yan Zhang, Ye Jin, Fan Yang, Haixue Zheng, Bo Yang, Weijun Cao, Hong Yin, and Huanan Liu
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0301 basic medicine ,Cancer Research ,Antigenicity ,viruses ,Antibodies, Viral ,Virus ,Epitope ,Genomic Instability ,law.invention ,03 medical and health sciences ,Epitopes ,FLAG-tag ,law ,Neutralization Tests ,Virology ,RGD motif ,Recombination, Genetic ,biology ,Staining and Labeling ,biology.organism_classification ,Antibodies, Neutralizing ,Reverse Genetics ,030104 developmental biology ,Infectious Diseases ,Capsid ,Foot-and-Mouth Disease Virus ,Recombinant DNA ,Foot-and-mouth disease virus - Abstract
The VP1 G-H loop of the foot-and-mouth disease virus (FMDV) contains the primary antigenic site, as well as an Arg-Gly-Asp (RGD) binding motif for the αv-integrin family of cell surface receptors. We anticipated that introducing a foreign epitope tag sequence downstream of the RGD motif would be tolerated by the viral capsid and would not destroy the antigenic site of FMDV. In this study, we have designed, generated, and characterized two recombinant FMDVs with a FLAG tag or histidine (HIS) inserted in the VP1 G-H loop downstream of the RGD motif +9 position. The tagged viruses were genetically stable and exhibited similar growth properties with their parental virus. What is more, the recombinant viruses rFMDV-FLAG and rFMDV-HIS showed neutralization sensitivity to FMDV type Asia1-specific mAbs, as well as to polyclonal antibodies. Additionally, the r1 values of the recombinant viruses were similar to that of the parental virus, indicating that the insertion of FLAG or HIS tag sequences downstream of the RGD motif +9 position do not eradicate the antigenic site of FMDV and do not affect its antigenicity. These results indicated that the G-H loop of Asia1 FMDV is able to effectively display the foreign epitopes, making this a potential approach for novel FMDV vaccines development.
- Published
- 2015
14. Disruption of the unfolded protein response (UPR) by lead compound selectively suppresses cancer cell growth
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Kailong Jiang, Jia Li, Hejing Huang, Huanan Liu, Chang-Mei Liu, Xianchao Cao, Fajun Nan, Li-xia Fan, Jian Hou, Kun-Zhi Zhang, Hu Xiaobei, Xinwen Zhang, Anhui Gao, and Yubo Zhou
- Subjects
Cancer Research ,XBP1 ,Cell cycle checkpoint ,Antineoplastic Agents ,Cell Growth Processes ,Thiophenes ,Biology ,Small Molecule Libraries ,chemistry.chemical_compound ,Mice ,Downregulation and upregulation ,Neoplasms ,Acetamides ,Animals ,Humans ,Endoplasmic Reticulum Chaperone BiP ,Tumor microenvironment ,Mice, Inbred BALB C ,Aniline Compounds ,Cell cycle ,HCT116 Cells ,Molecular biology ,Xenograft Model Antitumor Assays ,HEK293 Cells ,Oncology ,chemistry ,Cancer cell ,Unfolded protein response ,Cancer research ,Unfolded Protein Response ,Female ,Growth inhibition ,HeLa Cells - Abstract
Identifying chemotherapy candidates with high selectivity against cancer cells is a major challenge in cancer treatment. Tumor microenvironments cause chronic endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR) as an adaptive response. Here, one novel small-molecule compound, 17#, was discovered as a potent pan-UPR inhibitor. It exhibited good selection for growth inhibition when cancer cells were cultured in 2-deoxy-D-glucose (2DG), mimicking an in vitro glucose-deprived status. Additionally, 17# alone could mildly suppress the growth of HeLa tumor xenografts, and a synergistic anti-cancer effect was observed when 17# was combined with 2DG. A mechanistic study showed that 17#-induced selective anti-cancer effects were highly dependent on UPR inhibition, and overexpressing GRP78 or XBP1s reversed the 17#-induced growth inhibition and cell cycle arrest, partially by delaying the downregulation of the cell cycle regulator cyclin B1. Furthermore, 17# improved the sensitivity of anti-cancer drugs such as doxorubicin or etoposide. Our study presents evidence that disrupting the UPR has selective therapeutic potential and may enhance drug sensitivity.
- Published
- 2014
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