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Papers by Giorgi Metreveli

Advanced healthcare materials, 2014

This is the first time a 100% natural, unmodified nanofibrous polymer-based membrane is demonstra... more This is the first time a 100% natural, unmodified nanofibrous polymer-based membrane is demonstrated capable of removing viruses solely based on the size-exclusion principle, with a log10 reduction value (LRV) ≥ 6.3 as limited by the assay lower detection limit and the feed virus titre, thereby matching the performance of industrial synthetic polymer virus removal filters.

Virus Genes, 2011

The influenza A virus subtypes H1N1, H1N2 and H3N2 are prevalent in pig populations worldwide. In... more The influenza A virus subtypes H1N1, H1N2 and H3N2 are prevalent in pig populations worldwide. In the present study, two relatively uncommon swine influenza virus (SIV) H1N2 subtypes, isolated in Sweden in 2009 and 2010, were compared regarding their molecular composition and biological characteristics. The differences regarding markers purportedly related to pathogenicity, host adaptation or replication efficiency. They included a truncated PB1-F2 protein in the earlier isolate but a full length version in the more recent one; differences in the number of haemagglutinin glycosylation sites, including a characteristic human one; and a nuclear export protein with altered export signal. Of particular interest, the NS1 amino acid sequence of swine H1N2-2009 and 2010 has a 'unique or very unusual' PDZ binding domain (RPKV) at the C-terminal of the protein, a motif that has been implicated as a virulence marker. Concerning biological properties, these viruses reached lower titre and showed reduced cytopathogenicity in MDCK cells compared with an avianlike H1N1 isolate A/swine/Lidkoping/1193/2002 belonging to the same lineage as the 2009 and 2010 isolates. The findings should contribute to better understanding of factors related to the survival/extinction of this uncommon reassortant variant.

Virus Genes, 2009

In order to provide additional information to the epidemiological situation in Middle Europe and ... more In order to provide additional information to the epidemiological situation in Middle Europe and open further possibilities to investigate the transmission of influenza viruses between species, the viral genomes of three influenza A virus isolates (one human and two swine) collected from North-East Hungary in 2006–2007 have been fully sequenced and characterized. The sequence analysis reveals strong geographical relationships between the internal genes of the two swine viruses; the human isolate shows strict conservation to recent H1N1 strains, while the swine strains demonstrate and reflect a mixed avian–human origin, a characteristic of European swine influenza viruses. No evidence of interspecies interaction has been found among the studied isolates.

Virology Journal, 2010

Background: The unique property of some avian H10 viruses, particularly the ability to cause seve... more Background: The unique property of some avian H10 viruses, particularly the ability to cause severe disease in mink without prior adaptation, enabled our study. Coupled with previous experimental data and genetic characterization here we tried to investigate the possible influence of different genes on the virulence of these H10 avian influenza viruses in mink.

Virology Journal, 2010

In our previous study concerning the genetic relationship among H10 avian influenza viruses with ... more In our previous study concerning the genetic relationship among H10 avian influenza viruses with different pathogenicity in mink (Mustela vison), we found that these differences were related to amino acid variations in the NS1 protein. In this study, we extend our previous work to further investigate the effect of the NS1 from different gene pools on type I IFN promoter activity, the production of IFN-β, as well as the expression of the IFN-β mRNA in response to poly I:C. Using a model system, we first demonstrated that NS1 from A/mink/Sweden/84 (H10N4) (allele A) could suppress an interferon-stimulated response element (ISRE) reporter system to about 85%. The other NS1 (allele B), from A/chicken/Germany/N/49 (H10N7), was also able to suppress the reporter system, but only to about 20%. The differences in the abilities of the two NS1s from different alleles to suppress the ISRE reporter system were clearly reflected by the protein and mRNA expressions of IFN-β as shown by ELISA and RT-PCR assays. These studies reveal that different non-structural protein 1 (NS1) of influenza viruses, one from allele A and another from allele B, show different abilities to suppress the type I interferon β expression. It has been hypothesised that some of the differences in the different abilities of the alleles to suppress ISRE were because of the interactions and inhibitions at later stages from the IFN receptor, such as the JAK/STAT pathway. This might reflect the additional effects of the immune evasion potential of different NS1s.

Virology Journal, 2009

The European swine influenza viruses (SIVs) show considerable diversity comprising different type... more The European swine influenza viruses (SIVs) show considerable diversity comprising different types of H1N1, H3N2, and H1N2 strains. The intensifying full genome sequencing efforts reveal further reassortants within these subtypes. Here we report the identification of an uncommon reassortant variant of H1N2 subtype influenza virus isolated from a pig in a multisite herd where H1N2 swine influenza was diagnosed for the first time in Sweden during the winter of

Veterinary Microbiology, 2010

Two low pathogenic (LP) avian influenza virus strains, A/mallard/Hungary/19616/07 (H3N8) and A/mu... more Two low pathogenic (LP) avian influenza virus strains, A/mallard/Hungary/19616/07 (H3N8) and A/mute swan/Hungary/5973/07 (H7N7), isolated as part of the National Surveillance Program in Hungary, were fully sequenced and characterized. The two viruses showed the closest phylogenetic relationship regarding their acidic polymerase genes. The H7N7 Hungarian virus and some H5N2 influenza viruses isolated from Korean pigs appeared to have their basic polymerase gene 1 from a relatively recent common ancestor. The matrix gene nucleotide sequence of each Hungarian virus showed close relationship with contemporaneous Czech H3N8 mallard isolates, which belonged to distinct phylogenetic branches. The non-structural protein genes belonged to different alleles, rendering a peculiar characteristic to the H7N7 isolate compared to the so far analyzed Eurasian H7 viruses. The surface glycoprotein genes of the H3N8 isolate showed a close phylogenetic relationship and high nucleotide identities to H3N8 subtype isolates from Northern Europe collected in 2003-2006, and to an H3N2 isolate in Italy in 2006, extending the perceptions of this HA subtype across Northern and Southern Europe close to this period. These findings provide further data to the diversity of influenza viruses found in wild migratory birds and present useful information for large scale studies on influenza virus evolution.

Veterinary Microbiology, 2012

PLoS ONE, 2009

Background: The analysis of the nonstructural (NS) gene of the highly pathogenic (HP) H5N1 avian ... more Background: The analysis of the nonstructural (NS) gene of the highly pathogenic (HP) H5N1 avian influenza viruses (AIV) isolated in Sweden early 2006 indicated the co-circulation of two sublineages of these viruses at that time. In order to complete the information on their genetic features and relation to other HP H5N1 AIVs the seven additional genes of twelve Swedish isolates were amplified in full length, sequenced, and characterized.

Journal of General Virology, 2011

Non-structural protein 1 (NS1) counteracts the production of host type I interferons (IFN-a/b) fo... more Non-structural protein 1 (NS1) counteracts the production of host type I interferons (IFN-a/b) for the efficient replication and pathogenicity of influenza A viruses. Here, we reveal another dimension of the NS1 protein of avian influenza A viruses in suppressing IFN-b production in cultured cell lines. We found that allele A NS1 proteins of H6N8 and H4N6 have a strong capacity to inhibit the activation of IFN-b production, compared with allele B from corresponding subtypes, as measured by IFN stimulatory response element (ISRE) promoter activation, IFN-b mRNA transcription and IFN-b protein expression. Furthermore, the ability to suppress IFN-b promoter activation was mapped to the C-terminal effector domain (ED), while the RNA-binding domain (RBD) alone was unable to suppress IFN-b promoter activation. Chimeric studies indicated that when the RBD of allele A was fused to the ED of allele B, it was a strong inhibitor of IFN-b promoter activity. This shows that well-matched ED and RBD are crucial for the function of the NS1 protein and that the RBD could be one possible cause for this differential IFN-b inhibition. Notably, mutagenesis studies indicated that the F103Y and Y103F substitutions in alleles A and B, respectively, do not influence the ISRE promoter activation. Apart from dsRNA signalling, differences were observed in the expression pattern of NS1 in transfected human and mink lung cells. This study therefore expands the versatile nature of the NS1 protein in inhibiting IFN responses at multiple levels, by demonstrating for the first time that it occurs in a manner dependent on allele type.

Avian Diseases, 2010

The H7 subtype of avian influenza (AI) has the capability to evolve into a highly pathogenic AI (... more The H7 subtype of avian influenza (AI) has the capability to evolve into a highly pathogenic AI (HPAI) virus. In this study, we have characterized the hemagglutinin (HA) genes of three avian H7N7 influenza A viruses isolated from healthy migratory mallards in Northern Europe in three different years to study the natural variation of these viruses in the natural reservoir. Phylogenetic analysis demonstrated that the H7 HA genes were all closely related to recent H7 isolates responsible for influenza outbreaks in poultry in Europe. The A/mallard/Sweden/S90735/2003 isolate clustered together with the HA gene of A/mallard/Netherlands/12/00/H7N3 (AY338460), which has been shown to be closely related to the H7N7 responsible for HPAI outbreaks in The Netherlands and Germany in 2003. In contrast, the HA gene of the two mallard strains A/mallard/Sweden/ S90597/2005 and A/mallard/Sweden/100993/2008 were more related to the chicken strain isolated in domestic poultry in England in 2006, A/Ch/England/4054/2006/H7N3 (EF467826), and 2008, A/Ch/England/2008/H7N7 (214011964). Analysis of the deduced HA amino acid sequence shows two different HA cleavage sites in these isolates. Although these HA cleavage sites are consistent with a low pathogenicity AI, the cleavage sites appear to posses an increasing numbers of basic amino acids over time (PEIPKGRGLF in 2003 and 2005 and PEIPKKRGLF in 2008). The conclusion from this study is that H7 subtypes isolated from healthy mallards are closely related to the H7 subtypes that have caused recent influenza outbreaks in poultry in Europe.

Acta Veterinaria Scandinavica, 2010

Virus Research, 2014

Swine appear to be a key species in the generation of novel human influenza pandemics. Previous p... more Swine appear to be a key species in the generation of novel human influenza pandemics. Previous pandemic viruses are postulated to have evolved in swine by reassortment of avian, human, and swine influenza viruses. The human pandemic influenza viruses that emerged in 1957 and 1968 as well as swine viruses circulating since 1998 encode PB1 segments derived from avian influenza viruses. Here we investigate the possible role in viral replication and virulence of the PB1 gene segments present in two swine H1N2 influenza A viruses, A/swine/Sweden/1021/2009(H1N2) (sw 1021) and A/swine/Sweden/9706/2010(H1N2) (sw 9706), where the sw 1021 virus has shown to be more pathogenic in mice. By using reverse genetics, we swapped the PB1 genes of these two viruses. Similar to the sw 9706 virus, chimeric sw 1021 virus carrying the sw 9706 PB1 gene was not virulent in mice. In contrast, replacement of the PB1 gene of the sw 9706 virus by that from sw 1021 virus resulted in increased pathogenicity. Our study demonstrated that differences in virulence of swine influenza virus subtype H1N2 are attributed at least in part to the PB1 segment.

Advanced healthcare materials, 2014

This is the first time a 100% natural, unmodified nanofibrous polymer-based membrane is demonstra... more This is the first time a 100% natural, unmodified nanofibrous polymer-based membrane is demonstrated capable of removing viruses solely based on the size-exclusion principle, with a log10 reduction value (LRV) ≥ 6.3 as limited by the assay lower detection limit and the feed virus titre, thereby matching the performance of industrial synthetic polymer virus removal filters.

Virus Genes, 2011

The influenza A virus subtypes H1N1, H1N2 and H3N2 are prevalent in pig populations worldwide. In... more The influenza A virus subtypes H1N1, H1N2 and H3N2 are prevalent in pig populations worldwide. In the present study, two relatively uncommon swine influenza virus (SIV) H1N2 subtypes, isolated in Sweden in 2009 and 2010, were compared regarding their molecular composition and biological characteristics. The differences regarding markers purportedly related to pathogenicity, host adaptation or replication efficiency. They included a truncated PB1-F2 protein in the earlier isolate but a full length version in the more recent one; differences in the number of haemagglutinin glycosylation sites, including a characteristic human one; and a nuclear export protein with altered export signal. Of particular interest, the NS1 amino acid sequence of swine H1N2-2009 and 2010 has a 'unique or very unusual' PDZ binding domain (RPKV) at the C-terminal of the protein, a motif that has been implicated as a virulence marker. Concerning biological properties, these viruses reached lower titre and showed reduced cytopathogenicity in MDCK cells compared with an avianlike H1N1 isolate A/swine/Lidkoping/1193/2002 belonging to the same lineage as the 2009 and 2010 isolates. The findings should contribute to better understanding of factors related to the survival/extinction of this uncommon reassortant variant.

Virus Genes, 2009

In order to provide additional information to the epidemiological situation in Middle Europe and ... more In order to provide additional information to the epidemiological situation in Middle Europe and open further possibilities to investigate the transmission of influenza viruses between species, the viral genomes of three influenza A virus isolates (one human and two swine) collected from North-East Hungary in 2006–2007 have been fully sequenced and characterized. The sequence analysis reveals strong geographical relationships between the internal genes of the two swine viruses; the human isolate shows strict conservation to recent H1N1 strains, while the swine strains demonstrate and reflect a mixed avian–human origin, a characteristic of European swine influenza viruses. No evidence of interspecies interaction has been found among the studied isolates.

Virology Journal, 2010

Background: The unique property of some avian H10 viruses, particularly the ability to cause seve... more Background: The unique property of some avian H10 viruses, particularly the ability to cause severe disease in mink without prior adaptation, enabled our study. Coupled with previous experimental data and genetic characterization here we tried to investigate the possible influence of different genes on the virulence of these H10 avian influenza viruses in mink.

Virology Journal, 2010

In our previous study concerning the genetic relationship among H10 avian influenza viruses with ... more In our previous study concerning the genetic relationship among H10 avian influenza viruses with different pathogenicity in mink (Mustela vison), we found that these differences were related to amino acid variations in the NS1 protein. In this study, we extend our previous work to further investigate the effect of the NS1 from different gene pools on type I IFN promoter activity, the production of IFN-β, as well as the expression of the IFN-β mRNA in response to poly I:C. Using a model system, we first demonstrated that NS1 from A/mink/Sweden/84 (H10N4) (allele A) could suppress an interferon-stimulated response element (ISRE) reporter system to about 85%. The other NS1 (allele B), from A/chicken/Germany/N/49 (H10N7), was also able to suppress the reporter system, but only to about 20%. The differences in the abilities of the two NS1s from different alleles to suppress the ISRE reporter system were clearly reflected by the protein and mRNA expressions of IFN-β as shown by ELISA and RT-PCR assays. These studies reveal that different non-structural protein 1 (NS1) of influenza viruses, one from allele A and another from allele B, show different abilities to suppress the type I interferon β expression. It has been hypothesised that some of the differences in the different abilities of the alleles to suppress ISRE were because of the interactions and inhibitions at later stages from the IFN receptor, such as the JAK/STAT pathway. This might reflect the additional effects of the immune evasion potential of different NS1s.

Virology Journal, 2009

The European swine influenza viruses (SIVs) show considerable diversity comprising different type... more The European swine influenza viruses (SIVs) show considerable diversity comprising different types of H1N1, H3N2, and H1N2 strains. The intensifying full genome sequencing efforts reveal further reassortants within these subtypes. Here we report the identification of an uncommon reassortant variant of H1N2 subtype influenza virus isolated from a pig in a multisite herd where H1N2 swine influenza was diagnosed for the first time in Sweden during the winter of

Veterinary Microbiology, 2010

Two low pathogenic (LP) avian influenza virus strains, A/mallard/Hungary/19616/07 (H3N8) and A/mu... more Two low pathogenic (LP) avian influenza virus strains, A/mallard/Hungary/19616/07 (H3N8) and A/mute swan/Hungary/5973/07 (H7N7), isolated as part of the National Surveillance Program in Hungary, were fully sequenced and characterized. The two viruses showed the closest phylogenetic relationship regarding their acidic polymerase genes. The H7N7 Hungarian virus and some H5N2 influenza viruses isolated from Korean pigs appeared to have their basic polymerase gene 1 from a relatively recent common ancestor. The matrix gene nucleotide sequence of each Hungarian virus showed close relationship with contemporaneous Czech H3N8 mallard isolates, which belonged to distinct phylogenetic branches. The non-structural protein genes belonged to different alleles, rendering a peculiar characteristic to the H7N7 isolate compared to the so far analyzed Eurasian H7 viruses. The surface glycoprotein genes of the H3N8 isolate showed a close phylogenetic relationship and high nucleotide identities to H3N8 subtype isolates from Northern Europe collected in 2003-2006, and to an H3N2 isolate in Italy in 2006, extending the perceptions of this HA subtype across Northern and Southern Europe close to this period. These findings provide further data to the diversity of influenza viruses found in wild migratory birds and present useful information for large scale studies on influenza virus evolution.

Veterinary Microbiology, 2012

PLoS ONE, 2009

Background: The analysis of the nonstructural (NS) gene of the highly pathogenic (HP) H5N1 avian ... more Background: The analysis of the nonstructural (NS) gene of the highly pathogenic (HP) H5N1 avian influenza viruses (AIV) isolated in Sweden early 2006 indicated the co-circulation of two sublineages of these viruses at that time. In order to complete the information on their genetic features and relation to other HP H5N1 AIVs the seven additional genes of twelve Swedish isolates were amplified in full length, sequenced, and characterized.

Journal of General Virology, 2011

Non-structural protein 1 (NS1) counteracts the production of host type I interferons (IFN-a/b) fo... more Non-structural protein 1 (NS1) counteracts the production of host type I interferons (IFN-a/b) for the efficient replication and pathogenicity of influenza A viruses. Here, we reveal another dimension of the NS1 protein of avian influenza A viruses in suppressing IFN-b production in cultured cell lines. We found that allele A NS1 proteins of H6N8 and H4N6 have a strong capacity to inhibit the activation of IFN-b production, compared with allele B from corresponding subtypes, as measured by IFN stimulatory response element (ISRE) promoter activation, IFN-b mRNA transcription and IFN-b protein expression. Furthermore, the ability to suppress IFN-b promoter activation was mapped to the C-terminal effector domain (ED), while the RNA-binding domain (RBD) alone was unable to suppress IFN-b promoter activation. Chimeric studies indicated that when the RBD of allele A was fused to the ED of allele B, it was a strong inhibitor of IFN-b promoter activity. This shows that well-matched ED and RBD are crucial for the function of the NS1 protein and that the RBD could be one possible cause for this differential IFN-b inhibition. Notably, mutagenesis studies indicated that the F103Y and Y103F substitutions in alleles A and B, respectively, do not influence the ISRE promoter activation. Apart from dsRNA signalling, differences were observed in the expression pattern of NS1 in transfected human and mink lung cells. This study therefore expands the versatile nature of the NS1 protein in inhibiting IFN responses at multiple levels, by demonstrating for the first time that it occurs in a manner dependent on allele type.

Avian Diseases, 2010

The H7 subtype of avian influenza (AI) has the capability to evolve into a highly pathogenic AI (... more The H7 subtype of avian influenza (AI) has the capability to evolve into a highly pathogenic AI (HPAI) virus. In this study, we have characterized the hemagglutinin (HA) genes of three avian H7N7 influenza A viruses isolated from healthy migratory mallards in Northern Europe in three different years to study the natural variation of these viruses in the natural reservoir. Phylogenetic analysis demonstrated that the H7 HA genes were all closely related to recent H7 isolates responsible for influenza outbreaks in poultry in Europe. The A/mallard/Sweden/S90735/2003 isolate clustered together with the HA gene of A/mallard/Netherlands/12/00/H7N3 (AY338460), which has been shown to be closely related to the H7N7 responsible for HPAI outbreaks in The Netherlands and Germany in 2003. In contrast, the HA gene of the two mallard strains A/mallard/Sweden/ S90597/2005 and A/mallard/Sweden/100993/2008 were more related to the chicken strain isolated in domestic poultry in England in 2006, A/Ch/England/4054/2006/H7N3 (EF467826), and 2008, A/Ch/England/2008/H7N7 (214011964). Analysis of the deduced HA amino acid sequence shows two different HA cleavage sites in these isolates. Although these HA cleavage sites are consistent with a low pathogenicity AI, the cleavage sites appear to posses an increasing numbers of basic amino acids over time (PEIPKGRGLF in 2003 and 2005 and PEIPKKRGLF in 2008). The conclusion from this study is that H7 subtypes isolated from healthy mallards are closely related to the H7 subtypes that have caused recent influenza outbreaks in poultry in Europe.

Acta Veterinaria Scandinavica, 2010

Virus Research, 2014

Swine appear to be a key species in the generation of novel human influenza pandemics. Previous p... more Swine appear to be a key species in the generation of novel human influenza pandemics. Previous pandemic viruses are postulated to have evolved in swine by reassortment of avian, human, and swine influenza viruses. The human pandemic influenza viruses that emerged in 1957 and 1968 as well as swine viruses circulating since 1998 encode PB1 segments derived from avian influenza viruses. Here we investigate the possible role in viral replication and virulence of the PB1 gene segments present in two swine H1N2 influenza A viruses, A/swine/Sweden/1021/2009(H1N2) (sw 1021) and A/swine/Sweden/9706/2010(H1N2) (sw 9706), where the sw 1021 virus has shown to be more pathogenic in mice. By using reverse genetics, we swapped the PB1 genes of these two viruses. Similar to the sw 9706 virus, chimeric sw 1021 virus carrying the sw 9706 PB1 gene was not virulent in mice. In contrast, replacement of the PB1 gene of the sw 9706 virus by that from sw 1021 virus resulted in increased pathogenicity. Our study demonstrated that differences in virulence of swine influenza virus subtype H1N2 are attributed at least in part to the PB1 segment.