The Virulence of 1997 H5N1 Influenza Viruses in the Mouse Model Is Increased by Correcting a Defect in Their NS1 Proteins

Spesock, April; Malur, Meghana; Hossain, M. Jaber; Chen, Li Mei; Njaa, Bradley L.; Davis, C. Todd; Lipatov, A. S.; York, Ian A.; Krug, Robert M.; Donis, Ruben O.

doi:10.1128/jvi.00417-11

Cited by 74 publications

(63 citation statements)

References 65 publications

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“…8). In agreement with our results, increasing the binding of NS1 protein to CPSF30 in H7N9 and H5N1 NS1 proteins by introducing the mutations L103F and I106M led to decreased type I IFN responses after infection, augmented virus titers in vivo, and increased virulence in mice (24,47). These results are in accordance with our previous work showing that an NS1 mutation (I64T) impairing the binding of NS1 to CPSF30 led to increased innate immune responses after infection, decreased virus titers in vivo, and resulted in virus attenuation (26).…”

Section: Discussionsupporting

confidence: 79%

NS1 Protein Amino Acid Changes D189N and V194I Affect Interferon Responses, Thermosensitivity, and Virulence of Circulating H3N2 Human Influenza A Viruses

Nogales

Martínez-Sobrido

Topham

et al. 2017

J Virol

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Influenza virus NS1 protein is a nonstructural, multifunctional protein that counteracts host innate immune responses, modulating virus pathogenesis. NS1 protein variability in subjects infected with H3N2 influenza A viruses (IAVs) during the 2010/2011 season was analyzed, and amino acid changes in residues 86, 189, and 194 were found. The consequences of these mutations for the NS1-mediated inhibition of IFN responses and the pathogenesis of the virus were evaluated, showing that NS1 mutations D189N and V194I impaired the ability of the NS1 protein to inhibit general gene expression, most probably because these mutations decreased the binding of NS1 to the cleavage and polyadenylation specificity factor 30 (CPSF30). A recombinant A/Puerto Rico/8/34 (PR8) H1N1 virus encoding the H3N2 NS1-D189N protein was slightly attenuated, whereas the virus encoding the H3N2 NS1-V194I protein was further attenuated in mice. The higher attenuation of this virus could not be explained by differences in the ability of the two NS1 proteins to counteract host innate immune responses, indicating that another factor must be responsible. In fact, we showed that the virus encoding the H3N2 NS1-V194I protein demonstrated a temperature-sensitive (ts) phenotype, providing a most likely explanation for the stronger attenuation observed. As far as we know, this is the first description of a mutation in NS1 residue 194 conferring a ts phenotype. These studies are relevant in order to identify new residues important for NS1 functions and in human influenza virus surveillance to assess mutations affecting the pathogenicity of circulating viruses.IMPORTANCE Influenza viral infections represent a serious public health problem, with influenza virus causing a contagious respiratory disease that is most effectively prevented through vaccination. The multifunctional nonstructural protein 1 (NS1) is the main viral factor counteracting the host antiviral response. Therefore, influenza virus surveillance to identify new mutations in the NS1 protein affecting the pathogenicity of the circulating viruses is highly important. In this work, we evaluated amino acid variability in the NS1 proteins from H3N2 human seasonal viruses and the effect of the mutations on innate immune responses and virus pathogenesis. NS1 mutations D189N and V194I impaired the ability of the NS1 protein to inhibit general gene expression, and recombinant viruses harboring these mutations were attenuated in a mouse model of influenza infection. Interestingly, a virus encoding the H3N2 NS1-V194I protein demonstrated a temperature-sensitive phenotype, further attenuating the virus in vivo.KEYWORDS NS1 protein, antiviral response, influenza virus, innate immunity, pathogenesis, virus-host interactions

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Section: Discussionsupporting

confidence: 79%

NS1 Protein Amino Acid Changes D189N and V194I Affect Interferon Responses, Thermosensitivity, and Virulence of Circulating H3N2 Human Influenza A Viruses

Nogales

Martínez-Sobrido

Topham

et al. 2017

J Virol

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“…Previously, it has been shown that the NS1 gene facilitates spread of HPAIV H5N1 from the lung to the brain of experimentally infected mice. 29 Taken together; our comprehensive analysis of the NS1 gene segments and animal experiments support that truncation of the C-terminal end of NS1 protein is not an essential virulence determinant of AIV, particularly for the Italian HPAIV H7N1, in chickens, however, it may be a host adaptation marker as indicated by efficient replication in-vitro and in-vivo.…”

Section: Discussionmentioning

confidence: 85%

Prevalence of the C-terminal truncations of NS1 in avian influenza A viruses and effect on virulence and replication of a highly pathogenic H7N1 virus in chickens

et al. 2016

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(2016) Prevalence of the C-terminal truncations of NS1 in avian influenza A viruses and effect on virulence and replication of a highly pathogenic H7N1 virus in chickens, Virulence, 7:5, 546-557, DOI: 10.1080/21505594.2016 protein sequences of all AIV subtypes in birds from 1902 to 2015 were analyzed to study the prevalence and distribution of CTE truncation (DCTE). Thirteen different DCTE forms were observed in NS1 proteins from 11 HA and 8 NA subtypes with high prevalences in H9, H7, H6 and H10 and N9, N2, N6 and N1 subtypes particularly in chickens and minor poultry species. With 88% NS217 lacking amino acids 218-230 was the most common DCTE form followed by NS224 (3.6%). NS217 was found in 10 and 8 different HA and NA subtypes, respectively, whereas NS224 was detected exclusively in the Italian HPAIV H7N1 suggesting relevance for virulence. To test this assumption, 3 recombinant HPAIV H7N1 were constructed carrying wild-type HP NS1 (Hp-NS224), NS1 with extended CTE (Hp-NS230) or NS1 from LPAIV H7N1 (Hp-NSLp), and tested in-vitro and in-vivo. Extension of CTE in Hp NS1 significantly decreased virus replication in chicken embryo kidney cells. Truncation in the NS1 decreased the tropism of Hp-NS224 to the endothelium, central nervous system and respiratory tract epithelium without significant difference in virulence in chickens. This study described the variable forms of DCTE in NS1 and indicated that CTE is not an essential virulence determinant particularly for the Italian HPAIV H7N1 but may be a host-adaptation marker required for efficient virus replication.

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“…Some mutations in PB1, PA, M1, and M2 associated with viral transmissibility, species specificity, virulence, or adamantine resistance were detected in reassortant C viruses due to their internal gene from H9N2 virus (27)(28)(29)(30). The reassortant A and B viruses with NS1 genes from H5N1 carried mutations that increased virulence in mice (31,32).…”

Section: Resultsmentioning

confidence: 99%

Genesis and Dissemination of Highly Pathogenic H5N6 Avian Influenza Viruses

Yang

Zhu

et al. 2017

J Virol

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The Virulence of 1997 H5N1 Influenza Viruses in the Mouse Model Is Increased by Correcting a Defect in Their NS1 Proteins

Cited by 74 publications

References 65 publications

NS1 Protein Amino Acid Changes D189N and V194I Affect Interferon Responses, Thermosensitivity, and Virulence of Circulating H3N2 Human Influenza A Viruses

NS1 Protein Amino Acid Changes D189N and V194I Affect Interferon Responses, Thermosensitivity, and Virulence of Circulating H3N2 Human Influenza A Viruses

Prevalence of the C-terminal truncations of NS1 in avian influenza A viruses and effect on virulence and replication of a highly pathogenic H7N1 virus in chickens

Genesis and Dissemination of Highly Pathogenic H5N6 Avian Influenza Viruses

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