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PMID:28189564

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Citation

Bertram, S, Thiele, S, Dreier, C, Resa-Infante, P, Preuß, A, van Riel, D, Mok, CKP, Schwalm, F, Peiris, JSM, Klenk, HD and Gabriel, G (2017) H7N9 Influenza A Virus Exhibits Importin-α7-Mediated Replication in the Mammalian Respiratory Tract. Am. J. Pathol. 187:831-840

Abstract

The acute respiratory distress syndrome (ARDS) is the leading cause of death in influenza A virus (IAV)-infected patients. Hereby, the cellular importin-α7 gene plays a major role. It promotes viral replication in the lung, thereby increasing the risk for the development of pneumonia complicated by ARDS. Herein, we analyzed whether the recently emerged H7N9 avian IAV has already adapted to human importin-α7 use, which is associated with high-level virus replication in the mammalian lung. Using a cell-based viral polymerase activity assay, we could detect a decreased H7N9 IAV polymerase activity when importin-α7 was silenced by siRNA. Moreover, virus replication was diminished in the murine cells lacking the importin-α7 gene. Consistently, importin-α7 knockout mice presented reduced pulmonary virus titers and lung lesions as well as enhanced survival rates compared to wild-type mice. In summary, our results show that H7N9 IAV have acquired distinct features of adaptation to human host factors that enable enhanced virulence in mammals. In particular, adaptation to human importin-α7 mediates elevated virus replication in the mammalian lung, which might have contributed to ARDS observed in H7N9-infected patients.

Links

PubMed Online version:10.1016/j.ajpath.2016.12.017

Keywords

Animals; Chemokines/metabolism; Cytokines/metabolism; DNA-Directed DNA Polymerase/metabolism; Gene Deletion; HEK293 Cells; Humans; Inflammation Mediators/metabolism; Influenza A Virus, H7N9 Subtype/pathogenicity; Influenza A Virus, H7N9 Subtype/physiology; Lung/metabolism; Lung/pathology; Lung/virology; Mammals/virology; Mice; Respiratory System/metabolism; Respiratory System/virology; Virulence; Virus Replication; alpha Karyopherins/genetics; alpha Karyopherins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:IMA7

acts_upstream_of_or_within

GO:0030682: mitigation of host defenses by symbiont

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3856636

P

Seeded From UniProt

complete

MOUSE:IMA7

acts_upstream_of_or_within

GO:0019079: viral genome replication

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3856636

P

Seeded From UniProt

complete

MOUSE:IMA7

acts_upstream_of_or_within

GO:1903902: positive regulation of viral life cycle

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3856636

P

  • occurs_in:(EMAPA:16728)

Seeded From UniProt

complete

MOUSE:IMA7

acts_upstream_of_or_within

GO:1900017: positive regulation of cytokine production involved in inflammatory response

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3856636

P

  • occurs_in:(EMAPA:16728)

Seeded From UniProt

complete

MOUSE:IMA1

acts_upstream_of_or_within

GO:0075506: entry of viral genome into host nucleus through nuclear pore complex via importin

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P52292

P

Seeded From UniProt

complete

MOUSE:IMA1

acts_upstream_of_or_within

GO:0075506: entry of viral genome into host nucleus through nuclear pore complex via importin

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IMA1

acts_upstream_of_or_within

GO:1903902: positive regulation of viral life cycle

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P52292

P

Seeded From UniProt

complete

MOUSE:IMA1

acts_upstream_of_or_within

GO:1903902: positive regulation of viral life cycle

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:IMA7

acts_upstream_of_or_within

GO:1903902: positive regulation of viral life cycle

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3856636

P

occurs_in:(EMAPA:16728)

Seeded From UniProt

complete

MOUSE:IMA7

acts_upstream_of_or_within

GO:0075506: entry of viral genome into host nucleus through nuclear pore complex via importin

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:O60684

P

Seeded From UniProt

complete

MOUSE:IMA7

acts_upstream_of_or_within

GO:0075506: entry of viral genome into host nucleus through nuclear pore complex via importin

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3856636

P

Seeded From UniProt

complete

MOUSE:IMA7

acts_upstream_of_or_within

GO:1903902: positive regulation of viral life cycle

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:O60684

P

Seeded From UniProt

complete

MOUSE:IMA7

acts_upstream_of_or_within

GO:1900017: positive regulation of cytokine production involved in inflammatory response

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3856636

P

occurs_in:(EMAPA:16728)

Seeded From UniProt

complete

MOUSE:IMA7

acts_upstream_of_or_within

GO:0030683: evasion or tolerance by virus of host immune response

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3856636

P

Seeded From UniProt

complete

Notes

See also

References

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