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Mammalian innate resistance to highly pathogenic avian influenza H5N1 virus infection is mediated through reduced proinflammation and infectious virus release

Nelli, Rahul K.; Dunham, Stephen P.; Kuchipudi, Suresh V.; White, Gavin A.; Baquero-Perez, Belinda; Pengxiang, Chang; Ghaemmaghami, Amir M.; Brookes, Sharon M.; Brown, Ian H.; Chang, Kin-Chow

Authors

Rahul K. Nelli

Stephen P. Dunham

Suresh V. Kuchipudi

Gavin A. White

Belinda Baquero-Perez

Chang Pengxiang

Amir M. Ghaemmaghami

Sharon M. Brookes

Ian H. Brown

Kin-Chow Chang



Abstract

Respiratory epithelial cells and macrophages are the key innate immune cells that play an important role in the pathogenesis of influenza A virus infection. We found that these two cell types from both human and pig showed comparable susceptibilities to initial infection with a highly pathogenic avian influenza (HPAI) H5N1 virus (A/turkey/Turkey/1/05) and a moderately pathogenic human influenza H1N1 virus (A/USSR/77), but there were contrasting differences in host innate immune responses. Human cells mounted vigorous cytokine (tumor necrosis factor alpha [TNF-α] and interleukin-6 [IL-6]) and chemokine (CXCL9, CXCL10, and CXCL11) responses to H5N1 virus infection. However, pig epithelial cells and macrophages showed weak or no TNF-α and chemokine induction with the same infections. The apparent lack of a strong proinflammatory response, corroborated by the absence of TNF-α induction in H5N1 virus-challenged pigs, coincided with greater cell death and the reduced release of infectious virus from infected pig epithelial cells. Suppressor of cytokine signaling 3 (SOCS3), a protein suppressor of the JAK-STAT pathway, was constitutively highly expressed and transcriptionally upregulated in H5N1 virus-infected pig epithelial cells and macrophages, in contrast to the corresponding human cells. The overexpression of SOCS3 in infected human macrophages dampened TNF-α induction. In summary, we found that the reported low susceptibility of pigs to contemporary Eurasian HPAI H5N1 virus infections coincides at the level of innate immunity of respiratory epithelial cells and macrophages with a reduced output of viable virus and an attenuated proinflammatory response, possibly mediated in part by SOCS3, which could serve as a target in the treatment or prevention of virus-induced hypercytokinemia, as observed for humans.

Journal Article Type Article
Publication Date Sep 1, 2012
Journal Journal of Virology
Print ISSN 0022-538X
Electronic ISSN 0022-538X
Publisher American Society for Microbiology
Peer Reviewed Peer Reviewed
Volume 86
Issue 17
APA6 Citation Nelli, R. K., Dunham, S. P., Kuchipudi, S. V., White, G. A., Baquero-Perez, B., Pengxiang, C., …Chang, K. (2012). Mammalian innate resistance to highly pathogenic avian influenza H5N1 virus infection is mediated through reduced proinflammation and infectious virus release. Journal of Virology, 86(17), doi:10.1128/JVI.00244-12
DOI https://doi.org/10.1128/JVI.00244-12
Publisher URL http://jvi.asm.org/content/86/17/9201.long
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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