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

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.

Citation

Nelli, R. K., Dunham, S. P., Kuchipudi, S. V., White, G. A., Baquero-Perez, B., Pengxiang, C., Ghaemmaghami, A. M., Brookes, S. M., Brown, I. H., & Chang, K.-C. (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), https://doi.org/10.1128/JVI.00244-12

• Journal Article Type: Article
• Publication Date: Sep 1, 2012
• Deposit Date: Apr 3, 2014
• Publicly Available Date: Apr 3, 2014
• Journal: Journal of Virology
• Print ISSN: 0022-538X
• Electronic ISSN: 1098-5514
• Publisher: American Society for Microbiology
• Peer Reviewed: Peer Reviewed
• Volume: 86
• Issue: 17
• DOI: https://doi.org/10.1128/JVI.00244-12
• Public URL: https://nottingham-repository.worktribe.com/output/1006695
• Publisher URL: http://jvi.asm.org/content/86/17/9201.long