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

Nelli, Rahul K. and Dunham, Stephen P. and Kuchipudi, Suresh V. and White, Gavin A. and Baquero-Perez, Belinda and Pengxiang, Chang and Ghaemmaghami, Amir M. and Brookes, Sharon M. and Brown, Ian H. and Chang, Kin-Chow (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). pp. 9201-9210. ISSN 0022-538X

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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.

Item Type: Article
Schools/Departments: University of Nottingham UK Campus > Faculty of Medicine and Health Sciences > School of Veterinary Medicine and Science
Identification Number: https://doi.org/10.1128/JVI.00244-12
Depositing User: Wahid, Ms. Haleema
Date Deposited: 03 Apr 2014 13:49
Last Modified: 13 Sep 2016 15:49
URI: http://eprints.nottingham.ac.uk/id/eprint/2750

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