Early regulation of viral infection reduces inflammation and rescues Mx-positive mice from lethal avian influenza infection

Min Suk Song, Young Hun Cho, Su Jin Park, Philippe Noriel Q. Pascua, Yun Hee Baek, Hyeok Il Kwon, Ok Jun Lee, Byung Whi Kong, Hyunggee Kim, Eui Cheol Shin, Chul Joong Kim, Young Ki Choi

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7 Citations (Scopus)

Abstract

Differing sensitivity of influenza A viruses to antiviral effects of the Myxovirus resistance (Mx) protein implies varying global gene expression profiles in the host. The role of Mx protein during lethal avian influenza (AI) virus infection was examined using Mx1-deficient C57BL/6 (B6-Mx1-/-) and congenic Mx1-expressing (B6-Mx1+/+) mice infected with a virulent, mouse-adapted avian H5N2 Ab/Korea/ma81/07 (Av/ma81) virus. After infection, B6-Mx1+/+ mice were completely protected from lethal AI-induced mortality, and exhibited attenuated clinical disease and reduced viral titers and pathology in the lungs, compared with B6-Mx1-/- mice. Transcriptional profiling of lung tissues revealed that most of the genes up-regulated after infection are involved in activation of the immune response and host defense. Notably, more abundant and sustained expression of cytokine/chemokine genes was observed up to 3 dpi in B6-Mx1-/- mice, and this was associated with excessive induction of cytokines and chemokines. Consequently, massive infiltration of macrophages/monocytes and granulocytes into lung resulted in severe viral pneumonia and potentially contributed to decreased survival of B6-Mx1-/- mice. Taken together, our data show that dysregulated gene transcriptional activity corresponded to persistent induction of cytokine/chemokines and recruitment of cytokine-producing cells that promote inflammation in B6-Mx1-/- mouse lungs. Thus, we provide additional evidence of the interplay of genetic, molecular, and cellular correlates governed by the Mx1 protein that critically determine disease outcome during lethal AI virus infection.

Original languageEnglish
Pages (from-to)1308-1321
Number of pages14
JournalAmerican Journal of Pathology
Volume182
Issue number4
DOIs
Publication statusPublished - 2013 Apr

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Song, M. S., Cho, Y. H., Park, S. J., Pascua, P. N. Q., Baek, Y. H., Kwon, H. I., Lee, O. J., Kong, B. W., Kim, H., Shin, E. C., Kim, C. J., & Choi, Y. K. (2013). Early regulation of viral infection reduces inflammation and rescues Mx-positive mice from lethal avian influenza infection. American Journal of Pathology, 182(4), 1308-1321. https://doi.org/10.1016/j.ajpath.2012.12.022