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United States Department of Agriculture

Agricultural Research Service

Research Project: Intervention Strategies to Control and Prevent Disease Outbreaks Caused by Avian Influenza and Other Emerging Poultry Pathogens

Location: Exotic and Emerging Avian Viral Diseases Research Unit

Title: Implication of inflammatory macrophages, nuclear receptors and interferon regulatory factors in increased virulence of pandemic 2009 H1N1 influenza a virus after host adaptation

Authors
item Josset, Laurence -
item Belser, Jessica -
item Chang, Jean -
item Pantin-Jackwood, Mary
item Chang, Stewart -
item Belisle, Sarah -
item Tumpey, Terrence -
item Katze, Michael -

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: April 13, 2012
Publication Date: July 15, 2012
Citation: Josset, L., Belser, J., Chang, J., Pantin Jackwood, M.J., Chang, S., Belisle, S., Tumpey, T.M., Katze, M.G. 2012. Implication of inflammatory macrophages, nuclear receptors and interferon regulatory factors in increased virulence of pandemic 2009 H1N1 influenza a virus after host adaptation. Journal of Virology. 86:7192-7206.

Interpretive Summary: The pandemic 2009 H1N1 influenza A viruses caused many severe infections in humans; however, these viruses do not usually cause a severe disease in mice, which are used as a model to study influenza. A virulent 2009 H1N1 virus obtained by serially infecting mice was used for examining the pathology caused by this virus in lungs. The host responses following infection with this adapted virus were studied. Microarray analysis revealed that increased pathogenicity of MA CA/04 was associated with: 1) early and sustained inflammatory and interferon response; 2) early and persistent infiltration of immune cells, including inflammatory macrophages; and 3) the absence of activation of lipid metabolism later in infection, with pro inflammatory consequences. Further investigation of these host responses to other H1N1 viruses of varied pathogenicity confirmed their general relevance for virulence of influenza virus. This study links for the first time differential host immune responses with influenza virulence in vivo.

Technical Abstract: While pandemic 2009 H1N1 influenza A viruses were responsible for numerous severe infections in humans, these viruses do not typically cause corresponding severe disease in mammalian models. However, the generation of a virulent 2009 H1N1 virus following serial lung passage in mice has allowed for the modeling of human lung pathology in this species. Genetic determinants of mouse-adapted 2009 H1N1 viral pathogenicity have been identified, but the molecular and signaling characteristics of the host response following infection with this adapted virus have not been described. Here, we compared the gene-expression response following infection of mice with A/CA/04/2009 (CA/04) or the virulent mouse-adapted strain (MA-CA/04). Microarray analysis revealed that increased pathogenicity of MA CA/04 was associated with: 1) early and sustained inflammatory and interferon response that could be driven in part by interferon regulatory factors (IRFs) and increased nuclear factor kappa B (NFKB) activation, as well as inhibition of the negative regulator tripartite motif-containing 24 (TRIM24); 2) early and persistent infiltration of immune cells, including inflammatory macrophages; and 3) the absence of activation of lipid metabolism later in infection, that may be mediated by nuclear receptors inhibition, with pro inflammatory consequences. Further investigation of these signatures in the host response to other H1N1 viruses of varied pathogenicity confirmed their general relevance for virulence of influenza virus and suggested that lung response to MA-CA/04 virus was similar to that following lethal H1N1 r1918 influenza virus. This study links for the first time differential activation of IRFs, nuclear receptors, and macrophage infiltration with influenza virulence in vivo.

Last Modified: 8/22/2014
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