Article ; Online: Implication of inflammatory macrophages, nuclear receptors, and interferon regulatory factors in increased virulence of pandemic 2009 H1N1 influenza A virus after host adaptation.
2012 Volume 86, Issue 13, Page(s) 7192–7206
Abstract: ... nuclear receptors, and macrophage infiltration with influenza virulence in vivo. ... by interferon regulatory factors (IRFs) and increased NF-κB activation, as well as inhibition of the negative regulator TRIM24, (ii ... relevance for virulence of influenza virus and suggested that lung response to MA-CA/04 virus was similar ...
| 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 the following: (i) an early and sustained inflammatory and interferon response that could be driven in part by interferon regulatory factors (IRFs) and increased NF-κB activation, as well as inhibition of the negative regulator TRIM24, (ii) early and persistent infiltration of immune cells, including inflammatory macrophages, and (iii) the absence of activation of lipid metabolism later in infection, which may be mediated by inhibition of nuclear receptors, including PPARG and HNF1A and -4A, with proinflammatory consequences. Further investigation of these signatures in the host response to other H1N1 viruses of various pathogenicities confirmed their general relevance for virulence of influenza virus and suggested that lung response to MA-CA/04 virus was similar to that following infection with lethal H1N1 r1918 influenza virus. This study links differential activation of IRFs, nuclear receptors, and macrophage infiltration with influenza virulence in vivo. |
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| MeSH term(s) | Adaptation, Biological ; Animals ; Disease Models, Animal ; Female ; Gene Expression Profiling ; Influenza A Virus, H1N1 Subtype/immunology ; Influenza A Virus, H1N1 Subtype/pathogenicity ; Interferon Regulatory Factors/immunology ; Lung/pathology ; Lung/virology ; Macrophages/immunology ; Mice ; Mice, Inbred BALB C ; Microarray Analysis ; Orthomyxoviridae Infections/immunology ; Orthomyxoviridae Infections/pathology ; Orthomyxoviridae Infections/virology ; Receptors, Cytoplasmic and Nuclear/immunology ; Serial Passage ; Virulence |
| Chemical Substances | Interferon Regulatory Factors ; Receptors, Cytoplasmic and Nuclear |
| Language | English |
| Publishing date | 2012-04-24 |
| Publishing country | United States |
| Document type | Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural |
| ZDB-ID | 80174-4 |
| ISSN | 1098-5514 ; 0022-538X |
| ISSN (online) | 1098-5514 |
| ISSN | 0022-538X |
| DOI | 10.1128/JVI.00563-12 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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