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Implication of inflammatory macrophages, nuclear receptors, and interferon
regulatory factors in increased virulence of pandemic 2009 H1N1 influenza A virus
after host adaptation
#MMPMID22532695
Josset L
; Belser JA
; Pantin-Jackwood MJ
; Chang JH
; Chang ST
; Belisle SE
; Tumpey TM
; Katze MG
J Virol
2012[Jul]; 86
(13
): 7192-206
PMID22532695
show ga
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-?B 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.
|Adaptation, Biological
[MESH]
|Animals
[MESH]
|Disease Models, Animal
[MESH]
|Female
[MESH]
|Gene Expression Profiling
[MESH]
|Influenza A Virus, H1N1 Subtype/*immunology/*pathogenicity
[MESH]
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