title: Differential microRNA expression following infection with a mouse-adapted, highly virulent avian H5N2 virus.
abstract: BACKGROUND
  MicroRNAs (miRNAs) are known to regulate various biological processes, including expression of cellular gene and virus-induced inflammation. Recently, studies have indicated that some miRNAs could regulate influenza virus replication. Due to differential sensitivities of influenza A virus strains to different species (avian and mammalian), variations in host responses may be observed. Therefore, we investigated and compared the differences in global host miRNA expression in mouse lungs infected with wild type low pathogenicity A/Aquatic bird/Korea/w81/2005 (H5N2) (w81) or mouse-adapted virulent A/Aquatic bird /Korea/ma81/2007 (H5N2) (ma81) virus.
  
  
  RESULTS
  Although the mice infected with ma81 exhibited much greater mortality than w81-infected mice, the parental w81 virus induced a higher number of differentially expressed miRNAs compared to the ma81 virus. Between these 2 viruses, a total of 27 and 20 miRNAs were commonly expressed at 1 dpi and 3 dpi, respectively. It is noteworthy that only 9 miRNAs (miR-100-5p, miR-130a-5p, miR-146b-3p, miR-147-3p, miR-151-5p, miR-155-3p, miR-223-3p, miR-301a-3p, and miR-495-3p) were significantly upregulated in both lungs infected with either wild type w81 or the mouse-adapted ma81 strain at both time points. Notably, expression levels of miR-147-3p, miR-151-5p, miR-155-3p, and miR-223-3p were higher in the lungs of mice infected with the ma81 virus than those infected with the w81 virus. To identify potential roles of these miRNAs in regulating influenza virus replication, each group of mice was intranasally treated with each inhibitor of specifically targeting 4 miRNAs, and then challenged with 5 mouse lethal dose 50% (MLD50) of the virulent ma81 virus on the following day. Although the specific miRNA inhibitors could not completely attenuate mortality or reduce viral replication, the miR-151-5p- and miR-223-3p-inhibitors reduced mortality of inoculated mice to 70% and substantially delayed death.
  
  
  CONCLUSIONS
  Our results suggest that the mammalian adaptation of avian influenza A virus results in a different miRNA expression pattern in lungs of virus-infected mice compared with its parental strain, and use of specific miRNA inhibitors to target genes associated with the immune response or cell death may affect virulence and virus replication.
authors.forename: Eun-Ji
authors.initials: EJ
authors.lastname: Choi
authors.forename: Hyeun Bum
authors.initials: HB
authors.lastname: Kim
authors.forename: Yun Hee
authors.initials: YH
authors.lastname: Baek
authors.forename: Eun-Ha
authors.initials: EH
authors.lastname: Kim
authors.forename: Philippe Noriel Q
authors.initials: PN
authors.lastname: Pascua
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Park
authors.forename: Hyeok-Il
authors.initials: HI
authors.lastname: Kwon
authors.forename: Gyo-Jin
authors.initials: GJ
authors.lastname: Lim
authors.forename: Semi
authors.initials: S
authors.lastname: Kim
authors.forename: Young-Il
authors.initials: YI
authors.lastname: Kim
authors.forename: Young-Ki
authors.initials: YK
authors.lastname: Choi
mesh_terms: D000818:Animals; D015870:Gene Expression / Q000502:physiology*; D020869:Gene Expression Profiling / Q000379:methods; D007249:Inflammation / Q000235:genetics / Q000821:virology; D053125:Influenza A Virus, H5N2 Subtype; D008168:Lung / Q000821:virology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009976:Orthomyxoviridae Infections / Q000235:genetics*; D014774:Virulence / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
chemical_list: D035683:MicroRNAs