The role of interferon in influenza virus tissue tropism.
We have studied the pathogenesis of influenza virus infection in mice that are unable to respond to type I or II interferons due to a targeted disruption of the STAT1 gene. STAT1-/- animals are 100-fold more sensitive to lethal infection with influenza A/WSN/33 virus than are their wild-type (WT) counterparts. Virus replicated only in the lungs of WT animals following intranasal (i.n.) virus inoculation, while STAT1-/- mice developed a fulminant systemic influenza virus infection following either i.n. or intraperitoneal inoculation. We investigated the mechanism underlying this altered virus tropism by comparing levels of virus replication in fibroblast cell lines and murine embryonic fibroblasts derived from WT mice, STAT-/- mice, and mice lacking gamma interferon (IFNgamma-/- mice) or the IFN-alpha receptor (IFNalphaR-/- mice). Influenza A/WSN/33 virus replicates to high titers in STAT1-/- or IFNalphaR-/- fibroblasts, while cells derived from WT or IFNgamma-/- animals are resistant to influenza virus infection. Immunofluorescence studies using WT fibroblast cell lines demonstrated that only a small subpopulation of WT cells can be infected and that in the few infected WT cells, virus replication is aborted at an early, nuclear phase. In all organs examined except the lung, influenza A WSN/33 virus infection is apparently prevented by an intact type I interferon response. Our results demonstrate that type I interferon plays an important role in determining the pathogenicity and tissue restriction of influenza A/WSN/33 virus in vivo and in vitro.
Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA.
A
A
García-Sastre
R K
RK
Durbin
H
H
Zheng
P
P
Palese
R
R
Gertner
D E
DE
Levy
J E
JE
Durbin
D000281:Administration, Intranasal; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D006389:Hemagglutinins, Viral / Q000502:physiology; D009980:Influenza A virus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity; D009976:Orthomyxoviridae Infections / Q000209:etiology* / Q000276:immunology / Q000821:virology*; D012367:RNA, Viral / Q000235:genetics; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000235:genetics / Q000502:physiology; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D014779:Virus Replication / Q000276:immunology
D017931:DNA Primers; D004268:DNA-Binding Proteins; D006389:Hemagglutinins, Viral; D012367:RNA, Viral; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D053633:Receptor, Interferon alpha-beta; D007371:Interferon-gamma