tetano
Editor, Senior Moderator
J Virol. 2015 Jul 8. pii: JVI.00996-15. [Epub ahead of print]
[h=1]Human and murine IFIT1 do not restrict infection of negative sense RNA viruses of the orthomyxoviridae, bunyaviridae, and filoviridae families.[/h] Pinto AK[SUP]1[/SUP], Williams GD[SUP]1[/SUP], Szretter KJ[SUP]1[/SUP], White JP[SUP]1[/SUP], Proen?a-M?dena JL[SUP]2[/SUP], Liu G[SUP]3[/SUP], Olejnik J[SUP]4[/SUP], Brien JD[SUP]1[/SUP], Ebihara H[SUP]5[/SUP], M?hlberger E[SUP]4[/SUP], Amarasinghe G[SUP]3[/SUP], Diamond MS[SUP]6[/SUP], Boon AC[SUP]7[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Interferon (IFN)-induced protein with tetratricopeptide repeats 1 (IFIT1) is a host gene with reported cell-intrinsic antiviral activity against several RNA viruses. The proposed basis for the activity against negative sense RNA viruses is the binding to exposed 5' -triphosphate (5' -ppp) on the genome of viral RNA. However, recent studies reported relatively low binding affinities of IFIT1 for 5' -ppp-RNA, suggesting that IFIT1 may not interact efficiently with this moiety under physiological conditions. To evaluate the ability of IFIT1 to impact negative sense RNA viruses, we infected Ifit1[SUP]-/-[/SUP] and control wild-type mice and primary cells with four negative sense RNA viruses (influenza A virus (IAV), La Crosse virus (LACV), Oropouche virus (OROV), and Ebola virus) corresponding to three distinct families. Unexpectedly, a lack of Ifit1 gene expression did not result in increased infection of any of these viruses in cell culture. Analogously, morbidity, mortality, and viral burden in tissues were identical between Ifit1[SUP]-/-[/SUP] and control mice after infection with IAV, LACV, or OROV. Finally, deletion of human IFIT1 protein in A549 cells did not affect IAV replication or infection and reciprocally, ectopic expression of IFIT1 in HEK293T cells did not inhibit IAV infection. To explain the lack of antiviral activity against IAV, we measured the binding affinity of IFIT1 for RNA oligonucleotides resembling the 5' -end of IAV gene-segments. The affinity for 5' -ppp-RNA was approximately 10-fold lower compared to that of non-2' -O-methylated cap 0-RNA oligonucleotides. Based on this analysis, we conclude that IFIT1 is not a dominant restriction factor against negative sense RNA viruses.
[h=4]IMPORTANCE:[/h] Negative sense RNA viruses including Influenza and Ebola are responsible for some of the most deadly outbreaks in recent history. The host interferon response and induction of antiviral genes contributes to the control of infection by these viruses. IFIT1 is highly induced after virus infection and reportedly has antiviral activity against several RNA and DNA viruses. However, its role in restricting infection by negative sense RNA viruses remains unclear. Here, we evaluated the ability of IFIT1 to inhibit negative sense RNA virus replication and pathogenesis both in vitro and in vivo. Detailed cell culture and animal studies demonstrate that that IFIT1 is not a dominant restriction factor against three different families of negative sense RNA viruses.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 26157117 [PubMed - as supplied by publisher]
[h=1]Human and murine IFIT1 do not restrict infection of negative sense RNA viruses of the orthomyxoviridae, bunyaviridae, and filoviridae families.[/h] Pinto AK[SUP]1[/SUP], Williams GD[SUP]1[/SUP], Szretter KJ[SUP]1[/SUP], White JP[SUP]1[/SUP], Proen?a-M?dena JL[SUP]2[/SUP], Liu G[SUP]3[/SUP], Olejnik J[SUP]4[/SUP], Brien JD[SUP]1[/SUP], Ebihara H[SUP]5[/SUP], M?hlberger E[SUP]4[/SUP], Amarasinghe G[SUP]3[/SUP], Diamond MS[SUP]6[/SUP], Boon AC[SUP]7[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Interferon (IFN)-induced protein with tetratricopeptide repeats 1 (IFIT1) is a host gene with reported cell-intrinsic antiviral activity against several RNA viruses. The proposed basis for the activity against negative sense RNA viruses is the binding to exposed 5' -triphosphate (5' -ppp) on the genome of viral RNA. However, recent studies reported relatively low binding affinities of IFIT1 for 5' -ppp-RNA, suggesting that IFIT1 may not interact efficiently with this moiety under physiological conditions. To evaluate the ability of IFIT1 to impact negative sense RNA viruses, we infected Ifit1[SUP]-/-[/SUP] and control wild-type mice and primary cells with four negative sense RNA viruses (influenza A virus (IAV), La Crosse virus (LACV), Oropouche virus (OROV), and Ebola virus) corresponding to three distinct families. Unexpectedly, a lack of Ifit1 gene expression did not result in increased infection of any of these viruses in cell culture. Analogously, morbidity, mortality, and viral burden in tissues were identical between Ifit1[SUP]-/-[/SUP] and control mice after infection with IAV, LACV, or OROV. Finally, deletion of human IFIT1 protein in A549 cells did not affect IAV replication or infection and reciprocally, ectopic expression of IFIT1 in HEK293T cells did not inhibit IAV infection. To explain the lack of antiviral activity against IAV, we measured the binding affinity of IFIT1 for RNA oligonucleotides resembling the 5' -end of IAV gene-segments. The affinity for 5' -ppp-RNA was approximately 10-fold lower compared to that of non-2' -O-methylated cap 0-RNA oligonucleotides. Based on this analysis, we conclude that IFIT1 is not a dominant restriction factor against negative sense RNA viruses.
[h=4]IMPORTANCE:[/h] Negative sense RNA viruses including Influenza and Ebola are responsible for some of the most deadly outbreaks in recent history. The host interferon response and induction of antiviral genes contributes to the control of infection by these viruses. IFIT1 is highly induced after virus infection and reportedly has antiviral activity against several RNA and DNA viruses. However, its role in restricting infection by negative sense RNA viruses remains unclear. Here, we evaluated the ability of IFIT1 to inhibit negative sense RNA virus replication and pathogenesis both in vitro and in vivo. Detailed cell culture and animal studies demonstrate that that IFIT1 is not a dominant restriction factor against three different families of negative sense RNA viruses.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 26157117 [PubMed - as supplied by publisher]