tetano
Editor, Senior Moderator
J Virol. 2015 May 27. pii: JVI.00845-15. [Epub ahead of print]
[h=1]Sequence-specific modifications enhance the broad spectrum antiviral response activated by RIG-I agonists.[/h] Chiang C[SUP]1[/SUP], Beljanski V[SUP]1[/SUP], Yin K[SUP]1[/SUP], Olagnier D[SUP]2[/SUP], Ben Yebdri F[SUP]3[/SUP], Steel C[SUP]1[/SUP], Goulet ML[SUP]3[/SUP], DeFilippis VR[SUP]4[/SUP], Streblow DN[SUP]4[/SUP], Haddad EK[SUP]1[/SUP], Trautmann L[SUP]1[/SUP], Ross T[SUP]1[/SUP], Lin R[SUP]3[/SUP], Hiscott J[SUP]5[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] The cytosolic RIG-I receptor plays a pivotal role in the initiation of the immune response against RNA virus infection by recognizing short 5' -triphosphate (5' ppp) containing viral RNA and activating the host antiviral innate response. In the present study, we generated novel 5' ppp RIG-I agonists of varied length, structure, and sequence and evaluated the generation of the antiviral and inflammatory response in human epithelial A549 cells, human innate immune primary cells, and murine models of influenza and chikunguna viral pathogenesis. A 99 nucleotide, uridine-rich, hairpin 5' -pppRNA termed M8 stimulated an extensive and robust interferon response compared to other modified 5' pppRNA structures, RIG-I aptamers, or poly (I:C). Interestingly, manipulation of the primary RNA sequence alone was sufficient to modulate antiviral activity and inflammatory response, in a manner dependent exclusively on RIG-I, and independent of MDA5 and TLR3. Both prophylactic and therapeutic administration of M8 effectively inhibited influenza and dengue viral replication in vitro. Furthermore, multiple strains of influenza virus that were resistant to oseltamivir, an FDA-approved therapeutic treatment for influenza, were highly sensitive to inhibition by M8. Finally, prophylactic M8 treatment in vivo prolonged survival and reduced lung viral titers of mice challenged with influenza, as well as reduced chikungunya-associated foot swelling and viral load. Altogether, these results demonstrate that 5' pppRNA can be rationally designed to achieve a maximal RIG-I-mediated protective antiviral response against human pathogenic RNA viruses.
[h=4]IMPORTANCE:[/h] The development of novel therapeutics to treat human pathogenic RNA viral infections is an important goal that seeks to reduce spread of infection and to improve human health and safety. This study investigated the design of an RNA agonist with enhanced antiviral and inflammatory properties against influenza, dengue, and chikungunya viruses. A novel, sequence-dependent, uridine-rich RIG-I agonist generated a protective antiviral response in vitro and in vivo and was effective at concentrations 100-fold lower than prototype sequences or other RNA agonists, highlighting the robust activity and potential clinical use of the 5' pppRNA against RNA virus infection. Altogether, the results identify a novel, sequence-specific RIG-I agonist as an attractive therapeutic candidate for the treatment of a broad range of RNA viruses, a pressing issue in which a need for new and more effective options persists.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 26018150 [PubMed - as supplied by publisher]
[h=1]Sequence-specific modifications enhance the broad spectrum antiviral response activated by RIG-I agonists.[/h] Chiang C[SUP]1[/SUP], Beljanski V[SUP]1[/SUP], Yin K[SUP]1[/SUP], Olagnier D[SUP]2[/SUP], Ben Yebdri F[SUP]3[/SUP], Steel C[SUP]1[/SUP], Goulet ML[SUP]3[/SUP], DeFilippis VR[SUP]4[/SUP], Streblow DN[SUP]4[/SUP], Haddad EK[SUP]1[/SUP], Trautmann L[SUP]1[/SUP], Ross T[SUP]1[/SUP], Lin R[SUP]3[/SUP], Hiscott J[SUP]5[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] The cytosolic RIG-I receptor plays a pivotal role in the initiation of the immune response against RNA virus infection by recognizing short 5' -triphosphate (5' ppp) containing viral RNA and activating the host antiviral innate response. In the present study, we generated novel 5' ppp RIG-I agonists of varied length, structure, and sequence and evaluated the generation of the antiviral and inflammatory response in human epithelial A549 cells, human innate immune primary cells, and murine models of influenza and chikunguna viral pathogenesis. A 99 nucleotide, uridine-rich, hairpin 5' -pppRNA termed M8 stimulated an extensive and robust interferon response compared to other modified 5' pppRNA structures, RIG-I aptamers, or poly (I:C). Interestingly, manipulation of the primary RNA sequence alone was sufficient to modulate antiviral activity and inflammatory response, in a manner dependent exclusively on RIG-I, and independent of MDA5 and TLR3. Both prophylactic and therapeutic administration of M8 effectively inhibited influenza and dengue viral replication in vitro. Furthermore, multiple strains of influenza virus that were resistant to oseltamivir, an FDA-approved therapeutic treatment for influenza, were highly sensitive to inhibition by M8. Finally, prophylactic M8 treatment in vivo prolonged survival and reduced lung viral titers of mice challenged with influenza, as well as reduced chikungunya-associated foot swelling and viral load. Altogether, these results demonstrate that 5' pppRNA can be rationally designed to achieve a maximal RIG-I-mediated protective antiviral response against human pathogenic RNA viruses.
[h=4]IMPORTANCE:[/h] The development of novel therapeutics to treat human pathogenic RNA viral infections is an important goal that seeks to reduce spread of infection and to improve human health and safety. This study investigated the design of an RNA agonist with enhanced antiviral and inflammatory properties against influenza, dengue, and chikungunya viruses. A novel, sequence-dependent, uridine-rich RIG-I agonist generated a protective antiviral response in vitro and in vivo and was effective at concentrations 100-fold lower than prototype sequences or other RNA agonists, highlighting the robust activity and potential clinical use of the 5' pppRNA against RNA virus infection. Altogether, the results identify a novel, sequence-specific RIG-I agonist as an attractive therapeutic candidate for the treatment of a broad range of RNA viruses, a pressing issue in which a need for new and more effective options persists.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 26018150 [PubMed - as supplied by publisher]