Melnichuk N. Effect of oligoribonucleotides on infectivity of influenza virus in vitro and іnfluenza-induced expression of innate immunity genes in vivo

The manuscript is dedicated to the study of possible inhibition of influenza virus infectivity by interaction of the ORNs with HA and prevention of the overexpression of the innate immunity genes in response to the influenza virus infection by the ORNs. For the first time, it has been shown, that the ORNs have the direct virucidal action on the influenza virus A/FM/1/47/H1N1, which manifested in the suppression of the cytopathic action of the influenza virus in MDCK cells. It was also found that ORNs and ORNs-D-M reduce the virus infectivity and have an inhibitory effect on the binding of influenza HA proteins to sialic acid residues of erythrocyte glycans. Experiments with isolated HA demonstrated the interaction between HA and ORNs, ORNs-D-M with a quite low affinity, which leads to the inhibition of HA activity. It was found out that the influenza virus A/FM/1/47/H1N1 causes hyperexpression mRNA of innate immunity genes (Xdh, Nos2, Arg2, Oas1α, Oas2, Oas3, Mx1, Eif2αk2, Ifnε, Ifnk, Ifnα2, Ifnβ1, Ifnγ, Ccl3, Ccl4, Ccl5, Cxcl9, Cxcl10, Cxcl11, Il6, Il1β, Il12α, Tnfα, Nfkb1, Nfkbia, Tlr3, Tlr7 та Тlr8) in the lungs tissue of BALB/c mice. Up-regulation of Ifnε and Ifnk mRNA expression in lung tissues of influenza-infected mice was determined for the first time. Both prevention and treatment of the influenza infection with the ORNs and ORNs-D-M decrease the mRNA levels of the innate immunity genes, whose transcription was induced by the influenza virus. The attenuated upregulation of the innate immunity genes (Nfkb1, Nfkbia, Xdh, Nos2) by the therapeutic ORNs was also observed at the translational level. It has been suggested that the ORNs and ORNs-D-M inhibit the overexpression mRNA of the Tlr3, Tlr7, Tlr8 that leads to suppression of the up-regulation of TLR-stimulated innate immune genes during influenza in the mice lungs. The natural ORNs inhibit the infectivity of the influenza virus by interaction with the HA and modulate the innate immune response to the influenza virus infection by interaction with the TLR-3, TLR-7, TLR-8.