Abstract
Human respiratory syncytial virus (HRSV) infection is a common cause of severe lower respiratory tract diseases such as bronchiolitis and pneumonia. Both virus replication and the associated inflammatory immune response are believed to be behind these pathologies. So far, no vaccine or effective treatment is available for this viral infection. With the aim of finding new strategies to counteract HRSV replication and modulate the immune response, specific small interfering RNAs (siRNAs) were generated targeting the mRNA coding for the viral fusion (F) protein or nucleoprotein (N), or for two proteins involved in intracellular immune signaling, which are named tripartite motif-containing protein 25 (TRIM25) and retinoic acid-inducible gene-I (RIG-I). Furthermore, two additional bispecific siRNAs were designed that silenced F and TRIM25 (TRIM25/HRSV-F) or N and RIG-I (RIG-I/HRSV-N) simultaneously. All siRNAs targeting N or F, but not those silencing TRIM25 or RIG-I alone, significantly reduced viral titers. However, while siRNAs targeting F inhibited only the expression of the F mRNA and protein, the siRNAs targeting N led to a general inhibition of viral mRNA and protein expression. The N-targeting siRNAs also induced a drastic decrease in the expression of genes of the innate immune response. These results show that both virus replication and the early innate immune response can be regulated by targeting distinct viral products with siRNAs, which may be related to the different role of each protein in the life cycle of the virus.
Highlights
Human respiratory syncytial virus (HRSV) is an enveloped, single-stranded, negative-sense RNA virus belonging to the Orthopneumovirus genus within the Pneumoviridae family, whose genome contains10 genes encoding 11 proteins [1,2]
Alignment of the Human Respiratory Syncytial Virus Genome with Innate Immune Genes and Selection of Bispecific Small Interfering RNAs. Since both virus replication and an inadequate inflammatory response seem to contribute to the severe pathology caused by HRSV, we wondered if it would be possible to design simple molecules to have an effect on the two processes at the same time
Pairwise alignment was performed between the HRSV genome and mRNAs from different genes involved in the regulation of intracellular immune pathways
Summary
Human respiratory syncytial virus (HRSV) is an enveloped, single-stranded, negative-sense RNA virus belonging to the Orthopneumovirus genus within the Pneumoviridae family, whose genome contains. genes encoding proteins [1,2]. Three of them (F, G, and SH) are glycoproteins inserted in the viral envelope. F and G are involved in virus attachment and entry into target cells, while the role of SH is less clear. Five proteins (N, P, L, M2-1, and M2-2) are involved in viral RNA replication and transcription. An additional structural protein (M) forms a protein layer under the viral envelope and participates in virus maturation. Two non-structural proteins (NS1 and NS2) have been implicated in counteracting the host immune response to HRSV infection [3,4]
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