Antiviral therapeutic approaches for human rhinovirus infections

Casanova, Victor; Sousa, Filipa H; Stevens, Craig; Barlow, Peter G

Recent studies have shown that RV is detected by different sensors on or within the host cell; components of the capsid are detected by TLR2; ssRNA genome is detected by TLR7/8 and dsRNA generated during viral replication is detected by TLR3 in endosomes or RIG-I and MDA5 in the cytosol [105, 106] . TLR3 is constitutively expressed in lung epithelial cells, whereas RIG-I and MDA5 are upregulated in response to infection [107, 108] . Importantly, gene silencing any of the dsRNA sensors using siRNA reduces the cytokine response and increases RV replication, suggesting a coordinated role for multiple sensors in antiviral responses to RV [109] . In this context, mice lacking TLR3 exhibit higher loads of RNA viruses and decreased production of type I IFN compared with wild-type mice [110, 111] . Significantly, a case study reported that a child harboring a homozygous missense mutation in the gene IFIH1, which encodes for MDA5, was highly susceptible to recurrent and life-threatening RV infections [112] . This gene mutation resulted in failure to recognize MDA5-ligands associated with RV infection, leading to reduced IFN production and therefore increased susceptibility to RV.