• Christopher McCrae, Anatoly Dzgoev, Marcus Ståhlman, Jenny Horndahl, Rebecka Svärd, Arend Große, Theresia Großkopf, Mary-Ann Skujat, Nicola Williams, Steffen Schubert, Christophe Echeverri, Clive Jackson, Anabel Guedán, Roberto Solari, Outi Vaarala, Maarten Kraan, and Madeleine Rådinger.
• 1 Respiratory Inflammation and Autoimmunity, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Gothenburg, Sweden.
• Am. J. Respir. Cell Mol. Biol. 2018 Dec 1; 59 (6): 713-722.

AbstractHuman rhinovirus (RV) infections are a significant risk factor for exacerbations of asthma and chronic obstructive pulmonary disease. Thus, approaches to prevent RV infection in such patients would give significant benefit. Through RNA interference library screening, we identified lanosterol synthase (LSS), a component of the cholesterol biosynthetic pathway, as a novel regulator of RV replication in primary normal human bronchial epithelial cells. Selective knock down of LSS mRNA with short interfering RNA inhibited RV2 replication in normal human bronchial epithelial cells. Small molecule inhibitors of LSS mimicked the effect of LSS mRNA knockdown in a concentration-dependent manner. We further demonstrated that the antiviral effect is not dependent on a reduction in total cellular cholesterol but requires a 24-hour preincubation with the LSS inhibitor. The rank order of antiviral potency of the LSS inhibitors used was consistent with LSS inhibition potency; however, all compounds showed remarkably higher potency against RV compared with the LSS enzyme potency. We showed that LSS inhibition led to an induction of 24(S),25 epoxycholesterol, an important regulator of the sterol pathway. We also demonstrated that LSS inhibition led to a profound increase in expression of the innate antiviral defense protein, IFN-β. We found LSS to be a novel regulator of RV replication and innate antiviral immunity and identified a potential molecular mechanism for this effect, via induction of 24(S),25 epoxycholesterol. Inhibition of LSS could therefore be a novel therapeutic target for prevention of RV-induced exacerbations.

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