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Lanosterol Synthase Regulates Human Rhinovirus Replication in Human Bronchial Epithelial Cells

Journal article
Authors Cristopher McCrae
A. Dzgoev
Marcus Ståhlman
J. Horndahl
R. Svard
A. Grosse
T. Grosskopf
M. A. Skujat
N. Williams
S. Schubert
C. Echeverri
C. Jackson
A. Guedan
R. Solari
O. Vaarala
M. Kraan
Madeleine Rådinger
Published in American Journal of Respiratory Cell and Molecular Biology
Volume 59
Issue 6
Pages 713-722
ISSN 1044-1549
Publication year 2018
Published at Krefting Research Centre
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 713-722
Language en
Links dx.doi.org/10.1165/rcmb.2017-0438OC
Keywords rhinovirus, lanosterol synthase, asthma, chronic obstructive pulmonary disease, host-pathogen, respiratory syncytial virus, disease virus, cholesterol, asthma, cyclase, 24(s),25-epoxycholesterol, exacerbations, inhibitors, infection, membrane
Subject categories Respiratory Medicine and Allergy

Abstract

Human 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-beta. 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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