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Lanosterol Synthase...
Lanosterol Synthase Regulates Human Rhinovirus Replication in Human Bronchial Epithelial Cells
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- McCrae, Cristopher (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Krefting Research Centre,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
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Dzgoev, A. (author)
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- Ståhlman, Marcus, 1975 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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Horndahl, J. (author)
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Svard, R. (author)
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Grosse, A. (author)
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Grosskopf, T. (author)
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Skujat, M. A. (author)
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Williams, N. (author)
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Schubert, S. (author)
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Echeverri, C. (author)
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Jackson, C. (author)
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Guedan, A. (author)
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Solari, R. (author)
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Vaarala, O. (author)
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Kraan, M. (author)
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- Rådinger, Madeleine, 1967 (author)
- Gothenburg University,Göteborgs universitet,Krefting Research Centre,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
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(creator_code:org_t)
- 2018
- 2018
- English.
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In: American Journal of Respiratory Cell and Molecular Biology. - 1044-1549. ; 59:6, s. 713-722
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Lungmedicin och allergi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Respiratory Medicine and Allergy (hsv//eng)
Keyword
- 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
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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McCrae, Cristoph ...
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Dzgoev, A.
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Ståhlman, Marcus ...
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Horndahl, J.
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Svard, R.
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Grosse, A.
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show more...
-
Grosskopf, T.
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Skujat, M. A.
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Williams, N.
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Schubert, S.
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Echeverri, C.
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Jackson, C.
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Guedan, A.
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Solari, R.
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Vaarala, O.
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Kraan, M.
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Rådinger, Madele ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Respiratory Medi ...
- Articles in the publication
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American Journal ...
- By the university
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University of Gothenburg