Prostasin Impairs Epithelial Growth Factor Receptor Activation to Suppress Dengue Virus Propagation

• Published in: The Journal of infectious diseases Vol. 219; no. 9; pp. 1377 - 1388
• Main Authors: Lin, Chun-Kuang, Tseng, Chin-Kai, Wu, Yu-Hsuan, Lin, Chun-Yu, Huang, Chung-Hao, Wang, Weng-Hung, Liaw, Chih-Chuang, Chen, Yen-Hsu, Lee, Jin-Ching
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 16.04.2019
• Subjects: AKT protein; Animals; Cell Line; Chromones - pharmacology; Copy number; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Dengue - blood; Dengue fever; Dengue hemorrhagic fever; Dengue Virus - genetics; Dengue Virus - physiology; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Fibroblast growth factor 2; Growth factors; Humans; Infections; Inositol; Mice; Monocytes - metabolism; Morpholines - pharmacology; Next-generation sequencing; NF-κB protein; Patients; Polymerase chain reaction; Receptor mechanisms; Ribonucleic acid; RNA; RNA, Messenger - metabolism; RNA, Small Interfering - pharmacology; RNA, Viral; Sequence analysis; Serine Endopeptidases - blood; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Signal Transduction; Suckling behavior; Transfection; Virus Replication - genetics; epithelial growth factor receptor; Akt; prostasin; dengue virus; cyclooxygenase-2
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiy677

Abstract Background Dengue virus (DENV), a common and widely spread arbovirus, causes life-threatening diseases, such as dengue hemorrhagic fever or dengue shock syndrome. There is currently no effective therapeutic or preventive treatment for DENV infection. Methods Next-generation sequencing analysis revealed that prostasin expression was decreased upon DENV infection. Prostasin expression levels were confirmed by real-time quantitative polymerase chain reaction in patients with dengue fever and a DENV-infected mice model. Short hairpin RNA against EGFR and LY294002 were used to investigate the molecular mechanism. Results Based on clinical studies, we first found relatively low expression of prostasin, a glycosylphosphatidyl inositol-anchored membrane protease, in blood samples from patients with dengue fever compared with healthy individuals and a high correlation of prostasin expression and DENV-2 RNA copy number. DENV infection significantly decreased prostasin RNA levels of in vivo and in vitro models. By contrast, exogenous expression of prostasin could protect ICR suckling mice from life-threatening DENV-2 infection. Mechanistic studies showed that inhibition of DENV propagation by prostasin was due to reducing expression of epithelial growth factor receptor, leading to suppression of the Akt/NF-κB–mediated cyclooxygenase-2 signaling pathway. Conclusion Our results demonstrate that prostasin expression is a noteworthy clinical feature and a potential therapeutic target against DENV infection. Clinically, prostasin expression and DENV-2 RNA copy number showed a significant negative correlation. Prostasin overexpression reduced DENV-2 propagation in vivo and in vitro. The molecular mechanism of prostasin against DENV-2 was due to suppression of EGFR/Akt/NF-κB–mediated cyclooxygenase-2 expression.