Chun-Kuang Lin1, Chin-Kai Tseng2, Yu-Hsuan Wu2, Chun-Yu Lin3,4, Chung-Hao Huang3,4, Weng-Hung Wang3, Chih-Chuang Liaw1,5, Yen-Hsu Chen3,4,6,7, Jin-Ching Lee8,9,10,11. 1. Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung, Taiwan. 2. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 3. Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Taiwan. 4. School of Medicine, Graduate Institute of Medicine, Sepsis Research Center, Center for Dengue Fever Control and Research, Kaohsiung Medical University, Taiwan. 5. Department of Marine Biotechnology and Resources, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung. 6. Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, HsinChu. 7. Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Taiwan. 8. Department of Medical Research, Kaohsiung Medical University Hospital, Taiwan. 9. Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Taiwan. 10. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Taiwan. 11. PhD program in Life Sciences, College of Life Science, Kaohsiung Medical University, Taiwan.
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.
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 DENVinfection. METHODS: Next-generation sequencing analysis revealed that prostasin expression was decreased upon DENVinfection. 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. DENVinfection 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 DENVinfection.
Authors: Jasmine Moshiri; David A Constant; Bowen Liu; Roberto Mateo; Steven Kearnes; Paul Novick; Ritika Prasad; Claude Nagamine; Vijay Pande; Karla Kirkegaard Journal: mBio Date: 2020-11-10 Impact factor: 7.867