Prostasin impairs epithelial growth factor receptor activation to suppress dengue virus propagation.

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 level were confirmed by RT-qPCR in patients with dengue fever and 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 glycosylphosphatidylinositol (GPI)-anchored membrane protease, in blood samples from patients with dengue fever compared with healthy individuals and revealed a high correlation between prostasin expression and DENV-2 RNA copy number. DENV infection significantly decreased prostasin RNA levels 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-B -mediated cyclooxygenase-2 signaling pathway.

Conclusion: Our results demonstrate prostasin expression as a noteworthy clinical feature and a potential therapeutic target against DENV infection.