Vimentin Inhibits Dengue Virus Type 2 Invasion of the Blood-Brain Barrier

Abstract

Dengue virus (DENV) causes dengue fever, which is prevalent in the tropical and subtropical regions, and in recent years, has resulted in several major epidemics. Vimentin, a cytoskeletal component involved in DENV infection, is significantly reorganized during infection. However, the mechanism underlying the association between DENV infection and vimentin is still poorly understood. We generated vimentin-knockout (Vim-KO) human brain microvascular endothelial cells (HBMECs) and a Vim-KO SV129 suckling mouse model, combining the dynamic vimentin changes observed in vitro and differences in disease course in vivo, to clarify the role of vimentin in DENV-2 infection. We found that the phosphorylation and solubility of vimentin changed dynamically during DENV-2 infection of HBMECs, suggesting the regulation of vimentin by DENV-2 infection. The similar trends observed in the phosphorylation and solubility of vimentin showed that these characteristics are related. Compared with that in control cells, the DENV-2 viral load was significantly increased in Vim-KO HBMECs, and after DENV-2 infection, Vim-KO SV129 mice displayed more severe disease signs than wild-type SV129 mice, as well as higher viral loads in their serum and brain tissue, demonstrating that vimentin can inhibit DENV-2 infection. Moreover, Vim-KO SV129 mice had more disordered cerebral cortical nerve cells, confirming that Vim-KO mice were more susceptible to DENV-2 infection, which causes severe brain damage. The findings of our study help clarify the mechanism by which vimentin inhibits DENV-2 infection and provides guidance for antiviral treatment strategies for DENV infections.

Potential therapeutic strategies to halt viral neuroinvasion

“…34 The enhancement of vimentin (a cellular cytoskeleton component) in ECs could also offer a therapeutic approach as the inhibition of vimentin in cultured human ECs or mice showed higher DENV loads in brain tissues and disordered cerebral cortex nerves. 35 The JEV-induced HMGB1 production in ECs is associated with the transmigration of infected monocytes across the ECs layer in an in vitro model of BBB, 36 suggesting blocking the release of HMGB1 as an alternative approach to protect CNS infections. Future studies are required to examine whether the harnessing of TAM receptors, vimentin, and HMGB1 offers protection against other neurotropic viruses in pre-clinical models.…”

“…Mice lacking Mertk and Axl showed enhanced entry by WNV and La Crosse virus into the brain associated with diminished expression of claudin‐5 and IFN‐beta in ECs 34 . The enhancement of vimentin (a cellular cytoskeleton component) in ECs could also offer a therapeutic approach as the inhibition of vimentin in cultured human ECs or mice showed higher DENV loads in brain tissues and disordered cerebral cortex nerves 35 . The JEV‐induced HMGB1 production in ECs is associated with the transmigration of infected monocytes across the ECs layer in an in vitro model of BBB, 36 suggesting blocking the release of HMGB1 as an alternative approach to protect CNS infections.…”