Dantrolene hinders dengue virus-induced upregulation and translocation of calmodulin to cardiac cell nuclei

Abstract

Dengue virus (DENV) infection elevates intracellular Ca²⁺ concentration ([Ca²⁺]_i), but it is unknown whether Ca²⁺ and calmodulin (CaM) are involved in DENV infection. We conducted immunofluorescence and western blot experiments and measured [Ca²⁺]_i examining the effects of DENV infection and drugs that alter Ca²⁺/CaM functions on CaM translocation, DENV2 infection, protein expression, virus-inducible STAT2 protein abundance, and CREB phosphorylation in H9c2 cells. DENV infection increased CaM expression, its nuclear translocation and NS3 and E viral proteins expression and colocalization in a manner that could be blocked by the ryanodine receptor antagonist dantrolene. DENV infection also increased CREB phosphorylation, an effect inhibited by either dantrolene or the CaM inhibitor W7. Dantrolene substantially hindered infection as assessed by focus assays in Vero cells. These results suggest that Ca²⁺ and CaM play an important role in DENV infection of cardiac cells and that dantrolene may protect against severe DENV cardiac morbidity.

Keywords: CREB; Calmodulin; Cardiac cells; Dantrolene; Dengue virus.