Chikungunya virus perturbs the Wnt/β-catenin signaling pathway for efficient viral infection

Abstract

ABSTRACT Viruses use various strategies to modulate host pathways and take benefit of host machineries for efficient infection. It has been reported that certain viruses manipulate the Wnt/β-catenin pathway; however, its role in Chikungunya virus (CHIKV) infection has not yet been investigated. Hence, the focus of the current study was to evaluate the importance of the Wnt/β-catenin pathway in CHIKV infection using in vitro , in vivo , and ex vivo models. The study revealed that CHIKV infection suppressed the active β-catenin protein associated with Wnt/β-catenin signaling, which, in turn, led to the reduction of cyclin-D1 and upregulation of glycogen synthase kinase-3β. Inhibition of β-catenin by an inhibitor (iCRT14) showed a drastic reduction in the viral RNA, protein, and new viral particle formation in vitro . Next, it was found that β-catenin is important in different phases of viral life cycle. Notably, the treatment of CHIKV-infected C57BL/6 mice with this drug reduced the disease score substantially with a 91.7% decrease in the viral load. Similar result was observed in human peripheral blood mononuclear cell-derived monocyte-macrophage populations and in physiologically relevant cells like RAW264.7 and C2C12 cells. Additionally, knockdown of β-catenin by siRNA drastically reduced viral particle formation. Further investigation revealed that CHIKV-nsP2 interacts with β-catenin during CHIKV infection. In conclusion, this work demonstrated for the first time the mechanistic insights regarding the role of the Wnt/β-catenin pathway for CHIKV infection that might contribute to the designing of effective therapeutics for the control of this virus infection in future. IMPORTANCE Being obligate parasites, viruses use various host cell machineries in effectively replicating their genome, along with virus-encoded enzymes. In order to carry out infection and pathogenesis, viruses are known to manipulate fundamental cellular processes in cells and interfere with host gene expression. Several viruses interact with the cellular proteins involved in the Wnt/β-catenin pathway; however, reports regarding the involvement of protein components of the Wnt/β-catenin pathway in Chikungunya virus (CHIKV) infection are scarce. Additionally, there are currently no remedies or vaccines available for CHIKV. This is the first study to report that modulation of the Wnt/β-catenin pathway is crucial for effective CHIKV infection. These investigations deepen the understanding of the underlying mechanisms of CHIKV infection and offer new avenue for developing effective countermeasures to efficiently manage CHIKV infection.