Beyond the Surface: Endocytosis of Mosquito-Borne Flaviviruses

Abstract

Flaviviruses are a group of positive-sense RNA viruses that are primarily transmitted through arthropod vectors and are capable of causing a broad spectrum of diseases. Many of the flaviviruses that are pathogenic in humans are transmitted specifically through mosquito vectors. Over the past century, many mosquito-borne flavivirus infections have emerged and re-emerged, and are of global importance with hundreds of millions of infections occurring yearly. There is a need for novel, effective, and accessible vaccines and antivirals capable of inhibiting flavivirus infection and ameliorating disease. The development of therapeutics targeting viral entry has long been a goal of antiviral research, but most efforts are hindered by the lack of broad-spectrum potency or toxicities associated with on-target effects, since many host proteins necessary for viral entry are also essential for host cell biology. Mosquito-borne flaviviruses generally enter cells by clathrin-mediated endocytosis (CME), and recent studies suggest that a subset of these viruses can be internalized through a specialized form of CME that has additional dependencies distinct from canonical CME pathways, and antivirals targeting this pathway have been discovered. In this review, we discuss the role and contribution of endocytosis to mosquito-borne flavivirus entry as well as consider past and future efforts to target endocytosis for therapeutic interventions.

Tau seeds translocate across the cell membrane to initiate aggregation

“…Beginning with a CRISPR screen to find genes involved in uptake of tau fibrils, we identified a role for the v-ATPase protein pump, which was confirmed using Bafilomycin A1, a v-ATPase inhibitor. Our top hit for the CRISPR screen was RNAseK, a v-ATPase associated factor that is required for the internalization of a diverse group of viruses, (Carro and Cherry, 2020; Hackett et al, 2015; Perreira et al, 2015; Zhang et al, 2017), indicating that v-ATPase disruption can be linked to endocytosis inhibition. However, we observed a paradoxical effect of increased seeding in the setting of v-ATPase inhibition.…”

Signaling events evoked by domain III of envelop glycoprotein of tick-borne encephalitis virus and West Nile virus in human brain microvascular endothelial cells

“…Two types of receptors have been described, the attachment factors and true receptors. Attachment factors bind to diverse moieties like phosphatidylserine and sugars on viral glycoprotein, while true receptors (entry factors) mediate interaction with viral proteins (protein E in case of flaviviruses) that leads to viral internalization 43 . In our study we looked at the expression of true receptors upon challenge with DIII of protein E. Amongst the true receptors supposed to be involved in flavivirus entry, the best characterized to date include TIM (T-cell immunoglobulin e.g.…”

Dengue Virus Infection: A Tale of Viral Exploitations and Host Responses

“…After binding to the cognate receptors of host cells, the virus is internalized into a clathrin-coated bubble-like structure, known as the endosome ( Figure 2 ). The virion is majorly found to be internalized into the early endosome having Rab5 and later either matures into or fuses with the pre-existing late endosome having Rab7 [ 12 ]. When the internalized virus experiences an acidic pH inside the endosome, the E protein (dimer) and PrM-E (trimer) undergo various conformational changes.…”