Abstract
The Flaviviridae family comprises a number of human pathogens, which, although sharing structural and functional features, cause diseases with very different outcomes. This can be explained by the plurality of functions exerted by the few proteins coded by viral genomes, with some of these functions shared among members of a same family, but others being unique for each virus species. These non-canonical functions probably have evolved independently and may serve as the base to the development of specific therapies for each of those diseases. Here it is discussed what is currently known about the non-canonical roles of dengue virus (DENV) non-structural proteins (NSPs), which may account for some of the effects specifically observed in DENV infection, but not in other members of the Flaviviridae family. This review explores how DENV NSPs contributes to the physiopathology of dengue, evasion from host immunity, metabolic changes, and redistribution of cellular components during infection.
Highlights
A large set of arthropod-borne diseases is caused by enveloped viruses of the Flaviviridae family, which includes dengue virus (DENV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), West Nile virus (WNV), Zika virus (ZIKV), and about 70 other members
Most of these non-structural proteins (NSPs) canonical functions are related to viral replication, which depends on the assembly of a membrane-bound multi-protein replication complex (RC) [11,12,13,14], formed by the association of different NSPs with host co-factors on interconnected lipid vesicles derived from the endoplasmic reticulum (ER) [12,13,15,16]
NS4B interacts with STAT1, blocking its phosphorylation, and NS5 mediates STAT2 degradation, so both proteins inhibit the expression of IFN-stimulated genes (ISGs) by interfering in IFN-stimulated response elements (ISRE) activation
Summary
A large set of arthropod-borne diseases is caused by enveloped viruses of the Flaviviridae family, which includes dengue virus (DENV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), West Nile virus (WNV), Zika virus (ZIKV), and about 70 other members. A number of dengue vaccines have been developed, some being in clinical trials, they have shown to be limited with regard to low immunogenicity and partial protection against different DENV serotypes [7]. Among these vaccines, Dengvaxia (developed by Sanofi Pasteur, Lyon, France) has been licensed in several countries, but it is still a matter of concern due to the reported low protection against DENV serotype 2, associated with an increased incidence of hospitalization due to severe dengue of seronegative individuals in the third year after the first dose [7,8]. While vaccination strategies are in development and improvement stages, dengue treatment is still mainly based on supportive clinical interventions that do not always prevent the evolution to the severe forms of the disease [9,10]
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