Overview on Chikungunya Virus Infection: From Epidemiology to State-of-the-Art Experimental Models

Abstract

Chikungunya virus (CHIKV) is currently one of the most relevant arboviruses to public health. It is a member of the Togaviridae family and alphavirus genus and causes an arthritogenic disease known as chikungunya fever (CHIKF). It is characterized by a multifaceted disease, which is distinguished from other arbovirus infections by the intense and debilitating arthralgia that can last for months or years in some individuals. Despite the great social and economic burden caused by CHIKV infection, there is no vaccine or specific antiviral drugs currently available. Recent outbreaks have shown a change in the severity profile of the disease in which atypical and severe manifestation lead to hundreds of deaths, reinforcing the necessity to understand the replication and pathogenesis processes. CHIKF is a complex disease resultant from the infection of a plethora of cell types. Although there are several in vivo models for studying CHIKV infection, none of them reproduces integrally the disease signature observed in humans, which is a challenge for vaccine and drug development. Therefore, understanding the potentials and limitations of the state-of-the-art experimental models is imperative to advance in the field. In this context, the present review outlines the present knowledge on CHIKV epidemiology, replication, pathogenesis, and immunity and also brings a critical perspective on the current in vitro and in vivo state-of-the-art experimental models of CHIKF.

Keywords: cell entry; chikungunya virus; epidemiology; in vitro cell model; non-human primate models; pathogenesis; replicative cycle; rodent models.

FIGURE 1

Chikungunya virus (CHIKV) cell entry and replication. E2 glycoprotein binds to the membrane receptor Mxra8, inducing the translocation of clathrin molecules to the plasma membrane (1). GAG, DC-SIGN, CD147, and TIM are also described as CHIKV co-receptors, but their role for entry process is not well elucidated. CHIKV entry occurs via clathrin-mediated endocytosis pathway (2) and once the early endosome is formed, clathrin molecules dissociate from the endocytic vesicle (3), and the endosome proceed in the endocytic pathway. The pH acidification of endocytic vesicles triggers the detachment of E1-E2 heterodimers, exposing the fusion loop, which will culminate in the fusion of the endosomal with the viral membranes (4). Then, the nucleocapsid is released in the cytoplasm, genomic RNA is exposed, and translation of the non-structural polyprotein P1234 will take place (5). The P1234 protein is thus cleaved by the viral protease nsP2, releasing the individual non-structural proteins, which will form the viral replicase complex (6). The replicase complex is responsible for the synthesis of the negative-strand RNA (7) that will be the template for new positive-strand RNA (8) as well as for the synthesis of 26S subgenomic RNA (9). The subgenomic RNA, in its turn, is translated into the structural polyprotein C-pE2-6K-E1 in the rough endoplasmic reticulum (RER) (10). The C protein, which contains a protease domain responsible for its self-cleavage, dissociates from the polyprotein just after its translation (10b) and will attach to the positive polarity genomic RNA to form the nucleocapsid in the cytoplasm (11). In this meantime, the pE2-6K-E1 precursor will be addressed to the lumen of the ER (10a), where its maturation process will take place (13). The structural proteins will proceed in the exocytic pathway (14), until the end of E1-E2 heterodimers is mature (15). E1-E2 dimers will be deposited in the cell membrane forming the ‘virus budding microdomain’, a membrane domain where the budding process will occur (16). The recently assembled nucleocapsid migrates to this region, and new virions will be released to the extracellular milieu by budding (17).