Chikungunya fever: epidemiology, clinical syndrome, pathogenesis and therapy

Abstract

Chikungunya virus (CHIKV) is the aetiological agent of the mosquito-borne disease chikungunya fever, a debilitating arthritic disease that, during the past 7years, has caused immeasurable morbidity and some mortality in humans, including newborn babies, following its emergence and dispersal out of Africa to the Indian Ocean islands and Asia. Since the first reports of its existence in Africa in the 1950s, more than 1500 scientific publications on the different aspects of the disease and its causative agent have been produced. Analysis of these publications shows that, following a number of studies in the 1960s and 1970s, and in the absence of autochthonous cases in developed countries, the interest of the scientific community remained low. However, in 2005 chikungunya fever unexpectedly re-emerged in the form of devastating epidemics in and around the Indian Ocean. These outbreaks were associated with mutations in the viral genome that facilitated the replication of the virus in Aedes albopictus mosquitoes. Since then, nearly 1000 publications on chikungunya fever have been referenced in the PubMed database. This article provides a comprehensive review of chikungunya fever and CHIKV, including clinical data, epidemiological reports, therapeutic aspects and data relating to animal models for in vivo laboratory studies. It includes Supplementary Tables of all WHO outbreak bulletins, ProMED Mail alerts, viral sequences available on GenBank, and PubMed reports of clinical cases and seroprevalence studies.

Keywords: Alphavirus; Antiviral therapy; Arbovirus; Chikungunya fever; Chikungunya virus.

Fig. 1

Publications related to outbreaks of chikungunya fever in the PubMed database. Articles published between 1950 and September, 2012 were identified using the MeSH term “chikungunya,” and are reported by 5-year periods.

Fig. 2

Organisation of the CHIKV genome and gene products. The genomic organisation is arranged as with other alphaviruses, with two open reading frames (ORFs), 5′ cap structures and a 3′ poly(A) tail. The 5′ and 3′ proximal sequences of the CHIKV genome include nontranslated regions (NTR). The junction region (J) is also noncoding. The 5′ ORF is translated from genomic RNA and encodes four nonstructural proteins (nsP1, 2, 3 and 4). The 3′ ORF is translated from a subgenomic 26S RNA and encodes the capsid protein (C), two surface envelope glycoproteins (E1 and E2) and two small peptides designated E3 and 6k. The different non-structural proteins (nsP1–nsP4) and structural proteins (C, Capsid; E1, E2, E3, envelope; 6k) are generated after proteolytic cleavage of polyprotein precursors (adapted from Solignat et al., 2009, with authors’ permission).

Fig. 3

Life cycle of CHIKV in infected cells. Virus enters cells at the plasma membrane, mostly by endocytosis, via a pH-dependent mechanism, which culminates in fusion pore formation and release of the nucleocapsid into the cytosol. It begins with attachment (E2 is primarily responsible for interactions with cellular receptors) and fusion of virus particles with the host cell membrane. The fusion peptide is located at the tip of the E1 molecule in domain II, close to amino acid 226. Following virus entry, two rounds of translation occur. Positive-sense genomic RNA acts directly as mRNA and is partially translated (5’ end) to produce non-structural proteins (nsP’s). These proteins are responsible for replication and formation of a complementary negative strand, the template for further positive-strand synthesis. Subgenomic mRNA (26S) replication occurs through the synthesis of full-length negative intermediate RNA, which is regulated by nsP4 and p123 precursor in early infection, and later by mature nsPs. Translation of the 26S sub-genomic RNA results in production of 5 structural proteins (C, E3, E2, 6k, E1), which are required for viral encapsidation and budding. Assembly occurs at the cell surface, and the envelope is acquired as the virus buds from the cell. Release and maturation occur almost simultaneously.

Fig. 4

Geographic distribution of CHIKV cases. Autochthonous cases before and after the emergence of CHIKV in the Indian Ocean (2005) are reported in Fig. 4A and B, respectively. Cases were collected from GenBank, PubMed, WHO weekly epidemiological records and the ProMED Mail alert databases. More details and complete tables are provided in the Supplementary Tables.

Fig. 4

Geographic distribution of CHIKV cases. Autochthonous cases before and after the emergence of CHIKV in the Indian Ocean (2005) are reported in Fig. 4A and B, respectively. Cases were collected from GenBank, PubMed, WHO weekly epidemiological records and the ProMED Mail alert databases. More details and complete tables are provided in the Supplementary Tables.

Fig. 5

Dispersal pattern of CHIKV from Africa to the Indian Ocean and Europe during the past 20–50 years. Viral evolution and spread are represented according to recent phylogenetic studies. Different evolutionary lineages are identified using arrows with specific colours. This figure was reproduced with permission (de Lamballerie et al., 2008).

Fig. 6

Geographic distribution of CHIKV isolates, according to genotype, as obtained from GenBank and PubMed publications.

Fig. 7

Phylogenetic reconstruction of CHIKV evolution. Phylogenetic trees were produced using Clustal W alignments of complete or nearly complete Chikungunya virus coding nucleotide sequences. Phylogenetic trees were produced using the Neighbour Joining method implemented in MEGA version 5. Bootstrap resampling values are indicated at the main branches. The major evolutionary groups are indicated. Colours identify the different lineages (East-, Central- South-African (ECSA), Asian and West African).

Fig. 8

Accumulation of CHIKV proteins in macaque monocyte-derived macrophages 21 days post-infection (Labadie et al., 2010). Monocyte-derived macrophages were separated from monocytes by adhesion for 7 days, then infected with 0.5 MOI of CHIKV expressing nsp3-ZsGreen protein. Macrophages growing on glass slides were fixed and conterstained with DAPI. Pictures were acquired using a Confocal SPE Leica microscope, (×40).