Chikungunya virus (CHIKV) and related arboviruses have been responsible for large epidemic outbreaks with serious economic and social impact. The immune mechanisms, which control viral multiplication and dissemination, are not yet known. Here, we studied the antibody response against the CHIKV surface antigens in infected patients. With plasma samples obtained during the early convalescent phase, we showed that the naturally-acquired IgG response is dominated by IgG3 antibodies specific mostly for a single linear epitope ‘E2EP3’. E2EP3 is located at the N-terminus of the E2 glycoprotein and prominently exposed on the viral envelope. E2EP3-specific antibodies are neutralizing and their removal from the plasma reduced the CHIKV-specific antibody titer by up to 80%. Screening of E2EP3 across different patient cohorts and in non-human primates demonstrated the value of this epitope as a good serology detection marker for CHIKV infection already at an early stage. Mice vaccinated by E2EP3 peptides were protected against CHIKV with reduced viremia and joint inflammation, providing a pre-clinical basis for the design of effective vaccine against arthralgia-inducing CHIKV and other alphaviruses.

https://www.embopress.org/doi/pdf/10.1002/emmm.201200213

Early neutralizing IgG response to Chikungunya virus in infected patients targets a dominant linear epitope on the E2 glycoprotein

Chikungunya virus (CHIKV) is an alphavirus of the Togaviridae family. After autoproteolytic cleavage, the CHIKV capsid protein (CP) is involved in RNA binding and assembly of the viral particle. The monomeric CP is approximately 30 kDa in size and is small enough for passive transport through nuclear pores. Some alphaviruses are found to harbor nuclear localization signals (NLS) and transport of these proteins between cellular compartments was shown to be energy dependent. The active nuclear import of cytoplasmic proteins is mediated by karyopherins and their export by exportins. As nuclear and cytoplasmic trafficking may play a role in the life cycle of CHIKV, we have sought to identify nuclear localization and nuclear export signals in CHIKV CP in a virus-free system. EGFP-fusion proteins of CHIKV CP and mutants thereof were created and used to monitor their intracellular localization. Binding of cellular proteins was confirmed in pull-down assays with purified CP using co-immuoprecipitation. Nuclear localization was demonstrated in a virus-free system using fluorescence microscopy. Here we show that CHIKV CP is a nuclear-cytoplasmic shuttling protein with an active NLS that binds to karyopherin α (Karα) for its nuclear translocation. We also found that the Karα4 C-terminal NLS binding site is sufficient for this interaction. We further demonstrate that CHIKV CP interacts directly with the export receptor CRM1 to transport this viral protein out of the nucleus via a nuclear export signal (NES). The CHIKV CP NES was mapped between amino acids 143 and 155 of CP. Deduced from in silico analyses we found that the NES has a mode of binding similar to the snurportin-1 CRM1 complex. We were able to show that in a virus-free system that the CHIKV capsid protein contains both, a NLS and a NES, and that it is actively transported between the cytoplasma and the nucleus. We conclude that CHIKV CP has the ability to shuttle via interaction with karyopherins for its nuclear import and, vice versa, by CRM1-dependent nuclear export.

/pdf/chikungunya-virus-capsid-protein-contains-nuclear-import-and-2hjqxax89f.pdf

Chikungunya virus capsid protein contains nuclear import and export signals

Ross River virus is an arthropod-borne alphavirus (family Togaviridae) causing epidemic polyarthritis in the Australia-Pacific region. The infection causes substantial morbidity due to long-lasting arthralgia. Despite being the most common arboviral infection in Australia, reports in travellers are scarce. Here, we describe the disease in a German traveller who was not aware of the prevalence of this infection in his holiday destination, the Northern Territory and Queensland, Australia. The patient had neither fever nor rash, but presented with chills, watery diarrhoea and severe, prolonged arthritis.

Ross River virus infection in a traveller returning from northern Australia

Background
The alphavirus capsid is multifunctional and plays a key role in the viral life cycle. The nucleocapsid domain is released by the self-cleavage activity of the serine protease domain within the capsid. All alphaviruses analyzed to date show this autocatalytic cleavage. Here we have analyzed the sequence requirements for the cleavage activity of Chikungunya virus capsid protease of genus alphavirus.

/pdf/functional-dissection-of-the-alphavirus-capsid-protease-3jr2g4p06w.pdf

Functional dissection of the alphavirus capsid protease: sequence requirements for activity

The 3′untranslated region (UTR) in alphavirus genomes functions in virus replication and plays a role in determining virus host range. However, the molecular evolution of virus UTRs is understudied compared to the evolution of protein-coding regions. Chikungunya virus (CHIKV) has the longest 3′UTR among the alphaviruses (500–700 nt), and 3′UTR length and sequence structure vary substantially among different CHIKV lineages. Previous studies showed that genomic deletions and insertions are key drivers of CHIKV 3′UTR evolution. Inspired by hypothesized deletion events in the evolutionary history of CHIKV, we used experimental evolution to examine CHIKV adaptation in response to a large 3′UTR deletion. We engineered a CHIKV mutant with a 258 nt deletion in the 3′UTR (ΔDR1/2). This deletion reduced viral replication on mosquito cells, but did not reduce replication on mammalian cells. To examine how selective pressures from vertebrate and invertebrate hosts shape CHIKV evolution after a deletion in the 3′UTR, we passaged ΔDR1/2 virus populations strictly on primate cells, strictly on mosquito cells, or with alternating primate/mosquito cell passages. We found that virus populations passaged on a single host cell line increased in fitness relative to the ancestral deletion mutant on their selected host, and viruses that were alternately passaged improved on both hosts. Surprisingly, whole genome sequencing revealed few changes in the 3′UTR of passaged populations. Rather, virus populations evolved improved fitness through mutations in protein coding regions that were associated with specific hosts.

/pdf/chikungunya-virus-evolution-following-a-large-3-utr-deletion-4cc1bqyzyi.pdf

Chikungunya virus evolution following a large 3′UTR deletion results in host-specific molecular changes in protein-coding regions

We have isolated a Chikungunya (Chik) virus from a patient who returned to Germany after a three-month visit to Mauritius in spring 2006. Upon return she developed a transient fever up to 40°C. This was followed by myalgia and joint pain. IgG antibodies in serum to Chik virus were undetectable. Virus (Chik-Wu1) was isolated on Vero cells. We molecularly cloned the whole genome of Chik-Wu1 from viral RNA by RT-PCR. The complete sequence was determined and functional domains of the genome were assigned. Chik-Wu1 clearly belongs to the group of viruses analysed from the recent Indian Ocean outbreak. In order to develop tools useful for further characterization of Chik-Wu1, we bacterially expressed and purified the capsid (C) and envelope (E) proteins and established an immunoblot assay. Twenty-two of 30 serum samples from Chik virus-infected patients that scored positive in indirect immunofluorescence previously were also reactive in immunoblot analysis with recombinant C and E2 antigens.

Characterisation of a chikungunya virus from a German patient returning from Mauritius and development of a serological test

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Characterisation of a chikungunya virus from a German patient returning from Mauritius and development of a serological test