Wednesday, July 18, 2012

Singapore - Infectious diseases: New hope for a Chikungunya vaccine

An investigation of Chikungunya virus yields two new antigens for vaccine development

Chikungunya virus has caused epidemics in Africa, Asia and recently Europe. It is transmitted to humans by Aedes (see image), a genus of mosquitoes that also transmit dengue fever. Symptoms of a Chikungunya viral infection include acute fever followed by joint pain that can last for days, weeks, or even years. The disease may be fatal for newborns and the elderly; what’s worse is that there are no vaccines or treatments currently available for the disease.

Lucile Warter at the A*STAR’s Singapore Immunology Network and co-workers have now identified two regions of the virus recognized by human antibodies that can neutralize Chikungunya virus1. The researchers have also shown the first proof that the virus is capable of direct cell-to-cell transmission. The findings could help explain how the virus avoids being bound by extracellular neutralizing antibodies and increases the efficiency of infection.

To discover the antibody-binding sites, researchers incubated the virus with previously identified antibodies and then isolated resistant variants. Sequencing and structural analysis revealed that the resistant variants had mutations in several regions, suggesting that these regions were the antibody binding sites. The mutations were in the viral fusion loop ‘groove,’ and the envelope E2 domain B. The latter domain has been shown to be important in neutralizing antibody recognition of related RNA viruses.

Results of analyses of the resistant strains, including rapid in vivo spread compared with wild-type virus, led the researchers to suspect that Chikungunya virus might be capable of direct cell-to-cell transmission. Warter and co-workers confirmed this hypothesis by culturing infected cells with uninfected cells in medium containing neutralizing antibodies. Many new cells became infected, but no viral particles were detectable outside the cells.

Microscopic examination of infected cells also showed increased concentrations of viral particles at points of cell-cell contact. Direct cell-to-cell transfer offers the advantage of spreading a large number of viral particles directly into another cell where they can begin reproducing, without the risks of traversing the extracellular space. This provides obvious advantages over the canonical mode of viral spread, broadcasting viral particles inside an organism.

“Chikungunya is the first alphavirus known to be capable of cell-to-cell transmission,” says Warter. “Additional studies will be necessary to identify molecular mechanisms associated with this route of transmission, as well as to investigate whether this kind of transmission occurs in vivo.”

The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network

  1. Lee, C. Y. et al. Chikungunya virus neutralization antigens and direct cell-to-cell transmission are revealed by human antibody-escape mutants. PLoS Pathogens 7, e1002390 (2011). | article

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