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
References
- 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
No comments:
Post a Comment