New study elucidates a key infection mechanism for chikungunya virus

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Researchers, led by Johns Hopkins Bloomberg School of Public Health (MD, USA), have identified a novel mechanism, which is utilized by chikungunya virus to infect host cells and also mediates the severity of disease.  The team suggested this mechanism may be conserved across both alphaviruses and coronaviruses, therefore presenting a treatment target for a wide range of related diseases.

The study, published recently in the Proceedings of the National Academy of Science, discovered that conserved viral protein domains, termed macrodomains, were crucial for infecting healthy cells. The researchers demonstrated these macrodomains are responsible for removing ADP-ribose groups, which are thought to have antiviral properties, from host proteins therefore allowing viral replication.

Lead author Anthony K. L. Leung, from the Johns Hopkins Bloomberg School of Public Health, commented:  “We feel we have now identified a fundamental mechanism which the chikungunya virus uses during infection that determines how dangerous the chikungunya infection will be. Now we need to use this information to help us find drugs or develop vaccines to stop the virus.”

The team utilized mutated versions of the virus that were unable to remove ADP-ribose groups and discovered these viruses did not replicate in the host or cause any infection. They also created viruses with a reduced ability to remove ADP-ribose groups and demonstrated that, when compared with the wild-type virus, the mutated virus had a decreased ability to replicate in in vitro neural cells and mouse models.

For example, mice infected with wild-type chikungunya died within 3 days, whereas those infected with reduced-function virus were still alive after 10 days.  The team therefore proposed that a drug that could interfere with the ADP-ribose mechanism may present a future treatment.

Leung explained:  “This shows us that the virus must break the bond between protein and ADP-ribose to cause infection – which gives us a road map for how to keep infected cells intact and healthy.”

Chikungunya presents an emerging threat, since 2013 it has spread through the Americas with more than 1.7 million suspected cases in this region alone. The viral macrodomain identified in this study is similar across all alphaviruses and coronaviruses; finding a treatment based on this mechanism could therefore be beneficial to a wide range of infectious diseases that currently have no treatments or licensed vaccines.

Author Diane E. Griffin, from the Johns Hopkins Bloomberg School of Public Health, concluded: “The results of these studies open a whole new area of investigation into how cells control virus infection and how viruses that cause severe disease can circumvent that control. We will now be working to identify the proteins targeted, how they work and how we might interfere with these mechanisms.”

Source: McPherson PL, Abraham R, Sreekumar E et al. ADP-ribosylhydrolase activity of Chikungunya virus macrodomain is critical for virus replication and virulence, PNAS. doi:10.1073/pnas.1621485114 (2017) (Epub ahead of print); www.jhsph.edu/news/news-releases/2017/researchers-identify-mechanism-in-chikungunya-virus-that-controls-infection-and-severity.html

 

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