Mosquito-borne disease chikungunya is transmitted to humans by the mosquito and is characterised by intense joint and muscle pain as well as high fever. The pain can last for several months. While mechanisms of infection of human cells with the virus remain very poorly understood, researchers have now identified a protein that is crucial in order for the virus to replicate within its target cells.
The research, published in Science Daily, opens up therapeutic avenues in the fight against chikungunya.
According to researchers, while the clinical manifestations of the disease are well understood the mechanisms by which the virus infects human cells and subsequently multiply need more studies.
Notably, even though many studies had already identified certain host cell factors implicated in the replication of the virus, none had succeeded in explaining why the virus preferentially targets the muscle and joint cells.
Now, researchers from Inserm, CNRS and Université de Paris led by Dr. Ali Amara at the AP-HP Saint-Louis Hospital Research Institute in Paris, in collaboration with Marc Lecuit's team from Institut Pasteur, Inserm and Université de Paris, have identified that the FHL1 protein is a key cellular factor for the replication and pathogenesis of chikungunya.
Notably, FHL1 is a molecule present mainly in the muscle cells and fibroblasts, which are the preferred targets of the virus.
Usually, FHL1 contributes to healthy muscle physiology and it is now thought to be diverted from that function by the virus to ensure its replication in the target cells.
In order to conduct the study, Amara's team used the CRISPR-Cas9 technology to systematically screen the genome of human cells in order to identify the host factors necessary for viral replication.
By doing so, it isolated the gene coding for the FHL1 protein.
Through its research, the team conducted a series of experiments showing the inability of the virus to infect cells whose FHL1 expression had been abolished.
The researchers further showed that the virus was incapable of multiplying within cells derived from patients suffering Emery-Dreifuss muscular dystrophy -- a rare genetic disease.
This muscle disease is the result of mutations of the FHL1 gene responsible for the breakdown of the FHL1 protein. The researchers concluded that the cells of these patients are resistant to the virus.
Ali Amara and Laurent Meertens, the Inserm researchers in charge of the study explained that they now want to understand the interaction in molecular detail and define why FHL1 is so specific to the chikungunya virus, and to decipher its mechanism of action at the molecular level.
They believe elucidating the molecular structure of the FHL1-nsP3 complex could represent a major step forward in the development of antivirals that block the replication of the virus.