Virus World

The spread of vector-borne viruses, such as CHIKV, is a significant public health concern in the Americas, with over 120,000 cases and 51 deaths in 2023, of which 46 occurred in Paraguay. Using a suite of genomic, phylodynamic, and epidemiological techniques, we characterized the ongoing large CHIKV epidemic in Paraguay.

Preprint in medRxiv (April 17, 2023):

https://doi.org/10.1101/2023.04.16.23288635 

Originally from Africa, chikungunya is aptly named. It derives from a word in the Kimakonde language meaning "to become contorted," because the severe muscle and joint pains endured by the patients prevent them from moving normally or performing their daily activities.

While the clinical manifestations of the disease are well understood, the mechanisms by which the virus  infects human cells and multiplies remain poorly elucidated. Several studies have already identified certain host cell factors implicated in the replication of the virus. However, none has succeeded in explaining why the virus preferentially targets the muscle and joint cells, causing these clinical signs.

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 now report that the FHL1 protein is a key cellular factor for the replication and pathogenesis of chikungunya. FHL1 is a molecule present mainly in the muscle cells and fibroblasts, 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.

To conduct this study, Amara's team used the CRISPR-Cas9 technology to screen the genome of human cells in order to identify the host factors necessary for viral replication. In doing so, it isolated the gene coding for the FHL1 protein. The team then conducted a series of experiments showing the incapacity of the virus to infect cells whose FHL1 expression had been abolished. In addition, the researchers have shown 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 have shown that the cells of these patients are resistant to the virus. Finally, the researchers performed in vivo experiments in mice whose Fhl1 gene was invalidated. They have shown that these animals are totally resistant to infection and do not develop the disease, whereas the virus multiplies and causes major muscle lesions in mice expressing a functional FHL1 protein. These observations demonstrate that the FHL1 protein plays a key role in chikungunya virus replication and pathogenesis.

The precise role played by FHL1 in the viral infection is not fully understood. The researchers have discovered that FHL1 interacts with a viral protein known as nsP3. It is when binding to this that FHL1 participates in the replication of the virus. "We now want to understand this interaction in molecular detail. The next step is to define why FHL1 is so specific to the chikungunya virus, and to decipher its mechanism of action at the molecular level. 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," say Ali Amara and Laurent Meertens, the Inserm researchers in charge of the study. At present, only symptomatic treatments are available for patients infected with chikungunya.

Study published in Nature on Sept. 25, 2019:

https://doi.org/10.1038/s41586-019-1578-4

Chikungunya virus (CHIKV) is a reemerging mosquito-borne virus that causes swift outbreaks. Major concerns are the persistent and disabling polyarthralgia in infected individuals. Here we present the results from a first-in-human trial of the candidate simian adenovirus vectored vaccine ChAdOx1 Chik, expressing the CHIKV full-length structural polyprotein (Capsid, E3, E2, 6k and E1). 24 adult healthy volunteers aged 18–50 years, were recruited in a dose escalation, open-label, nonrandomized and uncontrolled phase 1 trial (registry NCT03590392). Participants received a single intramuscular injection of ChAdOx1 Chik at one of the three preestablished dosages and were followed-up for 6 months. The primary objective was to assess safety and tolerability of ChAdOx1 Chik.

The secondary objective was to assess the humoral and cellular immunogenicity. ChAdOx1 Chik was safe at all doses tested with no serious adverse reactions reported. The vast majority of solicited adverse events were mild or moderate, and self-limiting in nature. A single dose induced IgG and T-cell responses against the CHIKV structural antigens. Broadly neutralizing antibodies against the four CHIKV lineages were found in all participants and as early as 2 weeks after vaccination. In summary, ChAdOx1 Chik showed excellent safety, tolerability and 100% PRNT50 seroconversion after a single dose. Chikungunya virus (CHIKV) is a reemerging mosquito-borne virus that has caused outbreaks in various regions of the world. Here the authors present safety and immunogenicity data from a phase 1 trial with the simian adenovirus vectored vaccine ChAdOx1 Chik, showing induction of neutralizing antibodies to four CHIKV lineages.

Published in Nat. Communications (July 30, 2021):

https://doi.org/10.1038/s41467-021-24906-y