Griffith University: Studies reveal new mechanisms of arthritis caused by mosquito-borne viruses

Some therapies successful in treating rheumatoid arthritis (RA) may help us better understand how to tackle debilitating mosquito-borne viral diseases, new Griffith University research has found.

Chikungunya virus (CHIKV) and Ross River virus (RRV) are transmitted by mosquitoes, and infection causes severe arthritis, muscle pain and fever, and there are currently no specific drugs or therapies to prevent this.

“The disease caused by these viral infections bears several similarities with a form of auto-immune arthritis known as Rheumatoid Arthritis (RA),’’ said lead author Dr Ali Zaid from Menzies Health Institute Queensland.

“In severe RA, patients express high levels of an immune molecule called Interleukin-17 (or IL-17), which is a target of new anti-arthritis drugs.”

In two new studies published in PLoS Pathogens and mBio, the authors asked whether IL-17 was also seen in CHIKV and RRV infections, and whether it could be similarly targeted to reduce arthritic disease.

In collaboration with Professor Roque Almeida from the University Hospital, Federal University of Sergipe in Brazil, the research team analysed serum samples from CHIKV-infected patients collected during the 2019 outbreak in northern Brazil and found while some patients with acute disease showed elevated IL-17 levels, chronic CHIKV patients showed a significantly higher increase in levels compared to healthy controls.

“When we looked at serum samples from Ross River virus patients from the Dubbo Infection Outcomes Study (DIOS) in collaboration with Professor Andrew Lloyd from the University of New South Wales, levels of IL-17 were also elevated, which prompted us to ask whether this molecule was driving disease,’’ said Helen Mostafavi, whose PhD project investigated the role of IL-17 in RRV infection.

“Using an experimental mouse model of viral arthritis, we found that targeting IL-17 in virus-infected mice ameliorated disease and reduced inflammation, thus demonstrating that some therapies that have been successful in treating RA could be of potential benefit to treat people with alphavirus disease.”

However, the authors found that a complete lack of IL-17 was not necessarily ideal: genetically modified mice that lack IL-17 showed an increase in viral RNA in the post-acute phase of disease – despite showing reduced inflammation.

Co-author Dr Xiang Liu said the findings had implications for viral persistence and targeting IL-17 in alphavirus disease should be approached with caution.

In a separate study published in mBio, the authors investigated the role of a protein called TRIF, which cells use to ‘sense’ viral RNA and start a strong antiviral response, which alerts neighbouring cells.

Using genetically modified mice that lack the TRIF protein, the authors found that TRIF was needed to help generate neutralising antibodies against RRV.

“This was surprising because we knew that TRIF was very important in early antiviral responses (i.e., soon after infection), but we found this molecule was also important in supporting antibody responses that provide long-term immunity and reduce persistent viral infections,’’ Dr Liu said.

“These findings give new insights into how different arms of the immune response cooperate to ensure long-lasting defence against viruses like CHIKV and RRV and will pave the way into the development of new immunotherapies to treat these diseases.”