To tame a virus

Six years ago, biologist Sujatha Sunil cracked one of evolution's oldest riddles: how the chikungunya virus persists inside the Aedes aegypti mosquito, with harm to neither. Scientists had known for decades that the virus, which can cause fever and long-lasting joint pains in humans, coexists in the mosquitoes' midgut cells, salivary glands, ovaries, and other tissues throughout the infected mosquito's lifespan, without causing much deleterious effect to the insect. But the mechanism underlying this coexistence, which allows infected mosquitoes to transmit chikungunya virus to humans through their bites, remained an enigma.

Sunil and her colleagues at the International Centre for Genetic Engineering and Biotechnology, New Delhi, had in 2019 discovered (bit.ly/2019-virus) a tiny strand of genetic material called micro-RNA (miR) in Aedes aegypti that slows viral replication. The molecule, called miR-2944b, sticks to a fragment of the chikungunya virus' genome inside infected mosquito cells, limiting its ability to copy itself. It also curbs a biochemical process called oxidative stress – a surge of oxidative molecules that triggers the mosquito's immune system to fight the virus. This dual action allows the mosquito to tolerate the infection and maintain low viral load.

That finding marked the first evidence that an miR molecule could bind directly to a virus and restrain its ability to replicate. And it led Sunil to ask: "If this is happening in mosquitoes, might there be a similar micro-RNA in humans that could also work against the chikungunya virus?"

It expanded the known roles of miRs, a class of molecules discovered in 1993 that control the activity of myriad genes, working like dimmer switches – fine-tuning genes that control development, growth, immune responses, and cancers. Their ubiquity and precision in targeting specific genes and pathways have turned them into attractive candidates for new diagnostics and treatments. Several candidate therapies involving miRs or chemical mimics of miRs are undergoing clinical evaluation, mainly in the U.S., Europe, and Japan.

Sunil turned her attention to chikungunya after a nationwide outbreak in 2010. She collaborated with doctors in Bhubaneswar, Chandigarh, Delhi, Manipal, and Mumbai, to study disease patterns and viral genomes circulating in India. She also probed virus-human and virus-mosquito interactions.

Her studies coincided with a period when chikungunya was re-emerging across the country. Health authorities have documented more than 480 chikungunya outbreaks across India since 2015 and, with no antiviral or vaccine available, patients rely on painkillers, fever medicines, and sometimes steroids to battle lingering pains after infection. While the acute phase lasts no more than three weeks, three in ten patients progress to a chronic stage marked by pain in ankles, elbows, knees, or wrists that can persist for months.

Encouraged by the mosquito discovery, Sunil and her colleagues screened the catalogue of human miRs – around 2,000 – and found 10 that stick to the chikungunya virus genome. Two appeared to bind particularly strongly. When they designed experiments that blocked the action of the two miRs, they found that one of them, known as miR-122b, produced a dramatic effect: viral counts in cells with miR-122b blocked surged.

In their latest study (bit.ly/virus-replicate), the scientists describe how miR-122b also binds to the chikungunya virus genome, preventing the virus from replicating, just as miR-2944b does in mosquitoes. But miR-122b also has a second effect: it strengthens an arm of the human immune system and activates a cascade of biochemical pathways inside infected cells, curbing viral multiplication.

"The micro-RNA turns the infected cell's environment hostile to the virus," says Sunil. "The discovery points to a possible pathway to novel treatment strategies. One option would be to design a synthetic molecule that mimics the micro-RNA's action."

Her work fits into a broader scientific effort to exploit miRs as therapeutic tools expanding over the past decade. A September 2024 research review documented more than 550 studies on miRs, including clinical trials aimed at treating hepatitis-C, some cancers, heart failure, among others.

Yet, as Alessia Indrieri, a molecular therapy specialist at the Institute for Genetic and Biomedical Research, Italy, and her colleagues Simona Brillante and Mariagrazia Volpe wrote in the review (bit.ly/virus-review): "Several candidates have been discontinued due to toxicity concerns..." Key challenges include ensuring miRs act only on intended genes, avoiding undesirable side effects on others, and minimising immune responses.

Although clinical progress has been slow – as of September 2024, no miR-based treatment had been approved by regulatory authorities – the promise of miRs remains evocative. Sunil's work shows that in both mosquitoes and humans, tiny RNA strands choreograph the balance between the virus and the host.