AGO4: a potential new universal target for antiviral therapeutics

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Published in Cell Reports, researchers at the Massachusetts General Hospital (MGH; MA, USA) may have elucidated the function of the AGO4 protein, suggesting that it may be a ‘universal’ target for antiviral treatment.

AGO proteins are essential in the formation of the RNA-induced silencing complex (RISC), which is critical for prevention of viral infection in mammals. Until now, researchers have been unable to determine their importance in the immune response to viral pathogens.

Initially, the researchers created macrophages deficient of each of the AGO subtypes (1–4) and demonstrated that AGO4-deficienct macrophages became ‘hyper-susceptible’ to influenza upon challenge, resulting in high levels of viral titers. The team also observed this same phenomenon when challenging the cells to encephalomyocarditis virus and vesicular stomatitis virus.

The researchers then sought to determine the role of AGO4 in the antiviral response by exposing AGO4 knockout macrophages to a range of RNA virus’ and when compared with the wild type, the knockout model displayed a significant reduction in IFN-B. This suggests that AGO4 promotes the IFN pathway in response to viral infection.

On a separate cell line, the team also determined that AG04 overexpression resulted in suppression of viral titers, suggesting AG04 could be used to ‘boost’ the immune response against viral pathogens.

“The goal is to understand how our immune system works so we can create treatments that work against a range of viruses, rather than just vaccines against a particular one,” stated author Kate Jeffrey (Harvard Medical School, MA, USA).

The next steps are to “determine how broad spectrum this is to any virus types” commented Jeffrey, “Then we need to discover how to boost AGO4 to ramp up protection against viral infections.”

With the current coronavirus outbreak, novel findings such as this may provide the starting point for the development of new treatments, which may prevent the devastating effects of viral pathogens.

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Sources: Adillagham F, Basavappa M, Saunders T et al. A requirement for Argonaute 4 in mammalian antiviral defence. Cell Rep. 30, 1690–1701 (2020); www.massgeneral.org/news/press-release/Mass-general-hospital-researchers-identify-new-universal-target-for-antiviral-treatment

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