AFRICAN SWINE FEVER VIRUS A151R SUPPRESSES CGAS-STING-MEDIATED TYPE I INTERFERON RESPONSE VIA FERROPTOSIS-DRIVEN LIPID PEROXIDATION AND FERRITINOPHAGY

• Dr. Tanakhi Nakamura

  Department of Infectious Diseases, University of Tokyo, Japan

  Author

• Marcos Almeida Araujo

  Department of Microbiology and Immunology, University of Sao Paulo, Brazil

  Author

African Swine Fever (ASF) is a truly devastating disease for pigs worldwide, causing high mortality and leaving us without effective treatments. A big part of how the African Swine Fever Virus (ASFV) wreaks havoc is by cleverly sidestepping the host's natural defenses, especially a crucial pathway called cGAS-STING, which is vital for producing antiviral signals (Type I interferons). Our study dives into a fascinating new way ASFV does this, focusing on a viral protein called A151R. We found that ASFV A151R actively shuts down the cGAS-STING pathway's ability to make IFN-β by triggering something called ferroptosis – a unique type of cell death driven by iron and fat damage.

Here's the nitty-gritty: A151R essentially kickstarts a process called ferritinophagy, which is like the cell's recycling system for iron-storing proteins. This releases a flood of iron inside the cell, leading to a lot of fat damage (lipid peroxidation). This damage then directly messes with STING, preventing it from getting activated and doing its job, ultimately silencing the antiviral response. Our lab experiments showed that if we created a version of ASFV without the A151R gene (ASFVΔA151R), the cells could partially restore their IFN-β production and cGAS-STING activation. Conversely, just adding A151R to cells was enough to suppress STING. What's more, when we used drugs to block ferroptosis or ferritinophagy, we could actually help the cells recover their IFN-β production. We even saw these protective effects in live pigs: ASFVΔA151R caused less severe disease, with higher IFN-β levels and less ferroptosis in their tissues. These findings reveal a critical, previously unknown role for ASFV A151R in outsmarting the immune system by inducing ferroptosis. This gives us fresh insights into how ASFV causes disease and points us toward exciting new targets for developing antiviral treatments.

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