Research Finds AIM2 Key Sensor in MPXV Infection

Abstract

Monkeypox, a zoonotic disease caused by the monkeypox virus (MPXV), has significant global public health implications. Inflammasomes serve as crucial components of the innate immune system, detecting pathogens and triggering cell death in infected cells to eliminate harmful agents. However, the precise molecular mechanisms governing the activation of inflammasomes during MPXV infection remain largely unclear. Using CRISPR-knockout cytosolic innate immune sensor screening, we identified AIM2 as the sensor for MPXV within the inflammasome, a trigger for inflammatory cell death. Mechanistically, AIM2 forms a complex with essential cell death molecules, including ASC and caspase-1 (CASP1), without interacting with RIPK3 or CASP8. Loss of ASC, CASP1, or gasdermin D (GSDMD) reduced cell death following MPXV infection, whereas loss of GSDME, CASP3, CASP6, CASP7, CASP9, RIPK3, or MLKL did not. Pyroptotic cell death was predominantly observed in infected cells, whereas apoptotic and necroptotic signaling pathways were primarily activated in uninfected bystander cells. Furthermore, we found that the transcription factor IRF1 serves as an upstream regulator of AIM2, controlling AIM2-dependent cell death. In experiments involving AIM2-deficient mice infected with MPXV, we observed a decrease in proinflammatory cytokines, multiple inflammatory cell death pathways, and leukocyte migration, culminating in increased viral spread. CAST/EiJ mice succumbed to high-dose MPXV infection within 8 days, whereas AIM2 inhibition increased survival, with 10% of the mice treated with an AIM2 inhibitor surviving the infection. In a low-dose infection model, AIM2 inhibition reduced IL-1β and IL-18 production, LDH release, and tissue pathology. These findings highlight the critical role of AIM2-mediated inflammasome activation, along with multiple programmed cell death pathways, in shaping the innate immune response to MPXV infection, offering valuable insights for developing therapeutic strategies targeting AIM2 and the broader innate immune response against monkeypox.

A team of researchers, affiliated with UNIST, has identified a protein sensor that plays a key role in triggering severe inflammatory responses during monkeypox virus (MPXV) infection. The study reveals that this protein, known as AIM2, detects the viral DNA of MPXV within the body, leading to a potent inflammatory response that can contribute to disease severity.

Led by Professor SangJoon Lee of the Department of Biological Sciences at UNIST, in collaboration with Yujin Kim at the National Institute of Health (NIH) and Professor Daesik Kim at Sungkyunkwan University, the research team demonstrated that AIM2 functions as a critical immune sensor responsible for excessive inflammation during MPXV infection.

Although the reported fatality rate of monkeypox is relatively low at around 3%, severe cases can arise when the immune system mounts an excessive inflammatory response. While inflammation is essential for eliminating viruses, uncontrolled activation can damage healthy tissues and worsen clinical outcomes. Similar immune overreactions, often described as inflammatory cytokine storms, have been linked to severe complications and deaths in viral infections such as influenza and COVID-19.

The findings indicate that AIM2 recognizes MPXV DNA within infected cells and assembles a molecular complex known as the inflammasome. This complex activates caspase-1, an enzyme that induces inflammatory cell death and promotes the release of potent inflammatory cytokines, including IL-1β and IL-18.

Notably, the researchers found that AIM2-driven inflammation extends beyond cells directly infected by the virus. Infected cells primarily underwent pyroptosis, a highly inflammatory form of cell death, while neighboring uninfected cells activated alternative pathways, such as apoptosis and necroptosis. This coordinated but widespread response contributes to tissue damage and the progression of severe disease.

First author Jueun Oh explained, "This is the first experimental evidence demonstrating how AIM2 triggers inflammatory responses specifically during MPXV infection."

Furthermore, the team discovered that IRF1, a transcription factor, serves as an upstream regulator of AIM2, controlling its expression by binding to specific DNA regions involved in AIM2 synthesis.

To explore therapeutic potential, the researchers tested whether inhibiting AIM2 could mitigate severe inflammation. In MPXV-infected mouse models, treatment with an AIM2 inhibitor significantly reduced inflammation and cell death in lung tissue and improved survival compared with untreated groups.

"Our findings suggest that AIM2 could be a promising therapeutic target for reducing harmful inflammation in severe viral infections," said Professor Lee. "However, because AIM2 plays an essential role in alerting the immune system to pathogens, careful consideration is necessary to prevent compromising immune defense."

These findings were published in the Cellular & Molecular Immunology on November 12, 2025. The study was supported by the National Research Foundation (NRF) of Korea, the Korea National Institute of Health (NIH), the Korea Drug Development Fund (KDDF), the Korea Health Industry Development Institute (KHIDI), the Institute for Basic Science (IBS), the Circle Foundation, and the Center for Women In Science, Engineering, and Technology (WISET). Additional support came from research funding by UNIST, the Korean Ginseng Society (2023), and a grant from Yuhan Corporation.

Journal Reference

Jueun Oh, Yun-Ho Hwang, Jihye Lee, et al., "AIM2 drives inflammatory cell death and monkeypox pathogenesis," Cell Mol Immunol., (2025).