Novel mechanisms of cell death subversion by monkeypox virus

Monkeypox virus (MPXV) clade 2b has caused a global outbreak since 2022, affecting 88,000 people across >100 countries. A further outbreak of MPXV clade 1b started in the Democratic Republic of Congo in September 2023, causing ~20,000 cases and 1,300 deaths so far. MPXV causes a smallpox-like illness, and can cause life-threatening infection in immunocompromised individuals, children and pregnant women. Children under the age of 5 have accounted for 62% of the deaths from the most recent outbreak. MPXV was recently declared a public health emergency of international concern by the WHO, the category used in the past for Ebola outbreaks and COVID-19. MPXV has emerged and re-emerged over five decades yet basic aspects of its biology still remain to be discovered. Furthermore, there are only two antiviral drugs, with evidence already for drug resistance. New treatments based on a comprehensive understanding of how the virus interacts with the host are vital.   One of the first lines of defence against MPXV and other viruses are 'cell death pathways', by which infected cells die to prevent viral spread. To counteract this defence and promote their successful replication, some viruses including MPXV inhibit these cellular pathways.   We aim to understand how MPXV prevents cell death. We have made the crucial discovery that a viral protein called MPXV4 inhibits a key cell death pathway called pyroptosis. Furthermore, our initial data suggests the existence of other, as yet undiscovered MPXV inhibitors of cell death. Critically, a detailed understanding of how MPXV4 and other death inhibitors function will enable us to develop new antiviral treatments that restore cell death as a vital defence against infection.   We will (1) identify and characterise new ways MPXV inhibits cell death (2) determine how MPXV targets cell death pathway components for destruction; (3) gain a structural understanding of how each viral death inhibitor interacts with its cellular protein target. To achieve these aims, we will study skin cells and immune sensing cells, which both play vital yet distinct roles in MPXV infection.   Understanding how MPXV and other viruses subvert cell death pathways will eventually allow us to develop vital new treatments to prevent diseases caused by MPXV. Crucially, this knowledge will also improve our understanding of cell death in general, which will benefit multiple lines of research including into sepsis, neurodegenerative disease and cancer.