The inflammasome-activating poxvirus peptide IAMP29 promotes antimicrobial and anticancer responses

Abstract

Poxviruses are implicated in a variety of infectious diseases; however, little is known about the molecular mechanisms that underlie the immune response during poxvirus infection. We investigated the function and mechanisms of the monkeypox virus envelope protein (A30L) and its core peptide (IAMP29) during the activation of innate immune responses. The A30L protein and its core peptide, IAMP29 (a 29-amino-acid inflammasome-activating peptide encompassing His40 to Asp69 of A30L), strongly activated the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome by inducing the production of mitochondrial reactive oxygen species in human monocytes. Specifically, IAMP29 triggered metabolic reprogramming toward glycolysis and interacted with pyruvate kinase M isoforms (PKM1 and PKM2), thus activating the NLRP3 inflammasome and interleukin (IL)-1β production in human monocytes and murine macrophages. In human primary monocyte-derived macrophages, IAMP29-induced inflammasome activation promoted an antimicrobial response to rapidly growing non-tuberculous mycobacteria. Furthermore, IAMP29 exhibited cytotoxic activity against leukemia cells, which was mediated by pyroptosis and apoptosis. These findings provide insights into the immunological function of the poxvirus envelope peptide and suggest its therapeutic potential. Poxviruses, a group of viruses causing diseases like smallpox and mpox, can manipulate our immune system, but the exact process is not fully understood. This study reveals that a specific poxvirus protein, IAMP29, can stimulate our immune response. It does this by causing NLRP3 inflammasome activation and boosting our body’s defenses against infections and cancer. The research, which involved experiments with human immune cells and mice, found that IAMP29 increases the production of inflammation-causing molecules and strengthens the immune system’s ability to combat fast-growing non-tuberculous mycobacteria (bacteria that do not cause tuberculosis and leprosy) and leukemia cells. The study suggests that IAMP29 could be used as a treatment for these bacterial infections and certain cancers, providing a significant insight into how poxviruses interact with our immune system. This could pave the way for new treatments for infectious diseases and cancer. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.