Monkeypox virus infection of human astrocytes causes gasdermin B cleavage and pyroptosis

• 成果类型: Article
• 署名作者: Mahabadi, Hajar Miranzadeh; Lin, Y. C. James; Ogando, Natacha S.; Moussa, Eman W.; Mohammadzadeh, Nazanin; Julien, Oliver; Alto, Neal M.; Noyce, Ryan S.; Evans, David H.; Power, Christopher
• 署名单位: University of Alberta; University of Alberta; University of Alberta; University of Texas System; University of Texas Southwestern Medical Center; University of Alberta
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9573
• DOI: 10.1073/pnas.2315653121
• 发表日期: 2024-02-20
• 关键词: family

摘要

Monkeypox virus (MPXV) infections in humans cause neurological disorders while studies of MPXV- infected animals indicate that the virus penetrates the brain. Pyroptosis is an inflammatory type of regulated cell death, resulting from plasma membrane rupture (PMR) due to oligomerization of cleaved gasdermins to cause membrane pore formation. Herein, we investigated the human neural cell tropism of MPXV compared to another orthopoxvirus, vaccinia virus (VACV), as well as its effects on immune responses and cell death. Astrocytes were most permissive to MPXV (and VACV) infections, followed by microglia and oligodendrocytes, with minimal infection of neurons based on plaque assays. Aberrant morphological changes were evident in MPXV- infected astrocytes that were accompanied with viral protein (I3) immunolabelling and detection of over 125 MPXV- encoded proteins in cell lysates by mass spectrometry. MPXV- and VACV- infected astrocytes showed increased expression of immune gene transcripts (IL12, IRF3, IL1B, TNFA, CASP1, and GSDMB). However, MPXV infection of astrocytes specifically induced proteolytic cleavage of gasdermin B (GSDMB) (50 kDa), evident by the appearance of cleaved N- terminal-GSDMB (30 kDa) and C- terminal- GSDMB (18 kDa) fragments. GSDMB cleavage was associated with release of lactate dehydrogenase and increased cellular nucleic acid staining, indicative of PMR. Pre- treatment with dimethyl fumarate reduced cleavage of GSDMB and associated PMR in MPXV- infected astrocytes. Human astrocytes support productive MPXV infection, resulting in inflammatory gene induction with accompanying GSDMB- mediated pyroptosis. These findings clarify the recently recognized neuropathogenic effects of MPXV in humans while also offering potential therapeutic options.