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

Autor:	Miranzadeh Mahabadi H; Department of Medicine, University of Alberta, Edmonton, AB T5N 2S2, Canada., Lin YCJ; Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, AB T5N 2S2, Canada., Ogando NS; Department of Medicine, University of Alberta, Edmonton, AB T5N 2S2, Canada., Moussa EW; Department of Biochemistry, University of Alberta, Edmonton, AB T5N 2S2, Canada., Mohammadzadeh N; Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, AB T5N 2S2, Canada., Julien O; Department of Biochemistry, University of Alberta, Edmonton, AB T5N 2S2, Canada., Alto NM; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8816., Noyce RS; Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, AB T5N 2S2, Canada.; Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T5N 2S2, Canada., Evans DH; Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, AB T5N 2S2, Canada.; Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T5N 2S2, Canada., Power C; Department of Medicine, University of Alberta, Edmonton, AB T5N 2S2, Canada.; Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, AB T5N 2S2, Canada.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Feb 20; Vol. 121 (8), pp. e2315653121. Date of Electronic Publication: 2024 Feb 12.
DOI:	10.1073/pnas.2315653121
Abstrakt:	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. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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