{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:24:24Z","timestamp":1791822264462,"version":"4.3.4"},"reference-count":49,"publisher":"National Academy of Sciences","issue":"8","license":[{"start":{"date-parts":[[2024,2,12]],"date-time":"2024-02-12T00:00:00Z","timestamp":1707696000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100022991","name":"HIV\/AIDS and STBBI Research Initiative","doi-asserted-by":"publisher","award":["00000"],"award-info":[{"award-number":["00000"]}],"id":[{"id":"10.13039\/100022991","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,2,20]]},"abstract":"<jats:p>\n                    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 (\n                    <jats:italic>IL12, IRF3, IL1B, TNFA, CASP1<\/jats:italic>\n                    , and\n                    <jats:italic>GSDMB<\/jats:italic>\n                    ). 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2315653121","type":"journal-article","created":{"date-parts":[[2024,2,12]],"date-time":"2024-02-12T15:05:17Z","timestamp":1707750317000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":30,"title":["Monkeypox virus infection of human astrocytes causes gasdermin B cleavage and pyroptosis"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0467-4002","authenticated-orcid":false,"given":"Hajar","family":"Miranzadeh Mahabadi","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Alberta, Edmonton, AB T5N 2S2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. C. James","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology &amp; Immunology, University of Alberta, Edmonton, AB T5N 2S2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natacha S.","family":"Ogando","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Alberta, Edmonton, AB T5N 2S2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman W.","family":"Moussa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Alberta, Edmonton, AB T5N 2S2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9342-6227","authenticated-orcid":false,"given":"Nazanin","family":"Mohammadzadeh","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology &amp; Immunology, University of Alberta, Edmonton, AB T5N 2S2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7068-7299","authenticated-orcid":false,"given":"Olivier","family":"Julien","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Alberta, Edmonton, AB T5N 2S2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neal M.","family":"Alto","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8816"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9463-7314","authenticated-orcid":false,"given":"Ryan S.","family":"Noyce","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology &amp; Immunology, University of Alberta, Edmonton, AB T5N 2S2, Canada"},{"name":"Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T5N 2S2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5871-299X","authenticated-orcid":false,"given":"David H.","family":"Evans","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology &amp; Immunology, University of Alberta, Edmonton, AB T5N 2S2, Canada"},{"name":"Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T5N 2S2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Power","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Alberta, Edmonton, AB T5N 2S2, Canada"},{"name":"Department of Medical Microbiology &amp; Immunology, University of Alberta, Edmonton, AB T5N 2S2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,2,12]]},"reference":[{"key":"e_1_3_5_1_2","first-page":"104069","article-title":"The outbreak of monkeypox 2022: An overview","volume":"79","author":"Hraib M.","year":"2022","unstructured":"M. Hraib, S. Jouni, M. M. Albitar, S. Alaidi, Z. Alshehabi, The outbreak of monkeypox 2022: An overview. Ann. Med. Surg. (Lond.) 79, 104069 (2022).","journal-title":"Ann. Med. Surg. (Lond.)"},{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1003.030878"},{"key":"e_1_3_5_3_2","first-page":"165","article-title":"Human monkeypox, 1970\u201379","volume":"58","author":"Breman J. G.","year":"1980","unstructured":"J. G. Breman , Human monkeypox, 1970\u201379. Bull World Health Organ 58, 165\u2013182 (1980).","journal-title":"Bull World Health Organ"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-022-11339-w"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/156.2.293"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciaa143"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1086\/498115"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1086\/425039"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm7138e1"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1186\/1824-7288-40-57"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26597"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.3390\/v15040905"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1177\/0300985810378649"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.3700143"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.2007.76.757"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26473"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2014.11.015"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0005809"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1104.040907"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2022.10.016"},{"key":"e_1_3_5_21_2","doi-asserted-by":"crossref","unstructured":"L. Bauer Dissecting the neurotropism and neurovirulence of MPXV using human stem cell-based models. bioRxiv [Preprint] (2023). https:\/\/doi.org\/10.1101\/2023.08.25.554849 (Accessed 29 August 2023).","DOI":"10.1101\/2023.08.25.554849"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.3390\/v9080215"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens10010006"},{"key":"e_1_3_5_24_2","first-page":"39","article-title":"Multiple cell death modalities and their key features (Review)","volume":"2","author":"Yan G.","year":"2020","unstructured":"G. Yan, M. Elbadawi, T. Efferth, Multiple cell death modalities and their key features (Review). World Acad. Sci. J. 2, 39\u201348 (2020).","journal-title":"World Acad. Sci. J."},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2019.11.005"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygeno.2007.01.003"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202300573R"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-031210-101405"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202000735"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz7548"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11139-3"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb9818"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-015-0586-x"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02124823"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2005.02.014"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(22)00741-1"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00154-z"},{"key":"e_1_3_5_38_2","doi-asserted-by":"crossref","unstructured":"I. N. Boys A. G. Johnson M. Quinlan P. J. Kranzusch N. C. Elde Structural homology screens reveal poxvirus-encoded proteins impacting inflammasome-mediated defenses. Cell Rep. 42 112878 (2023).","DOI":"10.1016\/j.celrep.2023.112878"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0113690"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.00102-22"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.3390\/v15040974"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.04.036"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.3390\/v15071533"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2015.6622"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14122732"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2007.10.040"},{"key":"e_1_3_5_47_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02298200"},{"key":"e_1_3_5_48_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0312-22.2022"},{"key":"e_1_3_5_49_2","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4690-11-35"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2315653121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T15:21:02Z","timestamp":1713367262000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2315653121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,12]]},"references-count":49,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2024,2,20]]}},"alternative-id":["10.1073\/pnas.2315653121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2315653121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,12]]},"assertion":[{"value":"2023-09-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2315653121"}}