Monkeypox virus productively infects human induced pluripotent stem cell-derived astrocytes and neural progenitor cells

Chailangkarn, Thanathom; Teeravechyan, Samaporn; Attasombat, Khempitcha; Thaweerattanasinp, Theeradej; Sunchatawirul, Kitpong; Suwanwattana, Pawita; Pongpirul, Krit; Jongkaewwattana, Anan

doi:10.1016/j.jinf.2022.10.016

Cited by 4 publications

(4 citation statements)

References 10 publications

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“…1b, central panel). In contrast to previous reports 29 , hCO-derived neurons were observed to be susceptible to MPXV infection as well, as viral antigen was identified co-localizing with TUJ1 in both perikarya and neurites (Fig. 1c, bottom panels).…”

Section: Neural Progenitor Cells Astrocytes and Neurons Are Susceptib...contrasting

confidence: 99%

“…The infected hCOs were processed for immunofluorescence analysis. In line with recent findings 29 , we observed viral antigen localizing to the cytoplasm of SOX2-expressing cells (Fig. 1b, top panels), indicating susceptibility of NPCs to MPXV infection.…”

Section: Neural Progenitor Cells Astrocytes and Neurons Are Susceptib...supporting

confidence: 92%

“…Recently, Chailangkarn and colleagues, found induced pluripotent stem cell-derived neural progenitor cells and astrocytes to be susceptible to MPXV infection in a two-dimensional culture environment. This was demonstrated by changes in cell morphology and viability, as well as increased viral loads detected in supernatant by qPCR over time 29 . In contrast, 14 and 45-day old neurons did not show productive MPXV infection 27 .…”

Section: Discussionmentioning

confidence: 93%

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Mpox virus spreads from cell-to-cell and leads to neuronal injury in human cerebral organoids

Schultz-Pernice,

Fahmi,

Chiu

et al. 2023

Preprint

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In 2022-23 the world experienced the largest recorded mpox virus (MPXV) outbreak outside of endemic regions. Remarkably, cases of neurological manifestations were reported, some of which fatal. MPXV DNA and MPXV-specific IgM antibodies were detected in the cerebrospinal fluid of encephalitis-affected patients, suggesting neuroinvasive potential of MPXV. We explored the susceptibility of neural tissue to MPXV infection using human cerebral organoids (hCOs) exposed to a primary isolate belonging to clade IIb lineage. The virus efficiently replicates in hCOs as indicated by the exponential increase of infectious viral loads and the elevated frequency of MPXV-positive cells over time. Also, electron microscopy imaging revealed the presence of viral particles as well as perinuclear viral factories. We observed susceptibility of several cell lineages to the virus, including neural progenitor cells, neurons, and astrocytes. Furthermore, we detected the presence of viral antigens in neurites and in foci of grouped cells distributed throughout the tissue. In line with this, examining released and cell-associated MPXV titers, we observed significantly more cell-associated infectious virus, suggesting viral spread by cell-to-cell contact. While hCOs displayed no evident outer morphological changes upon infection, we detected the formation of varicosities in neurites, pointing to viral manipulation of axonal transport and neuronal injury. In accordance, the apoptosis marker cleaved caspase-3 was detected within neurite swellings. Our findings identify a mechanism potentially contributing to MPXV-mediated neuropathology that may have therapeutic implications.

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Section: Neural Progenitor Cells Astrocytes and Neurons Are Susceptib...contrasting

confidence: 99%

Section: Neural Progenitor Cells Astrocytes and Neurons Are Susceptib...supporting

confidence: 92%

Section: Discussionmentioning

confidence: 93%

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Mpox virus spreads from cell-to-cell and leads to neuronal injury in human cerebral organoids

Schultz-Pernice,

Fahmi,

Chiu

et al. 2023

Preprint

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“…In the future, by deleting candidate genes for receptors related to MPXV infection in human keratinocytes or colon organoids, it will be evident whether they truly contribute to MPXV infection. In addition to the skin, MPXV was detected in throat swabs and semen of human mpox patients [26][27][28] and a recent report showed that MPXV can infect human iPS cell-derived astrocytes and neural progenitor cells 29 ; altogether suggesting that MPXV likely has the potential to infect and replicate in these and other organs as well.…”

Section: Discussionmentioning

confidence: 99%

Virological characterization of the 2022 outbreak‐causing monkeypox virus using human keratinocytes and colon organoids

Watanabe¹,

Kimura

Hashimoto³

et al. 2023

Journal of Medical Virology

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The outbreak-causing monkeypox virus of 2022 (2022 MPXV) is classified as a clade IIb strain and phylogenetically distinct from prior endemic MPXV strains (clades I or IIa), suggesting that its virological properties may also differ. Here, we used human keratinocytes and induced pluripotent stem cell-derived colon organoids to examine the efficiency of viral growth in these cells and the MPXV infection-mediated host responses. MPXV replication was much more productive in keratinocytes than in colon organoids. We observed that MPXV infections, regardless of strain, caused cellular dysfunction and mitochondrial damage in keratinocytes. Notably, a significant increase in the expression of hypoxia-related genes was observed specifically in 2022 MPXV-infected keratinocytes. Our comparison of virological features between 2022 MPXV and prior endemic MPXV strains revealed signaling pathways potentially involved with the cellular damages caused by MPXV infections and highlights host vulnerabilities that could be utilized as protective therapeutic strategies against human mpox in the future.

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

Miranzadeh Mahabadi,

Lin,

Ogando

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Monkeypox virus productively infects human induced pluripotent stem cell-derived astrocytes and neural progenitor cells

Cited by 4 publications

References 10 publications

Mpox virus spreads from cell-to-cell and leads to neuronal injury in human cerebral organoids

Mpox virus spreads from cell-to-cell and leads to neuronal injury in human cerebral organoids

Virological characterization of the 2022 outbreak‐causing monkeypox virus using human keratinocytes and colon organoids

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

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