Modelling viral encephalitis caused by herpes simplex virus 1 infection in cerebral organoids.
Journal
Nature microbiology
ISSN: 2058-5276
Titre abrégé: Nat Microbiol
Pays: England
ID NLM: 101674869
Informations de publication
Date de publication:
07 2023
07 2023
Historique:
received:
22
07
2022
accepted:
10
05
2023
medline:
7
7
2023
pubmed:
23
6
2023
entrez:
22
6
2023
Statut:
ppublish
Résumé
Herpes simplex encephalitis is a life-threatening disease of the central nervous system caused by herpes simplex viruses (HSVs). Following standard of care with antiviral acyclovir treatment, most patients still experience various neurological sequelae. Here we characterize HSV-1 infection of human brain organoids by combining single-cell RNA sequencing, electrophysiology and immunostaining. We observed strong perturbations of tissue integrity, neuronal function and cellular transcriptomes. Under acyclovir treatment viral replication was stopped, but did not prevent HSV-1-driven defects such as damage of neuronal processes and neuroepithelium. Unbiased analysis of pathways deregulated upon infection revealed tumour necrosis factor activation as a potential causal factor. Combination of anti-inflammatory drugs such as necrostatin-1 or bardoxolone methyl with antiviral treatment prevented the damages caused by infection, indicating that tuning the inflammatory response in acute infection may improve current therapeutic strategies.
Identifiants
pubmed: 37349587
doi: 10.1038/s41564-023-01405-y
pii: 10.1038/s41564-023-01405-y
pmc: PMC10322700
doi:
Substances chimiques
Acyclovir
X4HES1O11F
Antiviral Agents
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1252-1266Informations de copyright
© 2023. The Author(s).
Références
Thellman, N. M. & Triezenberg, S. J. Herpes simplex virus establishment, maintenance, and reactivation: in vitro modeling of latency. Pathogens 6, 28 (2017).
pubmed: 28644417
pmcid: 5617985
doi: 10.3390/pathogens6030028
Marcocci, M. E. et al. Herpes simplex virus-1 in the brain: the dark side of a sneaky infection. Trends Microbiol. 28, 808–820 (2020).
pubmed: 32386801
doi: 10.1016/j.tim.2020.03.003
Piret, J. & Boivin, G. Immunomodulatory strategies in herpes simplex virus encephalitis. Clin. Microbiol. Rev. 33, e00105–e00119 (2020).
pubmed: 32051176
pmcid: 7018500
doi: 10.1128/CMR.00105-19
Rozenberg, F. Herpes simplex virus and central nervous system infections: encephalitis, meningitis, myelitis. Virologie 24, 283–294 (2020). Oct 1.
pubmed: 33111702
doi: 10.1684/vir.2020.0862
D’Aiuto, L. et al. Modeling herpes simplex virus 1 infections in human central nervous system neuronal cells using two- and three-dimensional cultures derived from induced pluripotent stem cells. J. Virol. https://doi.org/10.1128/jvi.00111-19 (2019).
Sehl, J. et al. An improved animal model for herpesvirus encephalitis in humans. PLoS Pathog. https://doi.org/10.1371/2Fjournal.ppat.1008445 (2020).
Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013).
pubmed: 23995685
doi: 10.1038/nature12517
Qian, X. et al. Generation of human brain region-specific organoids using a miniaturized spinning bioreactor. Nat. Protoc. 13, 565–580 (2018).
pubmed: 29470464
pmcid: 6241211
doi: 10.1038/nprot.2017.152
Quadrato, G. et al. Cell diversity and network dynamics in photosensitive human brain organoids. Nature 545, 48–53 (2017).
pubmed: 28445462
pmcid: 5659341
doi: 10.1038/nature22047
Dang, J. et al. Zika virus depletes neural progenitors in human cerebral organoids through activation of the innate immune receptor TLR3. Cell Stem Cell 19, 258–265 (2016).
pubmed: 27162029
pmcid: 5116380
doi: 10.1016/j.stem.2016.04.014
Garcez, P. P. et al. Zika virus impairs growth in human neurospheres and brain organoids. Science 352, 816–818 (2016).
pubmed: 27064148
doi: 10.1126/science.aaf6116
Qian, X. et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165, 1238–1254 (2016).
pubmed: 27118425
pmcid: 4900885
doi: 10.1016/j.cell.2016.04.032
Watanabe, M. et al. Self-organized cerebral organoids with human-specific features predict effective drugs to combat Zika virus infection. Cell Rep. 21, 517–532 (2017).
pubmed: 29020636
pmcid: 5637483
doi: 10.1016/j.celrep.2017.09.047
Zhang, B. et al. Differential antiviral immunity to Japanese encephalitis virus in developing cortical organoids. Cell Death Dis. 9, 719 (2018).
pubmed: 29915260
pmcid: 6006338
doi: 10.1038/s41419-018-0763-y
Deguchi, S. et al. SARS-CoV-2 research using human pluripotent stem cells and organoids. Stem Cells Transl. Med 10, 1491–1499 (2021).
pubmed: 34302450
pmcid: 8550698
doi: 10.1002/sctm.21-0183
Krenn, V. et al. Organoid modeling of Zika and herpes simplex virus 1 infections reveals virus-specific responses leading to microcephaly. Cell Stem Cell https://doi.org/10.1016/j.stem.2021.03.004 (2021).
Cairns, D. M. et al. A 3D human brain–like tissue model of herpes-induced Alzheimer’s disease. Sci. Adv. 6, eaay8828 (2020).
pubmed: 32494701
pmcid: 7202879
doi: 10.1126/sciadv.aay8828
Qiao, H. et al. Herpes simplex virus type 1 infection leads to neurodevelopmental disorder-associated neuropathological changes. PLoS Pathog. https://doi.org/10.1371/journal.ppat.1008899 (2020).
Nowakowski, T. J. et al. Spatiotemporal gene expression trajectories reveal developmental hierarchies of the human cortex. Science 358, 1318–1323 (2017).
pubmed: 29217575
pmcid: 5991609
doi: 10.1126/science.aap8809
Su, X. et al. Human brain organoids as an in vitro model system of viral infectious diseases. Front. Immunol. 12, 792316 (2021).
pubmed: 35087520
doi: 10.3389/fimmu.2021.792316
Kanton, S. et al. Organoid single-cell genomic atlas uncovers human-specific features of brain development. Nature 574, 418–422 (2019).
pubmed: 31619793
doi: 10.1038/s41586-019-1654-9
Camp, J. G. et al. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc. Natl Acad. Sci. USA 112, 15672–15677 (2015).
pubmed: 26644564
pmcid: 4697386
doi: 10.1073/pnas.1520760112
Qian, X. et al. Sliced human cortical organoids for modeling distinct cortical layer formation. Cell Stem Cell 26, 766–781.e9 (2020).
pubmed: 32142682
pmcid: 7366517
doi: 10.1016/j.stem.2020.02.002
Sandbaumhüter, M. et al. Cytosolic herpes simplex virus capsids not only require binding inner tegument protein pUL36 but also pUL37 for active transport prior to secondary envelopment: the role of pUL36 and pUL37 for HSV1 capsid transport. Cell. Microbiol. 15, 248–269 (2013).
pubmed: 23186167
doi: 10.1111/cmi.12075
Acuña-Hinrichsen, F. et al. Herpes simplex virus type 1 neuronal infection triggers disassembly of key structural components of dendritic spines. Front. Cell Neurosci. https://doi.org/10.3389/fncel.2021.580717 (2020).
Acuña-Hinrichsen, F. et al. Herpes simplex virus type 1 enhances expression of the synaptic protein arc for its own benefit. Front. Cell Neurosci. 12, 505 (2018).
pubmed: 30692913
doi: 10.3389/fncel.2018.00505
Yin, J. & VanDongen, A. M. Enhanced neuronal activity and asynchronous calcium transients revealed in a 3D organoid model of Alzheimer’s disease. ACS Biomater. Sci. Eng. 7, 254–264 (2021).
pubmed: 33347288
doi: 10.1021/acsbiomaterials.0c01583
Krus, K. L. et al. Loss of Stathmin-2, a hallmark of TDP-43-associated ALS, causes motor neuropathy. Cell Rep. 39, 111001 (2022).
pubmed: 35767949
pmcid: 9327139
doi: 10.1016/j.celrep.2022.111001
Melamed, Z. et al. Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration. Nat. Neurosci. 22, 180–190 (2019).
pubmed: 30643298
pmcid: 6348009
doi: 10.1038/s41593-018-0293-z
Kadowaki, M. et al. N-cadherin mediates cortical organization in the mouse brain. Dev. Biol. 304, 22–33 (2007).
pubmed: 17222817
doi: 10.1016/j.ydbio.2006.12.014
Wyler, E. et al. Widespread activation of antisense transcription of the host genome during herpes simplex virus 1 infection. Genome Biol. 18, 209 (2017).
pubmed: 29089033
pmcid: 5663069
doi: 10.1186/s13059-017-1329-5
Tunkel, A. R. et al. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin. Infect. Dis. 47, 303–327 (2008).
pubmed: 18582201
doi: 10.1086/589747
Song, B., Liu, J. J., Yeh, K. C. & Knipe, D. M. Herpes simplex virus infection blocks events in the G1 phase of the cell cycle. Virology 267, 326–334 (2000).
pubmed: 10662628
doi: 10.1006/viro.1999.0146
Squair, J. W. et al. Confronting false discoveries in single-cell differential expression. Nat. Commun. 12, 5692 (2021).
pubmed: 34584091
pmcid: 8479118
doi: 10.1038/s41467-021-25960-2
Dostert, C., Grusdat, M., Letellier, E. & Brenner, D. The TNF family of ligands and receptors: communication modules in the immune system and beyond. Physiol. Rev. 99, 115–160 (2019).
pubmed: 30354964
doi: 10.1152/physrev.00045.2017
Pahl, H. L. Activators and target genes of Rel/NF-κB transcription factors. Oncogene 18, 6853–6866 (1999).
pubmed: 10602461
doi: 10.1038/sj.onc.1203239
Wang, Y. Y., Yang, Y. X., Zhe, H., He, Z. X. & Zhou, S. F. Bardoxolone methyl (CDDO-Me) as a therapeutic agent: an update on its pharmacokinetic and pharmacodynamic properties. Drug Des. Dev. Ther. 8, 2075–2088 (2014).
Smith, I. L., Hardwicke, M. A. & Sandri-Goldin, R. M. Evidence that the herpes simplex virus immediate early protein ICP27 acts post-transcriptionally during infection to regulate gene expression. Virology 186, 74–86 (1992).
pubmed: 1309283
doi: 10.1016/0042-6822(92)90062-T
Furman, D. et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med 25, 1822–1832 (2019).
pubmed: 31806905
pmcid: 7147972
doi: 10.1038/s41591-019-0675-0
Mancini, M. & Vidal, S. M. Insights into the pathogenesis of herpes simplex encephalitis from mouse models. Mamm. Genome 29, 425–445 (2018).
pubmed: 30167845
pmcid: 6132704
doi: 10.1007/s00335-018-9772-5
Boivin, N., Menasria, R., Piret, J., Rivest, S. & Boivin, G. The combination of valacyclovir with an anti-TNF alpha antibody increases survival rate compared to antiviral therapy alone in a murine model of herpes simplex virus encephalitis. Antivir. Res 100, 649–653 (2013).
pubmed: 24416771
doi: 10.1016/j.antiviral.2013.10.007
Sergerie, Y., Boivin, G., Gosselin, D. & Rivest, S. Delayed but not early glucocorticoid treatment protects the host during experimental herpes simplex virus encephalitis in mice. J. Infect. Dis. 195, 817–825 (2007).
pubmed: 17299711
doi: 10.1086/511987
Qian, X., Song, H. & Ming, G. L. Brain organoids: advances, applications and challenges. Development 146(Apr 16), dev166074 (2019).
pubmed: 30992274
pmcid: 6503989
doi: 10.1242/dev.166074
Enquist, L. W. & Leib, D. A. Intrinsic and innate defenses of neurons: détente with the herpesviruses. J. Virol. 91, e01200–e01216 (2017).
pubmed: 27795407
doi: 10.1128/JVI.01200-16
Wang, X. et al. Genome-wide analysis of PDX1 target genes in human pancreatic progenitors. Mol. Metab. 9, 57–68 (2018).
pubmed: 29396371
pmcid: 5870105
doi: 10.1016/j.molmet.2018.01.011
Snijder, B. et al. Single‐cell analysis of population context advances RNAi screening at multiple levels. Mol. Syst. Biol. 8, 579 (2012).
pubmed: 22531119
pmcid: 3361004
doi: 10.1038/msb.2012.9
Wurmus, R. et al. PiGx: reproducible genomics analysis pipelines with GNU Guix. GigaScience 7, giy123 (2018).
pubmed: 30277498
pmcid: 6275446
doi: 10.1093/gigascience/giy123
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
pubmed: 23104886
doi: 10.1093/bioinformatics/bts635
Anders, S., Pyl, P. T. & Huber, W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166–169 (2015).
pubmed: 25260700
doi: 10.1093/bioinformatics/btu638
Frankish, A. et al. GENCODE reference annotation for the human and mouse genomes. Nucleic Acids Res. 47, D766–D773 (2019).
pubmed: 30357393
doi: 10.1093/nar/gky955
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
pubmed: 25516281
pmcid: 4302049
doi: 10.1186/s13059-014-0550-8
Seal, R. L. et al. Genenames.org: the HGNC resources in 2023. Nucleic Acids Res. 51, D1003–D1009 (2023).
pubmed: 36243972
doi: 10.1093/nar/gkac888
Maynard, K. R. et al. Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex. Nat. Neurosci. 24, 425–436 (2021).
pubmed: 33558695
pmcid: 8095368
doi: 10.1038/s41593-020-00787-0
Macosko, E. Z. et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell 161, 1202–1214 (2015).
pubmed: 26000488
pmcid: 4481139
doi: 10.1016/j.cell.2015.05.002
Sztanka-Toth, T. R., Jens, M., Karaiskos, N. & Rajewsky, N. Spacemake: processing and analysis of large-scale spatial transcriptomics data. GigaScience https://doi.org/10.1093/gigascience/giac064 (2022).
Satija, R., Farrell, J. A., Gennert, D., Schier, A. F. & Regev, A. Spatial reconstruction of single-cell gene expression data. Nat. Biotechnol. 33, 495–502 (2015).
pubmed: 25867923
pmcid: 4430369
doi: 10.1038/nbt.3192
Hafemeister, C. & Satija, R. Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression. Genome Biol. https://doi.org/10.1186/s13059-019-1874-1 (2019).
Haghverdi, L., Lun, A. T. L., Morgan, M. D. & Marioni, J. C. Batch effects in single-cell RNA-sequencing data are corrected by matching mutual nearest neighbors. Nat. Biotechnol. 36, 421–427 (2018).
pubmed: 29608177
pmcid: 6152897
doi: 10.1038/nbt.4091
Stuart, T. et al. Comprehensive integration of single cell data. Cell https://doi.org/10.1016/j.cell.2019.05.031 (2019).
Velasco, S. et al. Individual brain organoids reproducibly form cell diversity of the human cerebral cortex. Nature 570, 523–527 (2019).
pubmed: 31168097
pmcid: 6906116
doi: 10.1038/s41586-019-1289-x
Uzquiano, A. et al. Proper acquisition of cell class identity in organoids allows definition of fate specification programs of the human cerebral cortex. Cell 185, 3770–3788 (2022).
pubmed: 36179669
doi: 10.1016/j.cell.2022.09.010
Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010).
pubmed: 19910308
doi: 10.1093/bioinformatics/btp616
Wu, T. et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innovation 2, 100141 (2021).
pubmed: 34557778
pmcid: 8454663
Junek, S., Chen, T. W., Alevra, M. & Schild, D. Activity correlation imaging: visualizing function and structure of neuronal populations. Biophys. J. 96, 3801–3809 (2009).
pubmed: 19413986
pmcid: 2711456
doi: 10.1016/j.bpj.2008.12.3962