Sammanfattning
Enteroviruses, particularly the group B coxsackieviruses (CVBs), have been associated with the development of type 1 diabetes. Several CVB serotypes establish chronic infections in human cells in vivo and in vitro. However, the mechanisms leading to enterovirus persistency and, possibly, beta cell autoimmunity are not fully understood. We established a carrier-state-type persistent infection model in human pancreatic cell line PANC-1 using two distinct CVB1 strains and profiled the infection-induced changes in cellular transcriptome. In the current study, we observed clear changes in the gene expression of factors associated with the pancreatic microenvironment, the secretory pathway, and lysosomal biogenesis during persistent CVB1 infections. Moreover, we found that the antiviral response pathways were activated differently by the two CVB1 strains. Overall, our study reveals extensive transcriptional responses in persistently CVB1-infected pancreatic cells with strong opposite but also common changes between the two strains.
| Originalspråk | Engelska |
|---|---|
| Artikelnummer | 103653 |
| Tidskrift | iScience |
| Volym | 25 |
| Nummer | 1 |
| DOI | |
| Status | Publicerad - 21 jan. 2022 |
| MoE-publikationstyp | A1 Tidskriftsartikel-refererad |
Åtkomst av dokument
- Persistent coxsackievirus B1 infection triggers extensive changes in the transcriptome of human pancreatic ductal cellsSlutlig publicerad version, 3,42 MBLicens: CC BY-NC-ND
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I: iScience, Vol. 25, Nr. 1, 103653, 21.01.2022.
Forskningsoutput: Tidskriftsbidrag › Artikel › Vetenskaplig › Peer review
TY - JOUR
T1 - Persistent coxsackievirus B1 infection triggers extensive changes in the transcriptome of human pancreatic ductal cells
AU - Buchacher, Tanja
AU - Honkimaa, Anni
AU - Välikangas, Tommi
AU - Lietzén, Niina
AU - Hirvonen, M. Karoliina
AU - Laiho, Jutta E.
AU - Sioofy-Khojine, Amir Babak
AU - Eskelinen, Eeva Liisa
AU - Hyöty, Heikki
AU - Elo, Laura L.
AU - Lahesmaa, Riitta
N1 - Funding Information: We acknowledge Sarita Heinonen (Turku Bioscience Center, University of Turku) for the technical assistance and Saara Koskela (Turku Bioscience Center, University of Turku) for technical help with immunoblotting. Anne Karjalainen, Mervi Kekäläinen, Maria Ovaskainen, Eveliina Paloniemi, and Eeva Tolvanen (Faculty of Medicine and Health Technology, Tampere University) are acknowledged for their technical support. The RNA sequencing analyses presented in this work were performed at the Finnish Functional Genomics Centre of the Turku Bioscience Center that belongs to Biocenter Finland Genome-Wide Methods network. The microscopy experiments were performed at Tampere Imaging Facility, BioMediTech, Faculty of Medicine and Health Technology, Tampere University. The Finnish Centre for Scientific Computing (CSC) is acknowledged for its efficient servers and data analysis resources. The graphical abstract was created with BioRender.com. This work was financially supported by the European Commission (Persistent Virus Infection in Diabetes Network [PEVNET] Frame Programme 7, contract number 261441 ) and by the Finnish Diabetes Research Foundation (grant to R.L., including personal grant for T.B.). R.L. and L.L.E. groups are also supported by InFLAMES Flagship Programme of the Academy of Finland (decision number: 337530 ). R.L. has been supported by the Academy of Finland grants 292335 , 294337 , 319280 , 31444 , 329277 , 331790 , grants from the JDRF and the Sigrid Jusélius Foundation , the Finnish Cancer Foundation , and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115797 (INNODIA). This Joint Undertaking receives support from the Union's Horizon 2020 Research and Innovation Program and “EFPIA,” “JDRF,” and “The Leona M. and Harry B. Helmsley Charitable Trust.” N.L. was supported by the Academy of Finland 287423 . M.K.H. has been supported by the Turku Doctoral Programme of Molecular Medicine (TuDMM) of the University of Turku and by grants from The Finnish Cultural Foundation and Kyllikki and Uolevi Lehikoinen Foundation . T.V. is supported by the Doctoral Programme in Mathematics and Computer Sciences (MATTI) of the University of Turku. L.L.E. reports grants from the European Research Council ERC ( 677943 ), European Union's Horizon 2020 Research and Innovation Programme ( 955321 ), Academy of Finland ( 296801 , 310561 , 314443 , 329278 , 335434 and 335611 ), and Sigrid Jusélius Foundation, during the conduct of the study. H.H. has been supported by Sigrid Jusélius Foundation grant (no grant number), Academy of Finland grant (No. 288671 ), Reino Lahtikari Foundation grant (no grant number), The European Union program Frame Programme 7 (Persistent Virus Infection in Diabetes Network PEVNET, contract number 261441), and the European Union's Horizon 2020 Research and Innovation Programme (Human Exposomic Determinants of Immune Mediated Diseases HEDIMED consortium, Grant Agreement 874864). A.H. has got funding from Tampere University PhD Training Program and from Diabetes Research Foundation (no grant number) and J.E.L from Päivikki and Sakari Sohlberg’s Foundation (no grant number) and Yrjö Jahnsson’s Foundation (no grant number). Funding Information: We acknowledge Sarita Heinonen (Turku Bioscience Center, University of Turku) for the technical assistance and Saara Koskela (Turku Bioscience Center, University of Turku) for technical help with immunoblotting. Anne Karjalainen, Mervi Kek?l?inen, Maria Ovaskainen, Eveliina Paloniemi, and Eeva Tolvanen (Faculty of Medicine and Health Technology, Tampere University) are acknowledged for their technical support. The RNA sequencing analyses presented in this work were performed at the Finnish Functional Genomics Centre of the Turku Bioscience Center that belongs to Biocenter Finland Genome-Wide Methods network. The microscopy experiments were performed at Tampere Imaging Facility, BioMediTech, Faculty of Medicine and Health Technology, Tampere University. The Finnish Centre for Scientific Computing (CSC) is acknowledged for its efficient servers and data analysis resources. The graphical abstract was created with BioRender.com. This work was financially supported by the European Commission (Persistent Virus Infection in Diabetes Network [PEVNET] Frame Programme 7, contract number 261441) and by the Finnish Diabetes Research Foundation (grant to R.L. including personal grant for T.B.). R.L. and L.L.E. groups are also supported by InFLAMES Flagship Programme of the Academy of Finland (decision number: 337530). R.L. has been supported by the Academy of Finland grants 292335, 294337, 319280, 31444, 329277, 331790, grants from the JDRF and the Sigrid Jus?lius Foundation, the Finnish Cancer Foundation, and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115797 (INNODIA). This Joint Undertaking receives support from the Union's Horizon 2020 Research and Innovation Program and ?EFPIA,? ?JDRF,? and ?The Leona M. and Harry B. Helmsley Charitable Trust.? N.L. was supported by the Academy of Finland 287423. M.K.H. has been supported by the Turku Doctoral Programme of Molecular Medicine (TuDMM) of the University of Turku and by grants from The Finnish Cultural Foundation and Kyllikki and Uolevi Lehikoinen Foundation. T.V. is supported by the Doctoral Programme in Mathematics and Computer Sciences (MATTI) of the University of Turku. L.L.E. reports grants from the European Research Council ERC (677943), European Union's Horizon 2020 Research and Innovation Programme (955321), Academy of Finland (296801, 310561, 314443, 329278, 335434 and 335611), and Sigrid Jus?lius Foundation, during the conduct of the study. H.H. has been supported by Sigrid Jus?lius Foundation grant (no grant number), Academy of Finland grant (No. 288671), Reino Lahtikari Foundation grant (no grant number), The European Union program Frame Programme 7 (Persistent Virus Infection in Diabetes Network PEVNET, contract number 261441), and the European Union's Horizon 2020 Research and Innovation Programme (Human Exposomic Determinants of Immune Mediated Diseases HEDIMED consortium, Grant Agreement 874864). A.H. has got funding from Tampere University PhD Training Program and from Diabetes Research Foundation (no grant number) and J.E.L from P?ivikki and Sakari Sohlberg's Foundation (no grant number) and Yrj? Jahnsson's Foundation (no grant number). T.B. designed and performed the transcriptomics and immunoblotting experiments, analyzed data, interpreted results, prepared figures, and wrote the manuscript. A.H. and A.-B.S.-K. established the persistent infection model. A.H. A.-B.S.-K. and J.E.L. performed autophagic flux experiments and immunofluorescence staining and provided the samples. A.-B.S.-K. and J.E.L. critically revised the manuscript. A.H. was responsible for the imaging experiments and wrote part of the manuscript. T.V. performed major part of the computational analysis, prepared figures, and wrote part of the methods. N.L. and M.K.H. provided expertise and carefully revised the manuscript. E.-L.E. provided expertise in autophagy assessment, provided guidance, and critically revised the manuscript. L.L.E. provided expertise and critically revised the manuscript. H.H. initiated the study, provided expertise and supervision, and critically revised the manuscript. R.L. initiated and supervised the study, provided expertise and critically revised the manuscript. All authors have contributed to the final version of the manuscript. H.H. is a shareholder and chairman of the board of Vactech Ltd (http://www.vactech.fi/en/), which develops vaccines against picornaviruses. H.H. serves on the scientific advisory board of Provention Bio Inc. which is developing a clinical CVB vaccine in collaboration with Vactech Ltd. Publisher Copyright: © 2021
PY - 2022/1/21
Y1 - 2022/1/21
N2 - Enteroviruses, particularly the group B coxsackieviruses (CVBs), have been associated with the development of type 1 diabetes. Several CVB serotypes establish chronic infections in human cells in vivo and in vitro. However, the mechanisms leading to enterovirus persistency and, possibly, beta cell autoimmunity are not fully understood. We established a carrier-state-type persistent infection model in human pancreatic cell line PANC-1 using two distinct CVB1 strains and profiled the infection-induced changes in cellular transcriptome. In the current study, we observed clear changes in the gene expression of factors associated with the pancreatic microenvironment, the secretory pathway, and lysosomal biogenesis during persistent CVB1 infections. Moreover, we found that the antiviral response pathways were activated differently by the two CVB1 strains. Overall, our study reveals extensive transcriptional responses in persistently CVB1-infected pancreatic cells with strong opposite but also common changes between the two strains.
AB - Enteroviruses, particularly the group B coxsackieviruses (CVBs), have been associated with the development of type 1 diabetes. Several CVB serotypes establish chronic infections in human cells in vivo and in vitro. However, the mechanisms leading to enterovirus persistency and, possibly, beta cell autoimmunity are not fully understood. We established a carrier-state-type persistent infection model in human pancreatic cell line PANC-1 using two distinct CVB1 strains and profiled the infection-induced changes in cellular transcriptome. In the current study, we observed clear changes in the gene expression of factors associated with the pancreatic microenvironment, the secretory pathway, and lysosomal biogenesis during persistent CVB1 infections. Moreover, we found that the antiviral response pathways were activated differently by the two CVB1 strains. Overall, our study reveals extensive transcriptional responses in persistently CVB1-infected pancreatic cells with strong opposite but also common changes between the two strains.
KW - Cell biology
KW - Transcriptomics
KW - Virology
UR - http://www.scopus.com/inward/record.url?scp=85121974142&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2021.103653
DO - 10.1016/j.isci.2021.103653
M3 - Article
AN - SCOPUS:85121974142
SN - 2589-0042
VL - 25
JO - iScience
JF - iScience
IS - 1
M1 - 103653
ER -