Human otic progenitor cell models of congenital hearing loss reveal potential pathophysiologic mechanisms of Zika virus and cytomegalovirus infections
ABSTRACTCongenital hearing loss is a common chronic condition affecting children in both developed and developing nations. Viruses correlated with congenital hearing loss include human cytomegalovirus (HCMV) and Zika virus (ZIKV), which causes congenital Zika syndrome. The mechanisms by which HCMV a...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2024-04-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00199-24 |
| _version_ | 1797215320013799424 |
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| author | Alfred T. Harding Karen Ocwieja Minjin Jeong Yichen Zhang Valerie Leger Nairuti Jhala Konstantina M. Stankovic Lee Gehrke |
| author_facet | Alfred T. Harding Karen Ocwieja Minjin Jeong Yichen Zhang Valerie Leger Nairuti Jhala Konstantina M. Stankovic Lee Gehrke |
| author_sort | Alfred T. Harding |
| collection | DOAJ |
| description | ABSTRACTCongenital hearing loss is a common chronic condition affecting children in both developed and developing nations. Viruses correlated with congenital hearing loss include human cytomegalovirus (HCMV) and Zika virus (ZIKV), which causes congenital Zika syndrome. The mechanisms by which HCMV and ZIKV infections cause hearing loss are poorly understood. It is challenging to study human inner ear cells because they are encased in bone and also scarce as autopsy samples. Recent advances in culturing human stem cell-derived otic progenitor cells (OPCs) have allowed us herein to describe successful in vitro infection of OPCs with HCMV and ZIKV, and also to propose potential mechanisms by which each viral infection could affect hearing. We find that ZIKV infection rapidly and significantly induces the expression of type I interferon and interferon-stimulated genes, while OPC viability declines, at least in part, from apoptosis. In contrast, HCMV infection did not appear to upregulate interferons or cause a reduction in cell viability, and instead disrupted expression of key genes and pathways associated with inner ear development and function, including Cochlin, nerve growth factor receptor, SRY-box transcription factor 11, and transforming growth factor-beta signaling. These findings suggest that ZIKV and HCMV infections cause congenital hearing loss through distinct pathways, that is, by inducing progenitor cell death in the case of ZIKV infection, and by disruption of critical developmental pathways in the case of HCMV infection.IMPORTANCECongenital virus infections inflict substantial morbidity and devastating disease in neonates worldwide, and hearing loss is a common outcome. It has been difficult to study viral infections of the human hearing apparatus because it is embedded in the temporal bone of the skull. Recent technological advances permit the differentiation of otic progenitor cells (OPCs) from human-induced pluripotent stem cells. This paper is important for demonstrating that inner ear virus infections can be modeled in vitro using OPCs. We infected OPCs with two viruses associated with congenital hearing loss: human cytomegalovirus (HCMV), a DNA virus, or Zika virus (ZIKV), an RNA virus. An important result is that the gene expression and cytokine production profiles of HCMV/ZIKV-infected OPCs are markedly dissimilar, suggesting that mechanisms of hearing loss are also distinct. The specific molecular regulatory pathways identified in this work could suggest important targets for therapeutics. |
| first_indexed | 2024-04-24T11:28:11Z |
| format | Article |
| id | doaj.art-d952475ee8e2487e8275ecf2a527d2d4 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-24T11:28:11Z |
| publishDate | 2024-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-d952475ee8e2487e8275ecf2a527d2d42024-04-10T13:01:15ZengAmerican Society for MicrobiologymBio2150-75112024-04-0115410.1128/mbio.00199-24Human otic progenitor cell models of congenital hearing loss reveal potential pathophysiologic mechanisms of Zika virus and cytomegalovirus infectionsAlfred T. Harding0Karen Ocwieja1Minjin Jeong2Yichen Zhang3Valerie Leger4Nairuti Jhala5Konstantina M. Stankovic6Lee Gehrke7Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USAInstitute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USADepartment of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USAInstitute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USAInstitute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USAInstitute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USADepartment of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USAInstitute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USAABSTRACTCongenital hearing loss is a common chronic condition affecting children in both developed and developing nations. Viruses correlated with congenital hearing loss include human cytomegalovirus (HCMV) and Zika virus (ZIKV), which causes congenital Zika syndrome. The mechanisms by which HCMV and ZIKV infections cause hearing loss are poorly understood. It is challenging to study human inner ear cells because they are encased in bone and also scarce as autopsy samples. Recent advances in culturing human stem cell-derived otic progenitor cells (OPCs) have allowed us herein to describe successful in vitro infection of OPCs with HCMV and ZIKV, and also to propose potential mechanisms by which each viral infection could affect hearing. We find that ZIKV infection rapidly and significantly induces the expression of type I interferon and interferon-stimulated genes, while OPC viability declines, at least in part, from apoptosis. In contrast, HCMV infection did not appear to upregulate interferons or cause a reduction in cell viability, and instead disrupted expression of key genes and pathways associated with inner ear development and function, including Cochlin, nerve growth factor receptor, SRY-box transcription factor 11, and transforming growth factor-beta signaling. These findings suggest that ZIKV and HCMV infections cause congenital hearing loss through distinct pathways, that is, by inducing progenitor cell death in the case of ZIKV infection, and by disruption of critical developmental pathways in the case of HCMV infection.IMPORTANCECongenital virus infections inflict substantial morbidity and devastating disease in neonates worldwide, and hearing loss is a common outcome. It has been difficult to study viral infections of the human hearing apparatus because it is embedded in the temporal bone of the skull. Recent technological advances permit the differentiation of otic progenitor cells (OPCs) from human-induced pluripotent stem cells. This paper is important for demonstrating that inner ear virus infections can be modeled in vitro using OPCs. We infected OPCs with two viruses associated with congenital hearing loss: human cytomegalovirus (HCMV), a DNA virus, or Zika virus (ZIKV), an RNA virus. An important result is that the gene expression and cytokine production profiles of HCMV/ZIKV-infected OPCs are markedly dissimilar, suggesting that mechanisms of hearing loss are also distinct. The specific molecular regulatory pathways identified in this work could suggest important targets for therapeutics.https://journals.asm.org/doi/10.1128/mbio.00199-24human cytomegalovirusorganoidinner earZika virushearing lossvirus infection |
| spellingShingle | Alfred T. Harding Karen Ocwieja Minjin Jeong Yichen Zhang Valerie Leger Nairuti Jhala Konstantina M. Stankovic Lee Gehrke Human otic progenitor cell models of congenital hearing loss reveal potential pathophysiologic mechanisms of Zika virus and cytomegalovirus infections mBio human cytomegalovirus organoid inner ear Zika virus hearing loss virus infection |
| title | Human otic progenitor cell models of congenital hearing loss reveal potential pathophysiologic mechanisms of Zika virus and cytomegalovirus infections |
| title_full | Human otic progenitor cell models of congenital hearing loss reveal potential pathophysiologic mechanisms of Zika virus and cytomegalovirus infections |
| title_fullStr | Human otic progenitor cell models of congenital hearing loss reveal potential pathophysiologic mechanisms of Zika virus and cytomegalovirus infections |
| title_full_unstemmed | Human otic progenitor cell models of congenital hearing loss reveal potential pathophysiologic mechanisms of Zika virus and cytomegalovirus infections |
| title_short | Human otic progenitor cell models of congenital hearing loss reveal potential pathophysiologic mechanisms of Zika virus and cytomegalovirus infections |
| title_sort | human otic progenitor cell models of congenital hearing loss reveal potential pathophysiologic mechanisms of zika virus and cytomegalovirus infections |
| topic | human cytomegalovirus organoid inner ear Zika virus hearing loss virus infection |
| url | https://journals.asm.org/doi/10.1128/mbio.00199-24 |
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