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Measles Virus Infection Fosters Dendritic Cell Motility in a 3D Environment to Enhance Transmission to Target Cells in the Respiratory Epithelium

  • Transmission of measles virus (MV) from dendritic to airway epithelial cells is considered as crucial to viral spread late in infection. Therefore, pathways and effectors governing this process are promising targets for intervention. To identify these, we established a 3D respiratory tract model where MV transmission by infected dendritic cells (DCs) relied on the presence of nectin-4 on H358 lung epithelial cells. Access to recipient cells is an important prerequisite for transmission, and we therefore analyzed migration of MV-exposed DC cultures within the model. Surprisingly, enhanced motility toward the epithelial layer was observed for MV-infected DCs as compared to their uninfected siblings. This occurred independently of factors released from H358 cells indicating that MV infection triggered cytoskeletal remodeling associated with DC polarization enforced velocity. Accordingly, the latter was also observed for MV-infected DCs in collagen matrices and was particularly sensitive to ROCK inhibition indicating infected DCsTransmission of measles virus (MV) from dendritic to airway epithelial cells is considered as crucial to viral spread late in infection. Therefore, pathways and effectors governing this process are promising targets for intervention. To identify these, we established a 3D respiratory tract model where MV transmission by infected dendritic cells (DCs) relied on the presence of nectin-4 on H358 lung epithelial cells. Access to recipient cells is an important prerequisite for transmission, and we therefore analyzed migration of MV-exposed DC cultures within the model. Surprisingly, enhanced motility toward the epithelial layer was observed for MV-infected DCs as compared to their uninfected siblings. This occurred independently of factors released from H358 cells indicating that MV infection triggered cytoskeletal remodeling associated with DC polarization enforced velocity. Accordingly, the latter was also observed for MV-infected DCs in collagen matrices and was particularly sensitive to ROCK inhibition indicating infected DCs preferentially employed the amoeboid migration mode. This was also implicated by loss of podosomes and reduced filopodial activity both of which were retained in MV-exposed uninfected DCs. Evidently, sphingosine kinase (SphK) and sphingosine-1-phosphate (S1P) as produced in response to virus-infection in DCs contributed to enhanced velocity because this was abrogated upon inhibition of sphingosine kinase activity. These findings indicate that MV infection promotes a push-and-squeeze fast amoeboid migration mode via the SphK/S1P system characterized by loss of filopodia and podosome dissolution. Consequently, this enables rapid trafficking of virus toward epithelial cells during viral exit.show moreshow less

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Author details:Shaghayegh DerakhshaniORCiDGND, Andreas Kurz, Lukasz JaptokGND, Fabian SchumacherORCiDGND, Lisa Pilgram, Maria Steinke, Burkhard KleuserORCiDGND, Markus Sauer, Sibylle Schneider-SchauliesORCiD, Elita Avota
DOI:https://doi.org/10.3389/fimmu.2019.01294
ISSN:1664-3224
Pubmed ID:https://pubmed.ncbi.nlm.nih.gov/31231395
Title of parent work (English):Frontiers in immunology
Publisher:Frontiers Research Foundation
Place of publishing:Lausanne
Publication type:Article
Language:English
Date of first publication:2019/06/05
Publication year:2019
Release date:2021/01/26
Tag:3D tissue model; cell migration; dendritic cell; measles virus; sphingosine-1-phosphate
Volume:10
Number of pages:14
Funding institution:Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [DFG GRK 2157]; German Research Foundation (DFG)German Research Foundation (DFG); University ofWuerzburg
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft
DDC classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Peer review:Referiert
Publishing method:Open Access / Gold Open-Access
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License (German):License LogoCC-BY - Namensnennung 4.0 International
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