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

Abstract

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 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.

Overcoming the Barrier of the Respiratory Epithelium during Canine Distemper Virus Infection

“…In vitro studies revealed that MeV-infected human macrophages gain the ability to stretch and migrate through filter membranes with a pore size of 3.0 μm and to transmit infection to differentiated airway epithelial cells ( 26 ). Immunocyte-mediated transmission of MeV infection has also been demonstrated with 3D culture systems ( 39 , 40 ). It is believed that after the virus is systemically disseminated in the body, immunocytes carry MeV back to the subepithelial region and transmit the infection to airway epithelial cells ( 41 ).…”

The Manifold Roles of Sphingolipids in Viral Infections

“…In this respect, it is interesting that studies performed in 3D cultures modeling the respiratory tract supported a key role of MV-induced S1P to promote fast ameboid migration of dendritic cells toward the lung epithelial cell layer. As dendritic cells function as cellular ferries of MV, this may be important for transmitting MV during viral exit from the infected individual ( Derakhshani et al, 2019 ).…”

Sphingolipids: Effectors and Achilles Heals in Viral Infections?

“…Rather than acting on a viral target directly, the latter particularly affected cellular activities including mTORC1 and Hsp90, supporting the interpretation that MV promotes activation of these pathways to ensure efficient replication [ 132 ]. Recent studies performed in 3D cultures modeling the respiratory tract supported a key role of MV-induced S1P to promote fast ameboid migration of DCs toward the lung epithelial cell layer as important for transmission during viral exit from the infected individual [ 133 ].…”