Cell-to-Cell Contact and Nectin-4 Govern Spread of Measles Virus from Primary Human Myeloid Cells to Primary Human Airway Epithelial Cells

Brajesh K Singh; Ni Li; Anna C Mark; Mathieu Mateo; Roberto Cattaneo; Patrick L Sinn

doi:10.1128/JVI.00266-16

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Cell-to-Cell Contact and Nectin-4 Govern Spread of Measles Virus from Primary Human Myeloid Cells to Primary Human Airway Epithelial Cells

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Cell-to-Cell Contact and Nectin-4 Govern Spread of Measles Virus from Primary Human Myeloid Cells to Primary Human Airway Epithelial Cells

Brajesh K Singh, Ni Li, Anna C Mark, Mathieu Mateo, Roberto Cattaneo and Patrick L Sinn

Journal of virology, Vol.90(15), pp.6808-6817

08/01/2016

DOI: 10.1128/JVI.00266-16

PMCID: PMC4944272

PMID: 27194761

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Abstract

Measles is a highly contagious, acute viral illness. Immune cells within the airways are likely first targets of infection, and these cells traffic measles virus (MeV) to lymph nodes for amplification and subsequent systemic dissemination. Infected immune cells are thought to return MeV to the airways; however, the mechanisms responsible for virus transfer to pulmonary epithelial cells are poorly understood. To investigate this process, we collected blood from human donors and generated primary myeloid cells, specifically, monocyte-derived macrophages (MDMs) and dendritic cells (DCs). MDMs and DCs were infected with MeV and then applied to primary cultures of well-differentiated airway epithelial cells from human donors (HAE). Consistent with previous results obtained with free virus, infected MDMs or DCs were incapable of transferring MeV to HAE when applied to the apical surface. Likewise, infected MDMs or DCs applied to the basolateral surface of HAE grown on small-pore (0.4-μm) support membranes did not transfer virus. In contrast, infected MDMs and DCs applied to the basolateral surface of HAE grown on large-pore (3.0-μm) membranes successfully transferred MeV. Confocal microscopy demonstrated that MDMs and DCs are capable of penetrating large-pore membranes but not small-pore membranes. Further, by using a nectin-4 blocking antibody or recombinant MeV unable to enter cells through nectin-4, we demonstrated formally that transfer from immune cells to HAE occurs in a nectin-4-dependent manner. Thus, both infected MDMs and DCs rely on cell-to-cell contacts and nectin-4 to efficiently deliver MeV to the basolateral surface of HAE. Measles virus spreads rapidly and efficiently in human airway epithelial cells. This rapid spread is based on cell-to-cell contact rather than on particle release and reentry. Here we posit that MeV transfer from infected immune cells to epithelial cells also occurs by cell-to-cell contact rather than through cell-free particles. In addition, we sought to determine which immune cells transfer MeV infectivity to the human airway epithelium. Our studies are based on two types of human primary cells: (i) myeloid cells generated from donated blood and (ii) well-differentiated airway epithelial cells derived from donor lungs. We show that different types of myeloid cells, i.e., monocyte-derived macrophages and dendritic cells, transfer infection to airway epithelial cells. Furthermore, cell-to-cell contact is an important component of successful MeV transfer. Our studies elucidate a mechanism by which the most contagious human respiratory virus is delivered to the airway epithelium.

Measles - virology

Receptors, Virus - metabolism

Humans

Cells, Cultured

Myeloid Cells - virology

Cell Adhesion Molecules - metabolism

Nectins

Virus Internalization

Measles - metabolism

Measles virus - growth & development

Cell Fusion

Respiratory System - virology

Macrophages - virology

Epithelial Cells - virology

Dendritic Cells - virology

Details

Title: Subtitle: Cell-to-Cell Contact and Nectin-4 Govern Spread of Measles Virus from Primary Human Myeloid Cells to Primary Human Airway Epithelial Cells
Creators: Brajesh K Singh - Stead Family Department of Pediatrics, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
Ni Li - Stead Family Department of Pediatrics, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
Anna C Mark - Stead Family Department of Pediatrics, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
Mathieu Mateo - Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
Roberto Cattaneo - Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
Patrick L Sinn - Stead Family Department of Pediatrics, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA patrick-sinn@uiowa.edu
Resource Type: Journal article
Publication Details: Journal of virology, Vol.90(15), pp.6808-6817
DOI: 10.1128/JVI.00266-16
PMID: 27194761
PMCID: PMC4944272
ISSN: 0022-538X
eISSN: 1098-5514
Grant note: R21 AI125747 / NIAID NIH HHS
Language: English
Date published: 08/01/2016
Academic Unit: Microbiology and Immunology; Pulmonary Medicine; Anatomy and Cell Biology; Stead Family Department of Pediatrics
Record Identifier: 9984093477202771

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