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

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 ( IMPORTANCEMeasles 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. M easles virus (MeV) is extremely contagious and infects its human host via the respiratory route. For many years, MeV was thought to enter through the apical surface of airway epithelial cells (1), a misconception based on studies performed with polarized immortalized cell lines (2, 3). Using well-differentiated primary cultures of airway epithelial cells from human donors (HAE), we demonstrated that MeV has a clear preference for basolateral entry (4). HAE differentiate into a pseudostratified columnar epithelium sheet comprised of ciliated, nonciliated, basal, and goblet cells. This model system is highly representative of the in vivo airways (5). MeV infection of HAE results in the formation of infectious centers that, unlike syncytia, retain intact plasma membranes (4, 6, 7). MeV-mediated infectious-center formation in HAE differs from that of most paramyxoviruses (7) and may result from the unique receptor specificity of the Morbillivirus genus (8-11). Indeed, we have shown that infectious-center formation in HAE results from direct cell-to-cell spread and is facilitated by the nectin-4/afadin complex (7). These studies highlight the importance of using an appropriate model system to study MeV entry and spread.How MeV eventually reaches the airway epithelium during a natural infection is less clear. Initially, the infection may be ferried through the epithelium by myeloid cells that sample the airway lumen and express the primary MeV receptor signaling lymphocyte a...

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