Measles virus blind to its epithelial cell receptor remains virulent in rhesus monkeys but cannot cross the airway epithelium and is not shed
Vincent H.J. Leonard, … , Michael B. McChesney, Roberto Cattaneo
Vincent H.J. Leonard, … , Michael B. McChesney, Roberto Cattaneo
Published June 20, 2008
Citation Information: J Clin Invest. 2008;118(7):2448-2458. https://doi.org/10.1172/JCI35454.
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Research Article

Measles virus blind to its epithelial cell receptor remains virulent in rhesus monkeys but cannot cross the airway epithelium and is not shed

Abstract

The current model of measles virus (MV) pathogenesis implies that apical infection of airway epithelial cells precedes systemic spread. An alternative model suggests that primarily infected lymphatic cells carry MV to the basolateral surface of epithelial cells, supporting MV shedding into the airway lumen and contagion. This model predicts that a mutant MV, unable to enter cells through the unidentified epithelial cell receptor (EpR), would remain virulent but not be shed. To test this model, we identified residues of the MV attachment protein sustaining EpR-mediated cell fusion. These nonpolar or uncharged polar residues defined an area located near the binding site of the signaling lymphocytic activation molecule (SLAM), the receptor for MV on lymphatic cells. We then generated an EpR-blind virus maintaining SLAM-dependent cell entry and inoculated rhesus monkeys intranasally. Hosts infected with the selectively EpR-blind MV developed rash and anorexia while averaging slightly lower viremia than hosts infected with wild-type MV but did not shed virus in the airways. The mechanism restricting shedding was characterized using primary well-differentiated human airway epithelial cells. Wild-type MV infected columnar epithelial cells bearing tight junctions only when applied basolaterally, while the EpR-blind virus did not infect these cells. Thus, EpR is probably a basolateral protein, and infection of the airway epithelium is not essential for systemic spread and virulence of MV.

Authors

Vincent H.J. Leonard, Patrick L. Sinn, Gregory Hodge, Tanner Miest, Patricia Devaux, Numan Oezguen, Werner Braun, Paul B. McCray Jr., Michael B. McChesney, Roberto Cattaneo

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Figure 7

Space-filling representations of the solvent-accessible surface of MV Edmonston strain H protein structure with selectively receptor-sensitive amino acids.

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Space-filling representations of the solvent-accessible surface of MV Ed...
Right: side view of the homodimeric protein; left: left monomer after rotation of 90° in a mathematically positive direction around the y axis. The most relevant residues whose mutation selectively abolished receptor-dependent fusion are shown in red or orange (EpR), purple (SLAM), and yellow (CD46). The EpR-relevant residues identified by Tahara et al. (12) are shown in orange. The membrane is represented by a horizontal gray box; those parts of the H protein that were not crystallized (cytoplasmic tail, transmembrane domain, and part of the stalk; that is, amino acids 1–153) are shown by vertical gray boxes. The short red bars between the vertical boxes represent 2 disulfide bonds. The β-sheet propeller blades 4, 5, and 6 are in pink, light blue, and light green, respectively; the other blades are in white. Residue 154, anchor of the protein stalk region, is shown in black.