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Nectin-4 Is the Measles Virus Host Exit Receptor: Implications for Other Respiratory Infections and for Oncolysis

Mateo, Mathieu; Muehlebach, Michael D; Sinn, Patrick L; Pruefer, Steffen; Uhlig, Katharina M; Leonard, Vincent H J; Navaratnarajah, Chanakha K; Frenzke, Marie; Wong, Xiao Xiang; Sawatsky, Bevan; Ramachandran, Shyam; McCray, Paul B; Cichutek, Klaus; von Messling, Véronika; Lopez, Marc et Cattaneo, Roberto (2012). Nectin-4 Is the Measles Virus Host Exit Receptor: Implications for Other Respiratory Infections and for Oncolysis In: 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), May 16-19, 2012, Philadelphia, PA.

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While developing methods for direct pulmonary gene transfer a decade ago, we observed that vaccine-lineage measles virus transduces the basolateral, rather than the apical, surface of human airway epithelia (Sinn et al., 2002, J. Virol. 76, 2403-9). This observation prompted experimental scrutiny of the textbook assumption that measles replicates in the respiratory epithelium before disseminating. We now know that it does not: wild type and vaccine measles strains initially infect macrophages and dendritic cells of the airways that express the primary receptor SLAM. These cells then cross the respiratory epithelium and ferry the virus to lymphatic organs, where it replicates vigorously. However, how and where the virus crosses back into the airways remained unknown. On the basis of functional analyses of surface proteins preferentially expressed on virus-permissive human epithelial cell lines, we have identified nectin-4 (also called poliovirus receptor like 4, PVRL4) as a candidate host exit receptor (Muehlebach et al., 2011, Nature 480, 530-3). We also showed that this adherens junction protein of the immunoglobulin superfamily interacts with the viral attachment protein with high affinity through its membrane-distal domain (dissociation constant: 20 nM that is 4-5 stronger than that of the primary receptor SLAM, and that of the attenuation receptor CD46). Nectin-4 sustains virus entry in well-differentiated primary human airway epithelial sheets infected basolaterally, and is downregulated in infected epithelial cells, including those in the trachea of experimentally infected macaques. While measles virus emergence in the tracheobronchial airways may account for its extraordinarily high reproductive rate in naive populations, we suggest that other respiratory viruses use proteins expressed basolaterally in airways epithelia as host exit receptors. Identification of the measles virus epithelial receptor may have direct consequences for current measles-based cancer clinical trials: because most ovarian cancers are of epithelial origin, nectin-4 expression is worth considering as inclusion criterion. Moreover, since nectin-4 is abundant in lung and breast tumors, measles-based oncolytic therapy should be considered. More generally, it is striking that most viruses currently in cancer clinical trials exploit junction proteins as receptors. Thus enhanced accessibility of these proteins in disordered cancer tissue may facilitate viral entry, and contribute to efficient oncolysis.

Type de document: Document issu d'une conférence ou d'un atelier
Informations complémentaires: Présentation orale 103 Molecular Therapy 20 (suppl.1):S43-S43
Mots-clés libres: -
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 28 janv. 2024 14:56
Dernière modification: 28 janv. 2024 14:56
URI: https://espace.inrs.ca/id/eprint/14132

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