Use of SLAM and PVRL4 and Identification of Pro-HB-EGF as Cell Entry Receptors for Wild Type Phocine Distemper Virus

Abstract

Signalling lymphocyte activation molecule (SLAM) has been identified as an immune cell receptor for the morbilliviruses, measles (MV), canine distemper (CDV), rinderpest and peste des petits ruminants (PPRV) viruses, while CD46 is a receptor for vaccine strains of MV. More recently poliovirus like receptor 4 (PVRL4), also known as nectin 4, has been identified as a receptor for MV, CDV and PPRV on the basolateral surface of polarised epithelial cells. PVRL4 is also up-regulated by MV in human brain endothelial cells. Utilisation of PVRL4 as a receptor by phocine distemper virus (PDV) remains to be demonstrated as well as confirmation of use of SLAM. We have observed that unlike wild type (wt) MV or wtCDV, wtPDV strains replicate in African green monkey kidney Vero cells without prior adaptation, suggesting the use of a further receptor. We therefore examined candidate molecules, glycosaminoglycans (GAG) and the tetraspan proteins, integrin β and the membrane bound form of heparin binding epithelial growth factor (proHB-EGF),for receptor usage by wtPDV in Vero cells. We show that wtPDV replicates in Chinese hamster ovary (CHO) cells expressing SLAM and PVRL4. Similar wtPDV titres are produced in Vero and VeroSLAM cells but more limited fusion occurs in the latter. Infection of Vero cells was not inhibited by anti-CD46 antibody. Removal/disruption of GAG decreased fusion but not the titre of virus. Treatment with anti-integrin β antibody increased rather than decreased infection of Vero cells by wtPDV. However, infection was inhibited by antibody to HB-EGF and the virus replicated in CHO-proHB-EGF cells, indicating use of this molecule as a receptor. Common use of SLAM and PVRL4 by morbilliviruses increases the possibility of cross-species infection. Lack of a requirement for wtPDV adaptation to Vero cells raises the possibility of usage of proHB-EGF as a receptor in vivo but requires further investigation.

Unraveling virus relationships by structure-based phylogenetic classification

“…Paramyxoviral RBPs categorize according to functionality into three groups: hemagglutinin-neuraminidase (HN), hemagglutinin (H), and attachment (G) glycoproteins. HN RBPs bind and hydrolyze sialic acid (Villar and Barroso 2006), H RBPs are presented by morbilliviruses and recognize SLAMF1 and nectin-4 receptors (Bieringer et al 2013;Birch et al 2013;Noyce, Delpeut, and Richardson 2013;Sakai et al 2013;Melia et al 2014;Ader-Ebert et al 2015;Alves et al 2015;Feng et al 2016;Khosravi et al 2016), and most henipaviral G RBPs are specific to ephrin receptors (Bonaparte et al 2005;Negrete et al 2005;Bowden, Jones, and Stuart 2011;Pernet, Wang, and Lee 2012;Rissanen et al 2017). SBPA of known paramyxoviral HN, H, and G RBP structures has shown that these viral proteins segregate according to receptor-specificity (Bowden et al 2008;Lee et al 2015;Rissanen et al 2017;Stelfox and Bowden 2019;Pryce et al 2020) (Fig.…”

Phocine Distemper Virus: Current Knowledge and Future Directions

“…The specific interaction of the viral H and F glycoproteins with the host cell receptor(s) determines host susceptibility, tissue tropism and viral pathogenesis. However, because morbilliviruses infect a number of different cell types in vivo including leucocytes, epithelial, endothelial and neural cells, more than one receptor type is required [ 59 ].…”

Candidate gene molecular markers as tools for analyzing genetic susceptibility to morbillivirus infection in stranded Cetaceans

“…Morbillivirus infections caused by MeV, CDV, and DMV share similar patho‐morphological features . The same type of morbillivirus entry receptors was identified in multiple host species . These facts, along with the common phylogenetic origin of morbilliviruses, support the idea of common basic pathogenetic mechanisms in all morbillivirus infections.…”

“…However, the role of SLAMF1 and other viral receptor molecules in infection outcome in Cetaceans and possible interspecies transmission remains unknown . The poliovirus receptor‐like 4 (NECTIN4) molecule has been identified as the epithelial cell receptor for MeV, PDV, CDV and peste‐des‐petits‐ruminants virus (PPRV) . Basigin ( BSG, CD147 ), which could be of special interest in SSPE‐affected patients, acts as a (cyclophilin B‐coated) MeV cell entry receptor on cells not expressing the SLAMF1 molecule, such as epithelial or neuronal cells.…”