Measles Virus: Identification in the M Protein Primary Sequence of a Potential Molecular Marker for Subacute Sclerosing Panencephalitis

Robin Buckland,Michelle Ainouze,Evelyne Manet,Denis Gerlier,Hasan Kweder,Joanna Brunel

doi:10.1155/2015/769837

Abstract

Subacute Sclerosing Panencephalitis (SSPE), a rare lethal disease of children and young adults due to persistence of measles virus (MeV) in the brain, is caused by wild type (wt) MeV. Why MeV vaccine strains never cause SSPE is completely unknown. Hypothesizing that this phenotypic difference could potentially be represented by a molecular marker, we compared glycoprotein and matrix (M) genes from SSPE cases with those from the Moraten vaccine strain, searching for differential structural motifs. We observed that all known SSPE viruses have residues P64, E89, and A209 (PEA) in their M proteins whereas the equivalent residues for vaccine strains are either S64, K89, and T209 (SKT) as in Moraten or PKT. Through the construction of MeV recombinants, we have obtained evidence that the wt MeV-M protein PEA motif, in particular A209, is linked to increased viral spread. Importantly, for the 10 wt genotypes (of 23) that have had their M proteins sequenced, 9 have the PEA motif, the exception being B3, which has PET. Interestingly, cases of SSPE caused by genotype B3 have yet to be reported. In conclusion, our results strongly suggest that the PEA motif is a molecular marker for wt MeV at risk to cause SSPE.

Highlights

Subacute Sclerosing Panencephalitis (SSPE) is caused by measles virus (MeV), a member of the genus Morbillivirus in the family Paramyxoviridae
This study’s starting point was the observation that SSPE is caused only by wt MeV, never by MeV vaccines [27]. This suggests that wt MeV strains possess a phenotypic marker that vaccine strains lack. Hypothesizing that such a phenotypic marker could be represented by an associated molecular marker we decided to compare H, F, and M sequences from SSPE cases with those from vaccine strains searching for differential structural motifs
We were unable to identify any type of molecular marker that differentiated SSPE glycoproteins from their vaccine counterparts except for the differences at residues 481 and 546 in the H protein that have been shown to play a role in allowing vaccine strains to use CD46 as a receptor in addition to SLAM [28, 29]

Summary

Introduction

Subacute Sclerosing Panencephalitis (SSPE) is caused by measles virus (MeV), a member of the genus Morbillivirus in the family Paramyxoviridae. The glycoproteins H (hemagglutinin) and F (fusion) project from the virion membrane as spikes. The H protein is responsible for attachment to the cellular receptors and the F protein for the consequent fusion of the virion membrane with the host cell’s plasma membrane [1]. The glycoproteins accumulate in the plasma membrane where they interact with cellular receptors on neighboring uninfected cells to cause cell-cell fusion (syncytia formation). The matrix protein M is believed to line the inner surface of the plasma membrane of the infected cell, interacting with the cytoplasmic tails of the glycoproteins [2, 3]. A long searched for third receptor, nectin-4, has been recently identified [5, 6] which allows MeV infection via epithelial cells. Of the three MeV receptors, only CD46 is expressed in the CNS [7]

Methods

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Discussion

Conclusion