[Source: Journal of Virology, full page: (LINK). Abstract, edited.]
Analysis of a subacute sclerosing panencephalitis (SSPE) Genotype B3 virus from the 2009/10 South African measles epidemic shows hyperfusogenic F proteins contribute to measles virus infection in the brain.
Fabrizio Angius, Heidi Smuts, Ksenia Rybkina, Debora Stelitano, Brian Eley, Jo Wilmshurst, Marion Ferren, Alexandre Lalande, Cyrille Mathieu, Anne Moscona, Branka Horvat,Takao Hashiguchi, Matteo Porotto, Diana Hardie
During a measles virus (MeV) epidemic in 2009 in South Africa, measles inclusion body encephalitis (MIBE) was identified in several HIV-infected patients. Years later, children are presenting with subacute sclerosing panencephalitis (SSPE). To investigate the features of established MeV neuronal infections, viral sequences were analysed from brain tissue samples of a single SSPE case and compared with MIBE sequences previously obtained from patients infected during the same epidemic. Both the SSPE and the MIBE viruses had amino acid substitutions in the ectodomain of the F protein that confer enhanced fusion properties. Functional analysis of the fusion complexes confirmed that both MIBE and SSPE F protein mutations promoted fusion with less dependence on interaction by the viral receptor-binding protein with known MeV receptors. While the SSPE F required the presence of a homotypic attachment protein MeV H in order to fuse, the MIBE F did not. Both F proteins had decreased thermal stability compared to the corresponding wild-type F protein. Finally, recombinant viruses expressing MIBE or SSPE fusion complexes spread in the absence of known MeV receptors, with MIBE F-bearing viruses causing large syncytia in these cells. Our results suggest that alterations to the MeV fusion complex that promote fusion and cell-to-cell spread in the absence of known MeV receptors is a key property for infection of the brain.
Measles virus can invade the central nervous system (CNS) and cause severe neurological complications such as MIBE and SSPE. However, mechanisms by which MeV enters the CNS and triggers the disease remain unclear. We analysed viruses from brain tissue of individuals with MIBE or SSPE, infected during the same epidemic, after the onset of neurological disease. Our findings indicate that the emergence of hyper-fusogenic MeV F proteins may be associated with infection of the brain. We also demonstrate that hyper-fusogenic F proteins permit MeV to enter cells and spread without the need to engage nectin-4 or CD150, known receptors for MeV that are not present on neural cells.
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Keywords: Measles; Subacute Sclerosing Panencephalitis; Measles Inclusion Body Encephalitis; Viral pathogenesis.