The F Gene of the Osaka-2 Strain of Measles Virus Derived from a Case of Subacute Sclerosing Panencephalitis Is a Major Determinant of Neurovirulence

Abstract

Measles virus (MV) is the causative agent for acute measles and subacute sclerosing panencephalitis (SSPE). Although numerous mutations have been found in the MV genome of SSPE strains, the mutations responsible for the neurovirulence have not been determined. We previously reported that the SSPE Osaka-2 strain but not the wild-type strains of MV induced acute encephalopathy when they were inoculated intracerebrally into 3-week-old hamsters. The recombinant MV system was adapted for the current study to identify the gene(s) responsible for neurovirulence in our hamster model. Recombinant viruses that contained envelope-associated genes from the Osaka-2 strain were generated on the IC323 wild-type MV background. The recombinant virus containing the M gene alone did not induce neurological disease, whereas the H gene partially contributed to neurovirulence. In sharp contrast, the recombinant virus containing the F gene alone induced lethal encephalopathy. This phenotype was related to the ability of the F protein to induce syncytium formation in Vero cells. Further study indicated that a single T461I substitution in the F protein was sufficient to transform the nonneuropathogenic wild-type MV into a lethal virus for hamsters.

Mutant Fusion Proteins with Enhanced Fusion Activity Promote Measles Virus Spread in Human Neuronal Cells and Brains of Suckling Hamsters

“…In the present study, we used 10-day-old suckling hamsters, as 3-week-old weanling hamsters were not susceptible to the viruses, unlike the prior report using virus-like particles (54). This suggests that the maturity of the host immune system is also important for MV neuropathogenicity in hamsters.…”

“…2). Using virus-like particles, Ayata et al have reported that the neurovirulence of one SSPE strain (Osaka-2) is related to the ability of its F protein to induce syncytia in Vero cells, which is attributed to a single substitution (T461I) (54).…”

Characteristics of Viruses Derived from Nude Mice with Persistent Measles Virus Infection

“…MV generally does not induce neurological disease in experimental small animals such as hamsters and ferrets, whereas the SSPE virus induces lethal neurological diseases in these animal models (1,37). However, the mutations responsible for the neurovirulence of the SSPE virus have not been identified.…”

“…Ayata et al reported that a recombinant virus containing the F gene of the SSPE Osaka-2 strain alone induced lethal encephalopathy in a hamster model. Furthermore, a single T461I substitution in the F protein transformed the nonneuropathogenic wild-type MV into a lethal virus (37). However, it is unknown whether the F-gene mutation is common among all SSPE virus strains.…”

Measles Virus Infection: Mechanisms of Immune Suppression

“…Some SSPE strains have mutations in the F gene that variously result in an elongated or a shortened cytoplasmic domain (Billeter et al, 1994;Ning et al, 2002). A single amino acid substitution in the F protein transformed the non neuropathogenic wild-type MV IC323 strain into a lethal virus similar to the SSPE Osaka-2 strain in hamsters (Ayata et al, 2010). The demyelination observed in SSPE could be the result of several mechanisms.…”