Cell-to-Cell Measles Virus Spread between Human Neurons Is Dependent on Hemagglutinin and Hyperfusogenic Fusion Protein.

Measles virus (MV) usually causes acute infection but in rare cases persists in the brain, resulting in subacute sclerosing panencephalitis (SSPE). Since human neurons, an important target affected in the disease, do not express the known MV receptors (signaling lymphocyte activation molecule [SLAM] and nectin 4), how MV infects neurons and spreads between them is unknown. Recent studies have shown that many virus strains isolated from SSPE patients possess substitutions in the extracellular domain of the fusion (F) protein which confer enhanced fusion activity. Hyperfusogenic viruses with such mutations, unlike the wild-type MV, can induce cell-cell fusion even in SLAM- and nectin 4-negative cells and spread efficiently in human primary neurons and the brains of animal models. We show here that a hyperfusogenic mutant MV, IC323-F(T461I)-EGFP (IC323 with a fusion-enhancing T461I substitution in the F protein and expressing enhanced green fluorescent protein), but not the wild-type MV, spreads in differentiated NT2 cells, a widely used human neuron model. Confocal time-lapse imaging revealed the cell-to-cell spread of IC323-F(T461I)-EGFP between NT2 neurons without syncytium formation. The production of virus particles was strongly suppressed in NT2 neurons, also supporting cell-to-cell viral transmission. The spread of IC323-F(T461I)-EGFP was inhibited by a fusion inhibitor peptide as well as by some but not all of the anti-hemagglutinin antibodies which neutralize SLAM- or nectin-4-dependent MV infection, suggesting the presence of a distinct neuronal receptor. Our results indicate that MV spreads in a cell-to-cell manner between human neurons without causing syncytium formation and that the spread is dependent on the hyperfusogenic F protein, the hemagglutinin, and the putative neuronal receptor for MV.IMPORTANCE Measles virus (MV), in rare cases, persists in the human central nervous system (CNS) and causes subacute sclerosing panencephalitis (SSPE) several years after acute infection. This neurological complication is almost always fatal, and there is currently no effective treatment for it. Mechanisms by which MV invades the CNS and causes the disease remain to be elucidated. We have previously shown that fusion-enhancing substitutions in the fusion protein of MVs isolated from SSPE patients contribute to MV spread in neurons. In this study, we demonstrate that MV bearing the hyperfusogenic mutant fusion protein spreads between human neurons in a cell-to-cell manner. Spread of the virus was inhibited by a fusion inhibitor peptide and antibodies against the MV hemagglutinin, indicating that both the hemagglutinin and hyperfusogenic fusion protein play important roles in MV spread between human neurons. The findings help us better understand the disease process of SSPE.

[Measles and pregnancy]. / Rougeole et grossesse.

Because of insufficient vaccine coverage, there is an outbreak of measles since 2008 in France with an increasing incidence of cases, most of them among children less than 1 year old or young adults. When measles occurs during pregnancy, maternal and fetal morbidity is increased. Particularly pregnant women are exposed to a higher risk of severe respiratory distress that might cause death. Measles virus can be detected in the placenta. Placental infection appears to be involved in some cases of fetal death. The virus is not responsible for congenital defects but can induce histologic damages inside the placenta which may lead to fetal death. Major perinatal risks are also miscarriage and prematurity. When measles occurs in late pregnancy, congenital infection is possible with variable expression and a risk of subacute sclerosing panencephalitis. Non immune pregnant women or neonates exposed to measles should receive an immunoglobulin prophylaxis within 6 days after contact in order to reduce the risk of infection and severe morbidity. In case of declared measles infection, symptomatic treatment can be proposed and tocolysis can be used if preterm labor is associated. Daily fetal monitoring during the 14 days following the beginning of the eruption can be offered when the fetus is viable. Vaccination is recommended for the people born in France after 1980 with 2 doses of vaccine against measles, rubeola and mumps. Measles vaccine, an attenuated living vaccine, should not be administered during pregnancy but must be proposed before pregnancy or during the post-partum period.

Subacute sclerosing panencephalitis after intrauterine infection.

UNLABELLED: Subacute sclerosing panencephalitis (SSPE), in the majority of cases, is caused by the wild measles virus, although there are some reports relating SSPE to vaccination. This paper presents an inborn that was infected during pregnancy by the measles virus and developed SSPE within the first year of life after a short incubation period. He progressed rapidly after a mild arrest with treatment. Subacute sclerosing panencephalitis is a fatal degenerative disease and, although it had largely disappeared because of nearly universal measles vaccination, it still remains a serious infection among children affected by human immunodeficiency virus (HIV). The lack of newer cases of SSPE occurring among normal children nowadays should not wane alertness by obstetricians and paediatricians, to recognize the risk with measles during pregnancy and the need for prevention and recognition of SSPE at an early stage. Although some references exist which report on SSPE cases related to vaccination, new work weakens the possible links between measles vaccine and SSPE. CONCLUSION: This report would like to stress the importance and success of reducing the SSPE problem with the aid of general measles vaccination with high coverage.

Environmental risk factors for subacute sclerosing panencephalitis (SSPE).

In Israel, SSPE has been shown to be much more frequent among Sephardic Jews and Arabs than among Ashkenazic Jews. In the present study, we tried to explore environmental factors that may be of etiological importance and explain these differences in prevalence. The study is a case-control one, which includes 95 patients and 2 groups of controls, with 95 people in each. The general population controls were group-matched to the case group by sex, age, and ethnic origin. The family controls consisted of the sibling closest in age to each patient. A statistically significant positive correlation was found between risk of SSPE and early measles infection, large family, overcrowding in the home, older age of the mother, higher birth order, fewer years of schooling of the parents, fewer cultural activities, and rural place of birth. All these factors are interpreted as contributing to a higher risk of early measles infections, which thus may well be the main risk factor for SSPE.

Transmission of measles virus encephalitis to ferrets by intracardiac inoculation of a cell-associated SSPE virus strain.

Ferret fibroblasts infected with a cell-associated strain of subacute sclerosing panencephalitis virus were inoculated into the hearts of ferrets in order to study whether the virus can spread from the blood to the brain in this animal model. Five of 21 inoculated ferrets developed encephalitis 5-7 days later and were sacrificed. Sick animals showed inflammatory lesions in the brain, both perivascular cuffings and infiltration of inflammatory cells in the choroid plexus and meninges. Virus was isolated in cell cultures from various parts of the brain and virus antigen was found by immunostaining, particularly in the cortex. Virus was not detected in inflammatory cells by immunostaining but in situ hybridization with a cDNA probe demonstrated measles virus RNA in neurons and glia cells surrounding perivascular inflammatory cuffings and in a lymph node of one ferret. Ferrets inoculated into the heart with cell-associated SSPE virus seem to be a suitable animal model to study how the virus spreads from the blood to the brain.

Comparison of survival times of mice inoculated with brain tissue from various neurological diseases.

Mice inoculated intracerebrally before the age of 5 days with homogenates of autopsied brain tissue from patients with Creutzfeldt-Jakob (C-J), Alzheimer's, or Pick's diseases showed highly significant decreases in life span when compared with sham-inoculated control mice. With C-J disease there was strong indication of horizontal transmission of the agent to uninoculated mice caged with the inoculated mice. While the results with C-J disease were not unexpected in view of the known infectious etiology of the disease, the results obtained with Alzheimer's and Pick's diseases suggest that previously undetermined infectious or toxic agents may be associated with these two diseases, which currently have unresolved etiologies. Mice inoculated with autopsied brain tissue from patients with multiple sclerosis or subacute sclerosing panencephalitis had life spans similar to those of the control mice.

Subacute sclerosing panencephalitis during pregnancy. A surviving normal infant.

A normal infant was born to a 15-year-old girl who developed subacute sclerosing panencephalitis in the fifth month of pregnancy. The serum measles antibody titers of the infant gradually declined during the first year of life. The child, now age 3, has no neurological abnormalities.

CNS disease following dissemination of SSPE measles virus from intraperitoneal inoculation of suckling hamsters.

Acute encephalitis was observed in suckling Golden Syrian hamsters following intraperitoneal (ip) inoculation of a hamster brain adapted strain of subacute sclerosing panencephalitis (SSPE) measles virus (HBS). Virus was isolated from the brains of all encephalitic animals by cocultivation of tissue with Vero cells. The histopathology of the encephalitis was characterized by perivascular mononuclear infiltrates, necrosis, eosinophilic inclusion bodies, and rare giant cells. Association of encephalitis with systemic viral infection was observed with virus present in lung and a kidney-spleen pool in addition to brain. Viral dissemination in asymptomatic animals was documented with virus being isolated from multiple non-neural tissues (spleen, lung, liver) of animals having no recoverable virus in their brains and no signs of encephalitis. Treatment of animals with cyclophosphamide prior to ip virus inoculation did not increase dissemination to brain. Absence of encephalitis in asymptomatic animals with proven viral dissemination to parenchymal organs indicates that neither viremia alone, nor viremia in conjunction with dissemination are sufficient conditions to establish central nervous system disease. The association of encephalitis with systemic viral infection and the dissemination to brain establish this model's potential value for the study of the pathogenesis of measles encephalitis.