In patients with subacute sclerosing panencephalitis (SSPE), which is associated with persistent measles virus (MV) infection in the brain, little infectious virus can be recovered despite the presence of viral RNA and protein. Based on studies of brain tissue from SSPE patients and our work with MV-infected NSE-CD46؉ mice, which express the measles receptor CD46 on neurons, several lines of evidence suggest that the mechanism of viral spread in the central nervous system differs from that in nonneuronal cells. To examine this alternate mechanism of viral spread, as well as the basis for the loss of normal transmission mechanisms, infection and spread of MV Edmonston was evaluated in primary CD46؉ neurons from transgenic mice and differentiated human NT2 neurons. As expected, unlike that between fibroblasts, viral spread between neurons occurred in the absence of syncytium formation and with minimal extracellular virus. Electron microscopy analysis showed that viral budding did not occur from the neuronal surface, although nucleocapsids were present in the cytoplasm and aligned at the cell membrane. We observed many examples of nucleocapsids present in the neuronal processes and aligned at presynaptic neuronal membranes. Cocultures of CD46؉ and CD46؊ neurons showed that cell contact but not CD46 expression is required for MV spread between neurons. Collectively, these results suggest that the neuronal environment prevents the normal mechanisms of MV spread between neurons at the level of viral assembly but allows an alternate, CD46-independent mechanism of viral transmission, possibly through the synapse.After the clearance of acute measles virus (MV) infection in children, a persistent infection of the brain can occur which, after several years, results in the progressive neurological disease subacute sclerosing panencephalitis (SSPE). The symptoms of SSPE consist of gradual deterioration of cognitive and motor functions, and in virtually all cases, the disease is fatal (22). Brain biopsies or postmortem brain analyses from SSPE patients show evidence of astrogliosis, neuronal loss, degeneration of dendrites, demyelination, neurofibrillary tangles, and infiltration of inflammatory cells (2).Despite the long interval between the acute infection and symptoms of SSPE, there is evidence that MV infection of the brain occurs soon after the acute infection, with subsequent spread throughout the brain (3, 19). However, in contrast to MV infection of nonneuronal cells, which is cytopathic and spreads both by extracellular virus and by cell fusion resulting in multinucleated syncytia, little extracellular infectious virus can be recovered from brains of SSPE patients unless tissues are cocultured with permissive fibroblasts (22). Furthermore, high levels of neutralizing antibody are present in the serum and cerebrospinal fluid of SSPE patients (37). Together, these results suggest that extracellular virus might not be responsible for MV spread in the central nervous system (CNS). In support of this hypothesis, extensive...

The recessive mutation at the pale ear (ep) locus on mouse chromosome 19 was found to be the homologue of human Hermansky-Pudlak syndrome (HPS). A positional cloning strategy using yeast artificial chromosomes spanning the HPS locus was used to identify the HPS gene and its murine counterpart. These genes and their predicted proteins are highly conserved at the nucleotide and amino acid levels. Sequence analysis of the mutant ep gene revealed the insertion of an intracisternal A particle element in a protein-coding 3 exon. Here we demonstrate that mice with the ep mutation exhibit abnormalities similar to human HPS patients in melanosomes and platelet-dense granules. These results establish an animal model of HPS and will facilitate biochemical and molecular analyses of the functions of this protein in the membranes of specialized intracellular organelles.

Our findings implicate p38 MAPK signaling as significant and selective in the formation and maturation of EMPs. EMPs elicited a proinflammatory response from targeted hAECs that was dependent on the conditions under which EMPs were generated. However, our results imply a unidirectional model in which p38 MAPK is critical at the source of microparticle formation, but not the target cell response to EMPs. These findings indicate a novel mechanism by which p38 inhibition may offer therapeutic benefit in vivo via direct inhibition of EMP formation.