Roles of host cell lipids and intracellular trafficking machinery in the pathogenesis of Sindbis virus.

摘要

Sindbis virus (SV), the prototype alphavirus, is an excellent model to study virus-induced pathogenesis. It causes encephalitis of varying severity in mice, dependent upon various viral and host factors. Previous experiments have suggested that ceramide generated by sphingomyelin (SM) pathway is involved in this virus-induced apoptosis. We have studied acid sphingomyelinase (ASMase) knock-out mice (ASM-KO mice) and found that they have higher mortality than wild type (WT) mice and heterozygous (Het) mice. There was also a significantly higher viral titer in the brains of these animals suggesting that a more rapid spread of SV in the brains of ASM-KO mice resulted in the increased susceptibility of these mice to SV infection.;In humans, a defect in the ASMase gene results in a condition known as type A Niemann-Pick Disease (NPD-A). Similar to the results obtained with the in vivo model, SV also replicated faster in NPD-A fibroblasts (NPAFs) and virion particles budding from NPAFs were more infectious than SV released from normal human fibroblasts (NHFs). NPAFs had an altered intracellular distribution of cholesterol and SM with large amounts of concentrated in acidic organelles near the nucleus. This increase in infectivity is postulated to be the result of differences in the lipid composition of the host plasma membrane caused by a defect in the ASMase gene.;We also found that as a result of an abnormal accumulation of cholesterol and sphingolipids in NPAFs, the multivesicular body (MVB) pathway involved in host cell intracellular trafficking was perturbed. Such disruptions of intracellular trafficking machineries of host cells have profound effects on SV replication.