title: Chandipura virus perturbs cholesterol homeostasis leading to neuronal apoptosis.
abstract: Chandipura virus (CHPV; genus Vesiculovirus, family Rhabdoviridae) induces neuronal death through the Fas-mediated extrinsic apoptosis pathway. What propels this apoptosis remains unclear, although oxysterols have been reported to be key players in neurodegeneration. In our study of CHPV-infected brain samples, we observed over-expression of genes such as apolipoprotein E, Cyp46a1, Srebf-1 and Nsdhl. This backs up the hypothesis that CHPV replication demands cholesterol that is supplied by apolipoprotein E through low density lipid receptors, lipid metabolism being pivotal for viral replication. We were able to illustrate this with over-expression of low density lipid receptors in CHPV-infected neurons. An upsurge of cholesterol concentration has been observed in neurons, triggering the expression of Cyp46a1 enzyme and culminating into the conversion of cholesterol to 24(S)-hydroxycholesterol. Increased 24(S)-hydroxycholesterol concentration is toxic to neurons, propelling neuronal apoptosis through the Fas-mediated extrinsic apoptosis pathway. For the first time, perturbation of cholesterol homeostasis in brain is shown to be utilized by the viruses for both maturation and the release of its matured virions outside the cells for continuous neuropathogenesis.
authors.affiliation: National Brain Research Centre, Manesar, Haryana, India.
authors.forename: Sourish
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: National Brain Research Centre, Manesar, Haryana, India.
authors.forename: Sriparna
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: National Brain Research Centre, Manesar, Haryana, India.
authors.forename: Anirban
authors.initials: A
authors.lastname: Basu
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D017209:Apoptosis; D002784:Cholesterol / Q000378:metabolism*; D000072556:Cholesterol 24-Hydroxylase; D055785:Gene Knockdown Techniques; D006706:Homeostasis; D006888:Hydroxycholesterols / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000473:pathology*; D061251:Primary Cell Culture; D011973:Receptors, LDL / Q000235:genetics; D018353:Rhabdoviridae Infections / Q000378:metabolism* / Q000473:pathology* / Q000821:virology; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D018116:Vesiculovirus / Q000254:growth & development
chemical_list: D001057:Apolipoproteins E; D006888:Hydroxycholesterols; D011973:Receptors, LDL; C044563:24-hydroxycholesterol; D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase
keywords: Chandipura virus; cholesterol homeostasis; neuronal apoptosis