title: Serine residues at positions 162 and 166 of the rabies virus phosphoprotein are critical for the induction of oxidative stress in rabies virus infection.
abstract: Our previous work in a mouse model of experimental rabies showed neuronal process (dendrites and axons) degeneration in association with severe clinical disease. Cultured adult rodent dorsal root ganglion (DRG) neurons infected with the challenge virus standard-11 (CVS) strain of rabies virus (RABV) showed axonal swellings and reduced axonal growth with evidence of oxidative stress. We have shown that CVS infection alters a variety of mitochondrial parameters and increases mitochondrial complex I activity and reactive oxygen species (ROS) production. Expression of a peptide from amino acid 139-172 of the CVS phosphoprotein (P) increased complex I activity and ROS generation similar to expression of the entire P. Site-directed mutational analyses illustrated the importance of the 145-151 and 157-169 regions of P and that serine residues at 162 and 166 are important single amino acid sites. Two CVS recombinant viruses with serine to alanine mutations at positions 162 (A162r) and 166 (A166r) did not increase complex I activity or ROS generation and also did not induce axonal swellings or inhibit axonal growth in DRG neurons. RABV infection is a mitochondrial disorder initiated by interaction of the RABV P and complex I; S162 and S166 are critical sites in the P for this interaction. The resulting mitochondrial dysfunction produces oxidative stress in neurons causing acute degenerative changes affecting neuronal processes resulting in a severe and fatal clinical disease. This information will be important for the future development of novel therapies for rabies.
authors.affiliation: Department of Internal Medicine (Neurology), University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Wafa
authors.initials: W
authors.lastname: Kammouni
authors.affiliation: Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, Winnipeg, MB, Canada.|Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Heidi
authors.initials: H
authors.lastname: Wood
authors.affiliation: Department of Internal Medicine (Neurology), University of Manitoba, Winnipeg, MB, Canada. ajackson2@hsc.mb.ca.|Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada. ajackson2@hsc.mb.ca.|Health Sciences Centre, GF-543, 820 Sherbrook Street, Winnipeg, MB, R3A 1R9, Canada. ajackson2@hsc.mb.ca.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Jackson
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000821:virology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000821:virology; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009474:Neurons / Q000378:metabolism* / Q000821:virology; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011820:Rabies virus / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D015678:Viral Structural Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D015678:Viral Structural Proteins; D012694:Serine; D042967:Electron Transport Complex I
keywords: Oxidative stress; Pathogenesis; Rabies; Rabies virus; Reactive oxygen species