title: Nonstructural protein sigma1s is a determinant of reovirus virulence and influences the kinetics and severity of apoptosis induction in the heart and central nervous system.
abstract: The mechanisms by which viruses kill susceptible cells in target organs and ultimately produce disease in the infected host remain poorly understood. Dependent upon the site of inoculation and strain of virus, experimental infection of neonatal mice with reoviruses can induce fatal encephalitis or myocarditis. Reovirus-induced apoptosis is a major mechanism of tissue injury, leading to disease development in both the brain and heart. In cultured cells, differences in the capacity of reovirus strains to induce apoptosis are determined by the S1 gene segment, which also plays a major role as a determinant of viral pathogenesis in both the heart and the central nervous system (CNS) in vivo. The S1 gene is bicistronic, encoding both the viral attachment protein sigma-1 and the nonstructural protein sigma-1-small (sigma1s). Although sigma1s is dispensable for viral replication in vitro, we wished to investigate the expression of sigma1s in the infected heart and brain and its potential role in reovirus pathogenesis in vivo. Two-day-old mice were inoculated intramuscularly or intracerebrally with either sigma1s(-) or sigma1s(+) reovirus strains. While viral replication in target organs did not differ between sigma1s(-) and sigma1s(+) viral strains, virus-induced caspase-3 activation and resultant histological tissue injury in both the heart and brain were significantly reduced in sigma1s(-) reovirus-infected animals. These results demonstrate that sigma1s is a determinant of the magnitude and extent of reovirus-induced apoptosis in both the heart and CNS and thereby contributes to reovirus pathogenesis and virulence.
authors.affiliation: Department of Neurology (B-182), University of Colorado Health Sciences Center, 4200 E. 9th Ave., Denver, CO 80262, USA.
authors.forename: Cristen C
authors.initials: CC
authors.lastname: Hoyt
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Richardson-Burns
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Goody
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Robinson
authors.forename: Roberta L
authors.initials: RL
authors.lastname: Debiasi
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Tyler
mesh_terms: D000818:Animals; D017209:Apoptosis; D002490:Central Nervous System / Q000473:pathology / Q000821:virology*; D002540:Cerebral Cortex / Q000473:pathology / Q000821:virology; D006321:Heart / Q000821:virology*; D006624:Hippocampus / Q000473:pathology / Q000821:virology; D007700:Kinetics; D012089:Mammalian orthoreovirus 3 / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D051379:Mice; D009206:Myocardium / Q000473:pathology; D013788:Thalamus / Q000473:pathology / Q000821:virology; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000502:physiology*; D014774:Virulence; D014779:Virus Replication
chemical_list: D017361:Viral Nonstructural Proteins; C071901:sigma 1NS protein, Reovirus