An attenuating mutation in a neurovirulent Sindbis virus strain interacts with the IPS-1 signaling pathway in vivo.
The AR86 strain of Sindbis virus causes lethal neurologic disease in adult mice. Previous studies have identified a virulence determinant at nonstructural protein (nsP) 1 position 538 that regulates neurovirulence, modulates clearance from the CNS, and interferes with the type I interferon pathway. The studies herein demonstrate that in the absence of type I interferon signaling, the attenuated mutant exhibited equivalent virulence to S300 virus. Furthermore, both S300 and nsP1 T538I viruses displayed similar neurovirulence and replication kinetics in IPS-1-/- mice. TRIF dependent signaling played a modest role in protecting against disease by both S300 and nsP1 T538I, but did not contribute to control of nsP1 T538I replication within the CNS, while MyD88 played no role in the disease process. These results indicate that the control of the nsP1 T538I mutant virus is largely mediated by IPS-1-dependent RLR signaling, with TRIF-dependent TLR signaling also contributing to protection from virus-induced neurologic disease.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Amy C
AC
Wollish
Martin T
MT
Ferris
Lance K
LK
Blevins
Yueh-Ming
YM
Loo
Michael
M
Gale
Mark T
MT
Heise
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D018354:Alphavirus Infections / Q000401:mortality / Q000821:virology; D000818:Animals; D002460:Cell Line; D020805:Central Nervous System Viral Diseases; D005260:Female; D005786:Gene Expression Regulation; D007370:Interferon Type I / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012845:Sindbis Virus / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity*; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism; D014774:Virulence / Q000235:genetics; D014779:Virus Replication
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D007370:Interferon Type I; D053594:Myeloid Differentiation Factor 88; D017361:Viral Nonstructural Proteins; C512612:MAVS protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C104211:nsP1 protein, Sindbis virus