Type 3 reovirus neuroinvasion after intramuscular inoculation: viral genetic determinants of lethality and spinal cord infection.
To better understand the mechanisms by which neurotropic viruses invade peripheral nerve pathways and produce CNS disease, we defined the type 3 (T3) reovirus genes that are determinants of the capacity of reovirus T3 strain Dearing (T3D) and T3 clone 9 (C9) to infect the spinal cord and kill mice after hindlimb injection. T3D and C9 viruses are both highly virulent (LD(50) < 10(1) PFU) after intracranial injection of neonatal mice. However, C9 is significantly more lethal than T3D after either intramuscular injection (LD(50) < 10(1) vs LD(50) 10(4) PFU) or peroral injection (LD(50) 10(3.4) vs LD(50) > 10(8.3) PFU). Using reassortant viruses containing different combinations of genes derived from T3D and C9, we found that the S1 gene, encoding the cell attachment protein sigma 1 and the nonstructural protein sigma 1s, and the L3 gene, encoding the core shell protein lambda 1 were the primary determinants of lethality after intramuscular injection. The L3 gene and the L2 gene encoding spike protein, lambda 2, determined differences in spinal cord titer after intramuscular injection. A C9 x T3D mono-reassortant containing all T3D genes except for the C9-derived L3 was lethal after peroral injection. These studies indicate that the S1, L2, and L3 genes all play a potential role in neuroinvasiveness and provide the first identification of a role in pathogenesis for the L3 gene.
Mann
Mary Anne
MA
Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, USA. mam2012@columbia.edu
Tyler
Kenneth L
KL
Knipe
David M
DM
Fields
Bernard N
BN
D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D007273:Injections, Intramuscular; D007739:L Cells; D007928:Lethal Dose 50; D012089:Mammalian orthoreovirus 3 / Q000235:genetics* / Q000472:pathogenicity*; D051379:Mice; D016865:Reassortant Viruses / Q000235:genetics; D012088:Reoviridae Infections / Q000821:virology*; D013116:Spinal Cord / Q000821:virology*