mRNA Expression of Proinflammatory Cytokines in Mouse CNS Correlates with Replication Rate of Semliki Forest Virus But Not with the Strain of Viral Proteins

Tissue expression in viral infection of immunological effector molecules may depend on virus structure or replication or both. We analyzed cytokine mRNA expression in the central nervous system (CNS) of Balb/c mice during viral infection with Semliki Forest virus (SFV) clones, which varied either in structure or virulence or both. Highly neurovirulent SFV4 effectively induced IFN-γ, TNF-α, IL-6 and TGF-β, but its avirulent derivative V4-opal with nsP3 arginine-476 to opal mutation, elicited only weak induction of these cytokines. Structurally different, avirulent rA774, obtained by cloning from avirulent SFV A7(74) strain, did not induce synthesis of proinflammatory Th1 or Th2 cytokines in murine CNS, but increased synthesis of TGF-β transcripts. In contrast, structurally identical but moderately virulent rA774-arg virus with sense codon at opal position in nsP3, markedly stimulated synthesis of IFN-γ, TNF-α, and IL-10 transcripts, without, however, reaching the levels elicited by lethal SFV4. The rA774-arg clone was more potent in attracting peripheral immune cells into the CNS than the completely avirulent strains. In conclusion, induction of proinflammatory cytokine mRNA in the CNS by SFV infection seemed to correlate with the rate of viral replication and was not significantly influenced by the virus envelope or nonstructural protein primary structure. The results also have relevance for development of CNS gene therapy vectors as SFV4 and A774 display differences in CNS infection characteristics.