Identification of genes involved in the host response to neurovirulent alphavirus infection

Single-amino-acid mutations in Sindbis virus proteins can convert clinicall y silent encephalitis into uniformly lethal disease. However, little is kno wn about the host gene response during avirulent and virulent central nervo us system (CNS) infections. To identify candidate host genes that modulate alphavirus neurovirulence, we utilized GeneChip Expression analysis to comp are CNS gene expression in mice infected with two strains of Sindbis virus that differ by one amino acid in the E2 envelope glycoprotein. Infection wi th Sindbis virus, dsTE12H (E2-55 HIS), resulted in 100% mortality in 10-day -old mice, whereas no disease was observed in mice infected with dsTE12Q (E 2-55 GLN). dsTE12H, compared with dsTE12Q, replicated to higher titers in m ouse brain and induced more CNS apoptosis. Infection with the neurovirulent dsTE12H strain was associated with both a greater number of host genes wit h increased expression and greater changes in levels of host gene expressio n than was infection with the nonvirulent dsTE12Q strain. In particular, ds TE12H infection resulted in greater increases in the levels of mRNAs encodi ng chemokines, proteins involved in antigen presentation and protein degrad ation, complement proteins, interferon-regulated proteins, and mitochondria l proteins. At least some of these increases may be beneficial for the host , as evidenced by the demonstration that enforced expression of the antiapo ptotic mitochondrial protein peripheral benzodiazepine receptor (PBR) prote cts neonatal mice against lethal Sindbis virus infection. Thus, our finding s identify specific host genes that may play a role in the host protective or pathologic response to neurovirulent Sindbis virus infection.