Tumor necrosis factor ␣ (TNF␣) is a potent immunomodulator and proinf lammatory cytokine that has been implicated in the pathogenesis of autoimmune and infectious diseases. For example, plasma levels of TNF␣ are positively correlated with severity and mortality in malaria and leishmaniasis. We have previously described a polymorphism at ؊308 in the TNF␣ promoter and shown that the rare allele, TNF2, lies on the extended haplotype HLA-A1-B8-DR3-DQ2, which is associated with autoimmunity and high TNF␣ production. Homozygosity for TNF2 carries a sevenfold increased risk of death from cerebral malaria. Here we demonstrate, with reporter genes under the control of the two allelic TNF promoters, that TNF2 is a much stronger transcriptional activator than the common allele (TNF1) in a human B cell line. Footprint analysis using DNase I and B cell nuclear extract showed the generation of a hypersensitive site at ؊308 and an adjacent area of protection. There was no difference in affinity of the DNA-binding protein(s) between the two alleles. These results show that this polymorphism has direct effects on TNF␣ gene regulation and may be responsible for the association of TNF2 with high TNF␣ phenotype and more severe disease in infections such as malaria and leishmaniasis.

Vaccinia virus (VV) and other orthopoxviruses express a soluble type I interferon (IFN) receptor that for VV strain Western Reserve is encoded by gene B18R. The 60-65 kDa glycoprotein is related to the interleukin-1 receptors and is a member of the immunoglobulin superfamily, unlike other type I IFN receptors, which belong to the class II cytokine receptor family. The receptor has high affinity (KD, 174 pM) for human IFN alpha and, unlike other type I IFN receptors, has broad species specificity, binding to human, rabbit, bovine, rat, and mouse type I IFNs. This may have aided VV replication in multiple host species during evolution. A VV B18R deletion mutant is attenuated in a murine intranasal model. This type I IFN receptor represents the fourth VV protein that interferes with IFN and the fourth soluble cytokine receptor expressed by poxviruses.

Poxviruses employ many strategies to evade and neutralize the host immune response. In this study, we have identified two vaccinia virus ORFs, termed A46R and A52R, that share amino acid sequence similarity with the Toll͞IL-1 receptor (TIR) domain, a motif that defines the IL-1͞Toll-like receptor (TLR) superfamily of receptors, which have a key role in innate immunity and inflammation. When expressed in mammalian cells, the protein products of both ORFs were shown to interfere specifically with IL-1 signal transduction. A46R partially inhibited IL-1-mediated activation of the transcription factor NF B, and A52R potently blocked both IL-1-and TLR4-mediated NF B activation. MyD88 is a TIR domaincontaining adapter molecule known to have a central role in both IL-1 and TLR4 signaling. A52R mimicked the dominant-negative effect of a truncated version of MyD88 on IL-1, TLR4, and IL-18 signaling but had no effect on MyD88-independent signaling pathways. Therefore, A46R and A52R are likely to represent a mechanism used by vaccinia virus of suppressing TIR domaindependent intracellular signaling.