The contribution of the T cell chemoattractant chemokine IFN-inducible protein 10 (IP-10) in host defense following viral infection of the CNS was examined. IP-10 is expressed by astrocytes during acute encephalomyelitis in mouse hepatitis virus-infected mice, and the majority of T lymphocytes infiltrating into the CNS expressed the IP-10 receptor CXCR3. Treatment of mice with anti-IP-10 antisera led to increased mortality and delayed viral clearance from the CNS as compared with control mice. Further, administration of anti-IP-10 led to a >70% reduction (p ≤ 0.001) in CD4+ and CD8+ T lymphocyte infiltration into the CNS, which correlated with decreased (p ≤ 0.01) levels of IFN-γ. These data indicate that IP-10 functions as a sentinel molecule in host defense and is essential in the development of a protective Th1 response against viral infection of the CNS.
Cytochrome c peroxidase (CCP) and ascorbate peroxidase (APX) have very similar structures, and yet neither CCP nor APX exhibit each others activities with respect to reducing substrates. APX has a unique substrate binding site near the heme propionates where ascorbate H-bonds with a surface Arg and one heme propionate (Sharp et al. (2003) Nat. Struc. Biol. 10, 303–307). The corresponding region in CCP has a much longer surface loop and the critical Arg residue that is required for ascorbate binding in APX is Asn in CCP. In order to convert CCP into an APX, the ascorbate binding loop and critical arginine were engineered into CCP to give the CCP2APX mutant. The mutant crystal structure shows that the engineered site is nearly identical to that found in APX. While wild type CCP shows no APX activity, CCP2APX catalyzes the peroxidation of ascorbate at a rate of ≈ 12 min−1 indicating that the engineered ascorbate binding loop can bind ascorbate.
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