Dendritic cell (DC) production of IL-12 is thought to be a major initiation step in host resistance to Toxoplasma gondii. We had previously shown that T. gondii stimulated IL-12 production by DC depends on the chemokine receptor CCR5 and on the toll-like receptor signalling element MYD88. This year we identified an important parasite molecule involved in this response. By fractionating STAg ,a soluble extract of the parasite, we obtained a homogeneous peak of IL-12 inducing activity which contained a single major protein identified by sequencing as cyclophilin-18 (C-18). When expressed in E.coli this molecule possessed low levels of IL-12 inducing activity while antibodies prepared against it blocked the induction of the cytokine by STAg. Importantly, C-18 was found to bind to CCR5 and induce signalling through this receptor while cyclophilins from other mammalian and protozoan species were inactive. Thus, T.gondii C-18 would appear to be a parasite mimic of a chemokine ligand and its interaction with CCR5 provides an explanation for the involvement of this receptor in IL-12 induction by the parasite. In addition to being a component in the stimulation of IL-12 production from DC, C-18 was shown through its binding of CCR5 to block the infectivity of R5 HIV-1 virus for human T cells and macrophages bearing the receptor and to inhibit viral synctia formation. This activity was again restricted to C-18 and not cyclophilins from other species and was reversed in the presence of cyclosporin-A a major ligand bound by cyclophilins. Interestingly, in contrast to other known CCR5 co-receptor antagonists, C-18 did not induce receptor internalization. For this reason, it or its derivitives could potentially serve as highly specific inhibitors of R5-HIV entry.
Showing the most recent 10 out of 54 publications
