It is now well established that Toll-like receptors (TLRs) are crucial for the recognition of bacteria and viruses, but their roles in innate responses to parasitic infections are less well known. Now, reporting in Science, Yarovinsky et al. identify a ligand derived from the protozoan parasite Toxoplasma gondii that is recognized by TLR11, contributing to resistance to infection with this parasite.

Previously, it has been shown that interleukin-12 (IL-12) is essential for host resistance to T. gondii and that parasite-induced IL-12 production requires the TLR adaptor MyD88 (myeloid differentiation primary-response gene 88). So, the authors set out to identify the parasitic component and the TLR that might be involved.

Using gel filtration, the authors fractionated STAg, a soluble extract of the tachyzoite stage of T. gondii, and identified a low-molecular-weight protein that stimulated the production of high levels of IL-12 by dendritic cells (DCs). This protein had marked sequence homology to profilin proteins present in other protozoa. Consistent with the known MyD88 dependence of T. gondii-induced IL-12 production, DCs from Myd88−/− mice had impaired IL-12 responses to the recombinant T. gondii profilin.

So far, only two TLRs have been shown to recognize microbial-protein ligands — TLR5 (flagellin) and TLR11 (uropathogenic-bacteria-derived protein) — so the authors tested these TLRs for their ability to recognize T. gondii profilin. Indeed, TLR11 transfectants, but not TLR5 (or other TLR) transfectants, displayed dose-dependent activation of nuclear factor-κB when stimulated with profilin. Moreover, TLR11-deficient DCs failed to produce IL-12 in response to profilin, whereas DC populations from other TLR-deficient mice had no marked cytokine defects, indicating a role for a profilin–TLR11 interaction in IL-12 production in vitro.

Next, the authors showed that the profilin–TLR11 interaction is important for resistance to infection with T. gondii, as TLR11-deficient mice developed more brain cysts in the chronic phase of infection than did wild-type animals. This was accompanied by reduced levels of IL-12 and interferon-γ, as observed for Myd88−/− mice. The fact that the TLR11-deficient mice survived acute infection with T. gondii, unlike Myd88−/− mice, indicates that other MyD88-dependent TLR-family members might also be involved in resistance to infection with T. gondii.

Future studies aim to identify whether T. gondii profilin homologues from other related parasites are also recognized by TLR11 and whether they are important in protective responses.