Uncharacterized TLR plays key role in Toxoplasma gondii response

By Liam Davenport, medwireNews Reporter

A previously uncharacterized toll-like receptor (TLR) appears to play a crucial role in the innate immune response to Toxoplasma gondii infection and may promote host resistance, potentially leading to anti-parasite vaccines, say US researchers.

Lead researcher Sankar Ghosh, from Columbia University in New York, commented: "Prior to this study, TLR12 had no known function in the immune system, and it was not known what pathogen this receptor recognized. We have demonstrated that TLR12 is essential for resistance to T. gondii in mice."

He added: "By investigating how immune cells expressing TLR12 organize the immune response against T. gondii infection, we hope to identify new means of promoting protective immune responses against T. gondii and potentially other important parasite pathogens."

TLR11 recognizes T. gondii profilin (TgPRF), yet mice deficient in TLR11 survive T. gondii infection. The researchers hypothesized that TLR12 - which has a similarity with TLR11 of 96% and physically interacts with the same receptor - might recognize the same ligands. They explored this possibility via experiments in tissue preparations and mice, including a strain lacking TLR11 and one lacking TLR12; as well as antibody, protein expression and cloning and sequence analysis experiments.

Ghosh et al found that, overall, TLR12 expression was more limited than that of TLR11, and was restricted to myeloid cells such as plasmacytoid dendritic cells (DCs) and conventional DCs, macrophages, and lymphoid cells, including T cells and B cells. TLR12 expression primarily occurred in the spleen, they report in Immunity.

In conventional DCs and macrophages, both TLR11 and TLR12 were required for recognition of T. gondii profilin (TgPRF), while TLR12 alone was sufficient for recognition of TgPRF in plasmacytoid DCs. The researchers also discovered that TLR12-deficient mice could not recognize or protect against T. gondii infection, and they quickly succumbed to infection.

The results showed that TLR12-dependent induction of interleukin-12 and interferon-α in plasmacytoid DCs led to interferon-γ production by natural killer cells. This finding was supported by the observation that depletion of plasmacytoid DC or natural killer cell eliminated the partial resistance of mice lacking TLR11 to T. gondii infection.

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