TLR3-TRIF pathway activation by Neospora caninum RNA enhances infection control in mice.

Neospora caninum is a protozoan parasite closely related to Toxoplasma gondii and has been studied for causing neuromuscular disease in dogs and abortions in cattle. It is recognized as one of the main transmissible causes of reproductive failures in cattle and consequent economic losses to the sector. In that sense, this study aimed to evaluate the role of TLR3-TRIF dependent resistance against N. caninum infection in mice. We observed that TLR3-/- and TRIF-/- mice presented higher parasite burden, increased inflammatory lesions and reduced production of IL-12p40, TNF, IFN-γ, and NO. Differently from T. gondii, N. caninum tachyzoites and its RNA recruited TLR3 to the parasitophorous vacuole (PV) and translocated IRF3 to the nucleus. We also observed that N. caninum upregulated the expression of TRIF in murine macrophages, which by its turn upregulated IFN-α and IFN-β in the presence of the parasite. Furthermore, TRIF-/- infected macrophages produced lower levels of IL-12p40, while exogenous IFN-α replacement was able to completely restore the production of this key cytokine. Our results show that TLR3-TRIF signaling pathway enhances resistance against N. caninum infection in mice, since it improves Th1 immune responses that results in controlled parasitism and reduced tissue inflammation, which are hallmarks of the disease.1.