Papel dos receptores do tipo Toll endossomais na resistência à infecção por Toxoplasma gondii

Abstract

Toxoplasma gondii is an obligate intracellular parasite belonging to the phylum apicomplexa and can virtually infect all warm-blood vertebrates. Although humans are considered accidental intermediate hosts, one third of the human population in the world is chronically infected with T. gondii. In immune-compromised individuals, this normally attenuated parasite becomes highly virulent, causing severe disease and lethality. Early activation of the innate immune system and cytokine production by myeloid cells is required for establishment of protective immunity to T.gondii infection. In mice, a mutation in the UNC93B1 gene abolishes signaling via Toll-like receptors (TLRs) 3, 7 and 9 and those mice, named 3d, are highly susceptible to infection with T. gondii. In this work we demonstrated that TLR12, TLR with a yet unknown ligand, recognize T.gondii profilin through TLR11/TLR12 heterodimers. We also showed that besides TLR3, TLR7, TLR9 and TLR11, TLR12 is also an intracellular TLR whose function is mediated by UNC93B1. Both T. gondii RNA e DNA activate macrophages and dendritic cells via TLR7 and TLR9, respectively. However, mice TLR3, TLR7, TLR9 KO or even the combination of them did not recapitulate the 3d phenotype. When we infected the triple TLR7/TLR9/TLR11 KO mice they had a huge defect in IL-12/IFN- production and were highly susceptible to T. gondii infection. Overall, our results showed that the susceptibility of 3d mice to the infection is due to a defect on the translocation of endosomal TLRs (i.e. TLR7/TLR9/TLR11) involved in the recognition of parasite molecules and induction of IL-12 by dendritic cells and macrophages, and consequent IFN- production. Regarding human infection, the human genome lacks functional TLR11 and TLR12 genes, so our study support the hypothesis that TLR7, TLR8 and TLR9 are the key TLRs in human toxoplasmosis.