Toxoplasma gondii-Derived Profilin Triggers Human Toll-Like Receptor 5-Dependent Cytokine Production

Abstract

Up to a third of the world's population is infected with Toxoplasma gondii. Natural infection in humans can be life threatening during pregnancy and in immunocompromised individuals. Toll-like receptor (TLR) 11 is the mouse innate sensor that recognizes T. gondii profilin; however, in humans the TLR11 gene leads to transcription of no functional protein. Herein, by using a multiple sequence alignment phylogenetic analysis program between human and mouse species, we found that human TLR5 seems to be the evolutionarily closest member of the TLR gene family to mouse tlr11. We therefore asked whether human TLR5 could mediate IL-6, IL-8 and IL-12p70 production in response to the T. gondii profilin. We found that this was the case both in human cell lines as well as peripheral blood monocytes. Moreover, TLR5 neutralization and gene silencing mediated specific ablation of cytokine production after profilin exposure. Finally, peripheral blood monocytes carrying the TLR5 R392X mutation failed to produce cytokines in response to stimulation with profilin. Taken together, the results presented herein reveal a previously unappreciated cross-recognition of a relevant human pathogen-derived pathogen-associated molecular pattern.