Characterisation of Toll-Like receptor 8 as a new innate immune receptor for Mycobacterium tuberculosis

Abstract

Previous reports have implicated the chemokine receptor CCR5 and Toll-like receptors TLR2 and TLR4 in the innate immune recognition of Mycobacterium tuberculosis (MTB). In this study, we provide comprehensive genetic, biochemical, cellular and mechanistic data linking intracellular TLR8 to the detection and host response to pathogenic mycobacteria. Natural polymorphisms in TLR8 have been implicated in susceptibility or protection from pulmonary MTB infections in Indonesian and Russian cohorts. Here we demonstrate that the protective polymorphism termed rs3764880 (M1V) generates a functional TLR8 receptor variant with an altered signal peptide, causing the trafficking of TLR8 to early rather than late endosomes. The protective TLR8 polymorphism results in increased inflammatory cytokine release, promotes phagosomal acidification and enhances intracellular killing of MTB. These results indicate that the TLR8 receptor pathway may represent a new target for pharmacological or immunological manipulation in MTB infection.