Human TLR1 Deficiency Is Associated with Impaired Mycobacterial Signaling and Protection from Leprosy Reversal Reaction

Abstract

Toll-like receptors (TLRs) are important regulators of the innate immune response to pathogens, including Mycobacterium leprae, which is recognized by TLR1/2 heterodimers. We previously identified a transmembrane domain polymorphism, TLR1_T1805G, that encodes an isoleucine to serine substitution and is associated with impaired signaling. We hypothesized that this TLR1 SNP regulates the innate immune response and susceptibility to leprosy. In HEK293 cells transfected with the 1805T or 1805G variant and stimulated with extracts of M. leprae, NF-κB activity was impaired in cells with the 1805G polymorphism. We next stimulated PBMCs from individuals with different genotypes for this SNP and found that 1805GG individuals had significantly reduced cytokine responses to both whole irradiated M. leprae and cell wall extracts. To investigate whether TLR1 variation is associated with clinical presentations of leprosy or leprosy immune reactions, we examined 933 Nepalese leprosy patients, including 238 with reversal reaction (RR), an immune reaction characterized by a Th1 T cell cytokine response. We found that the 1805G allele was associated with protection from RR with an odds ratio (OR) of 0.51 (95% CI 0.29–0.87, p = 0.01). Individuals with 1805 genotypes GG or TG also had a reduced risk of RR in comparison to genotype TT with an OR of 0.55 (95% CI 0.31–0.97, p = 0.04). To our knowledge, this is the first association of TLR1 with a Th1-mediated immune response. Our findings suggest that TLR1 deficiency influences adaptive immunity during leprosy infection to affect clinical manifestations such as nerve damage and disability. Mycobacterium leprae (ML) causes a disabling and stigmatizing disease that is characterized by distinct immune responses. ML produces a spectrum of illness in humans, and several lines of evidence indicate that host genetic factors influence susceptibility and clinical manifestations. Leprosy can occur as the lepromatous or tuberculoid forms, which are associated with different clinical manifestations, histopathology, T cell cytokine profiles, and bacterial burden in affected sites. Leprosy is also associated with unique immunologic reactions, such as reversal reaction, which is characterized by the rapid development of a Th1 T cell cytokine response that can cause substantial morbidity. We and others recently discovered a common human polymorphism in TLR1 (T1805G, I602S) that regulates cytokine production in response to lipopeptide stimulation, influences the cellular innate immune response to Mycobacteria, is associated with altered localization, and is present in 50% of individuals worldwide. Here, we show that in humans the 1805G variant does not mediate an inflammatory response to ML in vitro and that this polymorphism is associated with protection from reversal reaction. These data suggest that a common variant of TLR1 is associated with altered adaptive immune responses to ML as well as clinical outcome.