human tlr1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction人类tlr1缺乏与受损的麻风分枝杆菌信号和保护逆转反应.pdfVIP

Human TLR1 Deficiency Is Associated with Impaired Mycobacterial Signaling and Protection from Leprosy Reversal Reaction 1 2 2 2 1 Elizabeth A. Misch , Murdo Macdonald , Chaman Ranjit , Bishwa R. Sapkota , Richard D. Wells , M. Ruby 3 3 1 Siddiqui , Gilla Kaplan , Thomas R. Hawn * 1 University of Washington School of Medicine, Seattle, Washington, United States of America, 2 Mycobacterial Research Laboratory, Anandaban Hospital, Kathmandu, Nepal, 3 Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute at the University of Medicine and Dentistry of New Jersey, Newark, New Jersey, United States of America 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-kB 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