title: Differential trafficking of TLR1 I602S underlies host protection against pathogenic mycobacteria.
abstract: We recently identified I602S as a frequent single-nucleotide polymorphism of human TLR1 that greatly inhibits cell surface trafficking, confers hyporesponsiveness to TLR1 agonists, and protects against the mycobacterial diseases leprosy and tuberculosis. Because mycobacteria are known to manipulate the TLR system to their advantage, we hypothesize that the hyporesponsive 602S variant may confer protection by enabling the host to overcome this immune subversion. We report that primary human monocytes and macrophages from homozygous TLR1 602S individuals are resistant to mycobacterial-induced downregulation of macrophage MHC class II, CD64, and IFN-γ responses compared with individuals who harbor the TLR1 602I variant. Additionally, when challenged with mycobacterial agonists, macrophages from TLR1 602S/S individuals resist induction of host arginase-1, an enzyme that depletes cellular arginine stores required for the production of antimicrobial reactive nitrogen intermediates. The differences in cell activation mediated by TLR1 602S and TLR1 602I are observed upon stimulation with soluble mycobacterial-derived agonists but not with whole mycobacterial cells. Taken together, these results suggest that the TLR1 602S variant protects against mycobacterial disease by preventing soluble mycobacterial products, perhaps released from granulomas, from disarming myeloid cells prior to their encounter with whole mycobacteria.
authors.affiliation: Department of Microbiology, University of Illinois, Urbana, IL 61801, USA.
authors.forename: Bryan E
authors.initials: BE
authors.lastname: Hart
authors.forename: Richard I
authors.initials: RI
authors.lastname: Tapping
mesh_terms: D001119:Arginase / Q000235:genetics / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007532:Isoleucine / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity; D020641:Polymorphism, Single Nucleotide / Q000235:genetics* / Q000276:immunology; D021381:Protein Transport / Q000187:drug effects; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D012694:Serine / Q000235:genetics / Q000276:immunology; D051194:Toll-Like Receptor 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D000949:Histocompatibility Antigens Class II; D017452:Receptors, IgG; D051194:Toll-Like Receptor 1; D007532:Isoleucine; D012694:Serine; D007371:Interferon-gamma; C574619:ARG1 protein, human; D001119:Arginase