RESUMO
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.
Assuntos
Macrófagos/imunologia , Monócitos/imunologia , Mycobacterium tuberculosis/imunologia , Polimorfismo de Nucleotídeo Único/genética , Receptor 1 Toll-Like/metabolismo , Arginase/genética , Arginase/imunologia , Membrana Celular/imunologia , Membrana Celular/metabolismo , Membrana Celular/microbiologia , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Isoleucina/genética , Isoleucina/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Monócitos/efeitos dos fármacos , Monócitos/microbiologia , Mycobacterium tuberculosis/patogenicidade , Polimorfismo de Nucleotídeo Único/imunologia , Transporte Proteico/efeitos dos fármacos , Receptores de IgG/genética , Receptores de IgG/imunologia , Serina/genética , Serina/imunologia , Receptor 1 Toll-Like/genética , Receptor 1 Toll-Like/imunologiaRESUMO
Genetic association studies of leprosy cohorts across the world have identified numerous polymorphisms which alter susceptibility and outcome to infection with Mycobacterium leprae. As expected, many of the polymorphisms reside within genes that encode components of the innate and adaptive immune system. Despite the preponderance of these studies, our understanding of the mechanisms that underlie these genetic associations remains sparse. Toll-like receptors (TLRs) have emerged as an essential family of innate immune pattern recognition receptors which play a pivotal role in host defense against microbes, including pathogenic strains of mycobacteria. This paper will highlight studies which have uncovered the association of specific TLR gene polymorphisms with leprosy or tuberculosis: two important diseases resulting from mycobacterial infection. This analysis will focus on the potential influence these polymorphic variants have on TLR expression and function and how altered TLR recognition or signaling may contribute to successful antimycobacterial immunity.