M. tuberculosis Induces Potent Activation of IDO-1, but This Is Not Essential for the Immunological Control of Infection

Indoleamine 2,3-dioxygenesae-1 (IDO-1) catalyses the initial, rate-limiting step in tryptophan metabolism, thereby regulating tryptophan availability and the formation of downstream metabolites, including picolinic and quinolinic acid. We found that Mycobacterium tuberculosis infection induced marked upregulation of IDO-1 expression in both human and murine macrophages in vitro and in the lungs of mice following aerosol challenge with M. tuberculosis. The absence of IDO-1 in dendritic cells enhanced the activation of mycobacteria-specific T cells in vitro. Interestingly, IDO-1-deficiency during M. tuberculosis infection in mice was not associated with altered mycobacteria-specific T cell responses in vivo. The bacterial burden of infected organs, pulmonary inflammatory responses, and survival were also comparable in M. tuberculosis-infected IDO-1 deficient and wild type animals. Tryptophan is metabolised into either picolinic acid or quinolinic acid, but only picolinic acid inhibited the growth of M. tuberculosis in vitro. By contrast macrophages infected with pathogenic mycobacteria, produced quinolinic, rather than picolinic acid, which did not reduce M. tuberculosis growth in vitro. Therefore, although M. tuberculosis induces robust expression of IDO-1 and activation of tryptophan metabolism, IDO-1-deficiency fails to impact on the immune control and the outcome of the infection in the mouse model of tuberculosis.吲哚胺2,3-双加氧酶1（Indoleamine 2,3-dioxygenase-1, IDO-1）可催化色氨酸代谢过程中的初始限速步骤，进而调控色氨酸的可获得性以及包括吡啶甲酸（picolinic acid）和喹啉酸（quinolinic acid）在内的下游代谢产物生成。我们发现，结核分枝杆菌（Mycobacterium tuberculosis）感染可在体外实验中显著上调人源与鼠源巨噬细胞的IDO-1表达，同时在经结核分枝杆菌气溶胶感染的小鼠肺部组织中也可检测到该表达上调现象。树突状细胞中IDO-1的缺失可在体外增强结核分枝杆菌特异性T细胞的活化水平。值得注意的是，在小鼠结核分枝杆菌感染模型中，IDO-1基因缺失并未改变体内结核分枝杆菌特异性T细胞的应答反应。感染器官的细菌负荷、肺部炎症反应以及小鼠存活率，在结核分枝杆菌感染的IDO-1缺陷型小鼠与野生型小鼠中均无显著差异。色氨酸可代谢为吡啶甲酸或喹啉酸，且仅吡啶甲酸可在体外抑制结核分枝杆菌的生长。与之相反，被致病性分枝杆菌感染的巨噬细胞会产生喹啉酸而非吡啶甲酸，该产物无法在体外抑制结核分枝杆菌的增殖。综上，尽管结核分枝杆菌可诱导IDO-1的高表达并激活色氨酸代谢通路，但在肺结核小鼠模型中，IDO-1的缺失并不会影响机体对感染的免疫调控以及感染结局。