Differential Induction and Antimicrobial Function of Interferons in Leprosy

麻风病是一种由胞内致病菌麻风分枝杆菌（Mycobacterium leprae，mLEP）引起的人类疾病，为研究皮肤感染后先天性和适应性免疫应答的调控提供了一个有吸引力的模型。该疾病代表一个谱，其中临床表现与对病原体的免疫应答相关。通过研究麻风的适应性免疫应答，我们确定耐药、自限性、结核样（T-lep）患者在病变中表达Thi细胞因子IFN-γ，而播散性麻风（L-lep）患者在病变中表现出Th 2细胞因子IL-4和IL-10（1）。我们的新的初步数据表明干扰素（IFN）及其下游基因网络在麻风皮肤病变的差异表达。令人惊讶的发现是II型IFN、IFN-γ以及IFN-γ诱导基因（包括抗微生物基因程序）的表达在T-lep病变中富集。相反，IFN、IFN-β和IFN-β诱导基因的表达在L-lep病变中占主导地位。我们假设特异性mLEP分泌的蛋白/配体分别在T-lep和L-lep患者中差异性地触发II型和I型IFN的产生。为了验证这一假设，我们提出了翻译实验：1）鉴定推定的mLEP分泌组中的T细胞表位/抗原，其在麻风患者中诱导II型IFN、IFN-γ并触发抗微生物活性，2）确定特定的mLEP分泌蛋白是否诱导I型IFN并抑制抗微生物应答;以及3）研究分泌的mLEP糖脂、酚糖脂-1（PGL-1）触发单核细胞/巨噬细胞中I型IFN应答的机制。我们提出的研究旨在提供一个全面的分析机制，触发I型与II型干扰素在麻风病，包括这些途径在宿主防御和发病机制中的作用。我们希望这些见解将有助于麻风病的诊断和预防，并为开发各种人类皮肤病的免疫调节方法提供新的途径。

Leprosy, a human disease caused by the intracellular pathogen Mycobacterium leprae (mLEP), offers an attractive model for investigating the regulation of innate and adaptive immune responses to infection in skin. The disease represents a spectrum, in which the clinical manifestations correlate with the immune response to the pathogen. By investigating the adaptive immune response in leprosy, we established that resistant, self-limited, tuberculoid (T-lep) patients express the Thi cytokine IFN-gamma in lesions, whereas disseminated lepromatous (L-lep) patients manifest Th2 cytokines IL-4 and IL-10 in lesions (1). Our new preliminary data indicates the differential expression of interferons (IFNs) and their downstream gene networks in leprosy skin esions. The striking finding was that expression ofthe Type II IFN, IFN-gamma, as well as IFN-gamma inducible genes including the antimicrobial gene program, were enriched in T-lep lesions. In contrast, expression ofthe Type IFN, IFN-Beta, as well as IFN-Beta inducible genes, predominated in L-lep lesions. We hypothesize that specific mLEP secreted proteins/ligands differentially trigger production of Type II vs. Type I IFNs in T-lep vs. L-lep patients, respectively. To test this hypothesis, we propose translational experiments to: 1) identify the T cell epitopes/antigens in the putative mLEP secretome which induce the Type II IFN, IFN-gamma, in leprosy patients and trigger an antimicrobial activity, 2) determine whether specific mLEP secreted proteins induce Type I IFNs and inhibit antimicrobial responses; and, 3) investigate the mechanism by which the secreted mLEP glycolipid, phenolic glycolipid-1 (PGL-1), triggers Type I IFN responses in monocytes/macrophages. The studies we propose are intended to provide a comprehensive analysis of the mechanisms that trigger Type I vs. Type II IFNs in leprosy, including the role of these pathways in host defense and pathogenesis. We would hope that insights would assist in the diagnosis and prevention of leprosy, as well as provide new avenues for development of immunomodulatory approaches for a variety of human skin diseases.