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Identification of antigens presented by MHC for vaccines against tuberculosis.
npj Vaccines ( IF 6.9 ) Pub Date : 2020-01-03 , DOI: 10.1038/s41541-019-0148-y Paulo Bettencourt 1 , Julius Müller 1 , Annalisa Nicastri 2 , Daire Cantillon 3 , Meera Madhavan 1 , Philip D Charles 2 , Carine B Fotso 1 , Rachel Wittenberg 1 , Naomi Bull 1 , Nawamin Pinpathomrat 1 , Simon J Waddell 3 , Elena Stylianou 1 , Adrian V S Hill 1 , Nicola Ternette 1, 2 , Helen McShane 1
npj Vaccines ( IF 6.9 ) Pub Date : 2020-01-03 , DOI: 10.1038/s41541-019-0148-y Paulo Bettencourt 1 , Julius Müller 1 , Annalisa Nicastri 2 , Daire Cantillon 3 , Meera Madhavan 1 , Philip D Charles 2 , Carine B Fotso 1 , Rachel Wittenberg 1 , Naomi Bull 1 , Nawamin Pinpathomrat 1 , Simon J Waddell 3 , Elena Stylianou 1 , Adrian V S Hill 1 , Nicola Ternette 1, 2 , Helen McShane 1
Affiliation
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Mycobacterium tuberculosis (M.tb) is responsible for more deaths globally than any other pathogen. The only available vaccine, bacillus Calmette-Guérin (BCG), has variable efficacy throughout the world. A more effective vaccine is urgently needed. The immune response against tuberculosis relies, at least in part, on CD4+ T cells. Protective vaccines require the induction of antigen-specific CD4+ T cells via mycobacterial peptides presented by MHC class-II in infected macrophages. In order to identify mycobacterial antigens bound to MHC, we have immunoprecipitated MHC class-I and class-II complexes from THP-1 macrophages infected with BCG, purified MHC class-I and MHC class-II peptides and analysed them by liquid chromatography tandem mass spectrometry. We have successfully identified 94 mycobacterial peptides presented by MHC-II and 43 presented by MHC-I, from 76 and 41 antigens, respectively. These antigens were found to be highly expressed in infected macrophages. Gene ontology analysis suggests most of these antigens are associated with membranes and involved in lipid biosynthesis and transport. The sequences of selected peptides were confirmed by spectral match validation and immunogenicity evaluated by IFN-gamma ELISpot against peripheral blood mononuclear cell from volunteers vaccinated with BCG, M.tb latently infected subjects or patients with tuberculosis disease. Three antigens were expressed in viral vectors, and evaluated as vaccine candidates alone or in combination in a murine aerosol M.tb challenge model. When delivered in combination, the three candidate vaccines conferred significant protection in the lungs and spleen compared with BCG alone, demonstrating proof-of-concept for this unbiased approach to identifying new candidate antigens.
中文翻译：
鉴定由 MHC 呈递的用于结核病疫苗的抗原。
结核分枝杆菌 (M.tb) 在全球造成的死亡人数超过任何其他病原体。唯一可用的疫苗卡介苗（BCG）在世界范围内具有不同的功效。迫切需要一种更有效的疫苗。针对结核病的免疫反应至少部分依赖于 CD4+ T 细胞。保护性疫苗需要通过感染巨噬细胞中 MHC II 类呈递的分枝杆菌肽诱导抗原特异性 CD4+ T 细胞。为了鉴定与 MHC 结合的分枝杆菌抗原，我们免疫沉淀了来自感染 BCG 的 THP-1 巨噬细胞的 MHC I 类和 II 类复合物、纯化的 MHC I 类和 MHC II 类肽，并通过液相色谱串联质谱进行分析光谱法。我们已经成功地分别从 76 和 41 种抗原中鉴定了由 MHC-II 呈递的 94 种分枝杆菌肽和由 MHC-I 呈递的 43 种分枝杆菌肽。发现这些抗原在受感染的巨噬细胞中高度表达。基因本体分析表明，大多数这些抗原与膜相关，并参与脂质生物合成和运输。所选肽的序列通过光谱匹配验证和 IFN-γ ELISpot 评估的免疫原性对来自接种 BCG、M.tb 潜伏感染受试者或患有结核病的患者的外周血单核细胞的免疫原性进行了确认。三种抗原在病毒载体中表达，并在鼠气溶胶 M.tb 攻击模型中单独或组合作为候选疫苗进行评估。组合交付时，
更新日期：2020-01-03
中文翻译：
鉴定由 MHC 呈递的用于结核病疫苗的抗原。
结核分枝杆菌 (M.tb) 在全球造成的死亡人数超过任何其他病原体。唯一可用的疫苗卡介苗（BCG）在世界范围内具有不同的功效。迫切需要一种更有效的疫苗。针对结核病的免疫反应至少部分依赖于 CD4+ T 细胞。保护性疫苗需要通过感染巨噬细胞中 MHC II 类呈递的分枝杆菌肽诱导抗原特异性 CD4+ T 细胞。为了鉴定与 MHC 结合的分枝杆菌抗原，我们免疫沉淀了来自感染 BCG 的 THP-1 巨噬细胞的 MHC I 类和 II 类复合物、纯化的 MHC I 类和 MHC II 类肽，并通过液相色谱串联质谱进行分析光谱法。我们已经成功地分别从 76 和 41 种抗原中鉴定了由 MHC-II 呈递的 94 种分枝杆菌肽和由 MHC-I 呈递的 43 种分枝杆菌肽。发现这些抗原在受感染的巨噬细胞中高度表达。基因本体分析表明，大多数这些抗原与膜相关，并参与脂质生物合成和运输。所选肽的序列通过光谱匹配验证和 IFN-γ ELISpot 评估的免疫原性对来自接种 BCG、M.tb 潜伏感染受试者或患有结核病的患者的外周血单核细胞的免疫原性进行了确认。三种抗原在病毒载体中表达，并在鼠气溶胶 M.tb 攻击模型中单独或组合作为候选疫苗进行评估。组合交付时，
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