Mechanisms of Immune Regulation in Mycobacterium Tuberculosis Infection

结核分枝杆菌感染的免疫调节机制

• 批准号: 8317962
• 负责人: Cheryl Liane Day
• 金额: $ 9.87万
• 依托单位: UNIVERSITY OF CAPE TOWN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-28 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8317962
• 关键词: Acid Fast Bacillae Staining Method; Address; Animal Model; Antigens; B-Lymphocytes; Bacillus (bacterium); Bacteria; Bacterial Infections; Cell physiology; Cells; Cessation of life; Chronic; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Disease; Disease Progression; Exposure to; Failure; Family; Functional disorder; Generations; Health; Human; Immune; Immune response; Immunocompetent; Immunoglobulin Domain; Immunoglobulins; Immunotherapeutic agent; Individual; Infection; Interferons; Intervention; Investigation; Lung; Modeling; Mucins; Mus; Mycobacterium tuberculosis; Persons; Process; Production; Pulmonary Tuberculosis; Regulation; Regulatory Pathway; Relapse; Research; South Africa; Sputum; T cell response; T memory cell; T-Lymphocyte; Tuberculosis; Tuberculosis Vaccines; Up-Regulation; Viral Load result; Virus; Virus Diseases; cytokine; cytotoxicity; design; exhaustion; functional disability; innovation; member; mycobacterial; novel; peripheral blood; programs; receptor; receptor expression; therapy design

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis infects approximately 2 billion people worldwide and can persist for the lifetime of the host. Loss of immune control and progression to active tuberculosis (TB) disease occurs in a subset of infected individuals, however the precise mechanisms leading to this immunological failure are not known. Persistent antigen stimulation in human and animal models of chronic infections leads to antigen-specific T cell dysfunction, characterized by progressive loss of cytokine production, proliferative capacity, and cytolytic activity. This functional 'exhaustion' of T cells has been previously described in the context of chronic viral infections, and has been associated with antigen-driven upregulation of inhibitory receptors that negatively regulate antigen-specific T cells. Negative regulatory receptors expressed on activated T cells include members of the B7 family: programmed death 1 (PD-1), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and B and T lymphocyte attenuator (BTLA), as well as members of the immunoglobulin superfamily: CD160 and T cell immunoglobulin domain and mucin domain 3 (TIM-3). The relationship between chronic mycobacterial antigen stimulation and expression of receptors that negatively regulate activated M. tuberculosis-specific T cells has not been addressed. The underlying hypothesis of this proposal is that expression of negative regulatory receptors is related to mycobacterial antigen levels, and that upregulation of negative regulatory receptors is associated with dysregulation of protective M. tuberculosis- specific T cell responses in persons with pulmonary TB disease. The following specific aims will be addressed: (1) Characterize expression of negative regulatory receptors on cells from the lungs of individuals with latent and active pulmonary TB; (2) Characterize negative regulatory receptors in peripheral blood of individuals with latent and active pulmonary TB, before and after initiation of treatment; (3) Determine the effect of blockade of negative regulatory pathways on M. tuberculosis-specific T cell function. These studies will focus on individuals in Cape Town, South Africa with different mycobacterial antigen levels, including asymptomatic latent TB infection (LTBI), acid-fast bacilli (AFB) sputum smear- negative/culture-positive pulmonary TB, and AFB sputum smear-positive pulmonary TB. Elucidating mechanisms contributing to immunological failure in persons who develop active TB disease is essential for a better understanding of M. tuberculosis immunopathogenesis, and will facilitate new avenues of research on immunotherapeutic interventions and the rational design of novel TB vaccines. PUBLIC HEALTH RELEVANCE: In the majority of individuals infected with Mycobacterium tuberculosis, the immune response successfully contains the bacteria in a latent state and the host remains asymptomatic. Investigation of mechanisms of the cellular immune response that regulate M. tuberculosis- specific T cell responses in persons with latent and active disease is essential for a better understanding of why the immune response fails in some infected individuals who progress to develop active tuberculosis disease; such studies will open up new avenues of research on immunotherapeutic interventions and the design of more effective tuberculosis vaccines.

描述（由申请人提供）：结核分枝杆菌感染全球约 20 亿人，并可在宿主的一生中持续存在。部分受感染个体会丧失免疫控制并进展为活动性结核病 (TB)，但导致这种免疫失败的确切机制尚不清楚。人类和动物慢性感染模型中持续的抗原刺激会导致抗原特异性 T 细胞功能障碍，其特征是细胞因子产生、增殖能力和细胞溶解活性逐渐丧失。 T 细胞的这种功能性“耗竭”先前已在慢性病毒感染的背景下进行过描述，并且与抗原驱动的抑制性受体上调相关，从而负向调节抗原特异性 T 细胞。活化 T 细胞上表达的负调节受体包括 B7 家族成员：程序性死亡 1 (PD-1)、细胞毒性 T 淋巴细胞相关抗原 4 (CTLA-4)、B 和 T 淋巴细胞衰减因子 (BTLA)，以及免疫球蛋白超家族的成员：CD160 和 T 细胞免疫球蛋白结构域和粘蛋白结构域 3 (TIM-3)。慢性分枝杆菌抗原刺激与负向调节激活的结核分枝杆菌特异性 T 细胞的受体表达之间的关系尚未得到解决。该提议的基本假设是负调节受体的表达与分枝杆菌抗原水平相关，并且负调节受体的上调与肺结核患者中保护性结核分枝杆菌特异性T细胞反应的失调相关。将解决以下具体目标：（1）表征潜伏性和活动性肺结核个体肺部细胞上负调节受体的表达； (2) 潜伏性和活动性肺结核患者在开始治疗之前和之后外周血中负调节受体的特征； (3)确定阻断负调控途径对结核分枝杆菌特异性T细胞功能的影响。这些研究将重点关注南非开普敦具有不同分枝杆菌抗原水平的个体，包括无症状潜伏性结核感染 (LTBI)、抗酸杆菌 (AFB) 痰涂片阴性/培养阳性肺结核以及 AFB 痰涂片阳性肺结核。肺结核阳性。阐明活动性结核病患者免疫功能衰竭的机制对于更好地了解结核分枝杆菌免疫发病机制至关重要，并将促进免疫治疗干预研究的新途径和新型结核疫苗的合理设计。公共卫生相关性：在大多数感染结核分枝杆菌的个体中，免疫反应成功地将细菌抑制在潜伏状态，并且宿主保持无症状。研究调节潜伏性和活动性结核病患者体内结核分枝杆菌特异性 T 细胞反应的细胞免疫反应机制，对于更好地了解为什么一些感染者进展为活动性结核病时免疫反应失败至关重要；此类研究将为免疫治疗干预措施和设计更有效的结核病疫苗的研究开辟新途径。

项目成果

Dominant TNF-α+ Mycobacterium tuberculosis-specific CD4+ T cell responses discriminate between latent infection and active disease.

显性 TNF-α 结核分枝杆菌特异性 CD4 T 细胞反应可区分潜伏感染和活动性疾病。

• 发表时间: 2011-03
• 影响因子: 82.9
• 作者: Harari, Alexandre;Rozot, Virginie;Bellutti Enders, Felicitas;Perreau, Matthieu;Stalder, Jesica Mazza;Nicod, Laurent P;Cavassini, Matthias;Calandra, Thierry;Blanchet, Catherine Lazor;Jaton, Katia;Faouzi, Mohamed;Day, Cheryl L;Hanekom, Willem A
• 通讯作者: Hanekom, Willem A

Distinct T-cell responses when BCG vaccination is delayed from birth to 6 weeks of age in Ugandan infants.

乌干达婴儿从出生延迟至 6 周龄接种 BCG 时，T 细胞反应明显。

• 发表时间: 2014-03
• 作者: Lutwama, F;Kagina, B M;Wajja, A;Waiswa, F;Mansoor, N;Kirimunda, S;Hughes, E J;Kiwanuka, N;Joloba, M L;Musoke, P;Scriba, T J;Mayanja;Day, C L;Hanekom, W A
• 通讯作者: Hanekom, W A

Patients with tuberculosis disease have Mycobacterium tuberculosis-specific CD8 T cells with a pro-apoptotic phenotype and impaired proliferative capacity, which is not restored following treatment.

结核病患者具有结核分枝杆菌特异性 CD8 T 细胞，具有促凋亡表型和受损的增殖能力，且在治疗后不会恢复。

• 发表时间: 2014
• 影响因子: 3.7
• 作者: Day, Cheryl L;Moshi, Noella D;Abrahams, Deborah A;van Rooyen, Michele;O'rie, Terrence;de Kock, Marwou;Hanekom, Willem A
• 通讯作者: Hanekom, Willem A

Safety and immunogenicity of candidate vaccine M72/AS01E in adolescents in a TB endemic setting.

候选疫苗 M72/AS01E 在结核病流行环境中青少年中的安全性和免疫原性。

• 发表时间: 2015-07-31
• 影响因子: 5.5
• 作者: Penn;Geldenhuys, Hennie;Burny, Wivine;van der Most, Robbert;Day, Cheryl L;Jongert, Erik;Moris, Philippe;Hatherill, Mark;Ofori;Hanekom, Willem;Vaccine Study Team;Bollaerts, Anne;Demoitie, Marie;Kany Luabeya
• 通讯作者: Kany Luabeya

Mycobacterium tuberculosis-specific CD8+ T cells are functionally and phenotypically different between latent infection and active disease.

结核分枝杆菌特异性 CD8 T 细胞在潜伏感染和活动性疾病之间在功能和表型上有所不同。

• 发表时间: 2013-06
• 影响因子: 5.4
• 作者: Rozot, Virginie;Vigano, Selena;Mazza;Idrizi, Elita;Day, Cheryl L;Perreau, Matthieu;Lazor;Petruccioli, Elisa;Hanekom, Willem;Goletti, Delia;Bart, Pierre;Nicod, Laurent;Pantaleo, Giuseppe;Harari, Al
• 通讯作者: Harari, Al