Role of Myeloid Derived Suppressor Cells in Mycobacterium tuberculosis(Mtb)Reactivation in HIV-Mtb co-infected Individuals

骨髓源性抑制细胞在 HIV-Mtb 共感染个体结核分枝杆菌 (Mtb) 重新激活中的作用

• 批准号: 9204666
• 负责人: ANKITA GARG
• 金额: $ 23.27万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-04 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204666
• 关键词: Adopted; Antigen Presentation; Autophagocytosis; CD14 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Cell physiology; Cells; Cholecalciferol; Chronic; Clinical; Collaborations; Defect; Development; Dihydroxycholecalciferols; Disease; Exhibits; Frequencies; Genus Mycobacterium; Goals; Growth; HIV-1; Heating; ITGAM gene; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunology; Immunosuppression; Immunotherapeutic agent; In Vitro; India; Individual; Infection; Interferon Type II; International Aspects; Knowledge; Lysosomes; Manuscripts; Mediating; Mediator of activation protein; Mycobacterium tuberculosis; Myelogenous; Myeloid Cells; Outcome; Pathogenesis; Pathway interactions; Peptides; Persons; Phagosomes; Physicians; Plasma; Play; Population; Regulation; Research; Research Proposals; Resources; Risk; Risk Factors; Role; Sampling; Scientist; Specimen; Staging; Suppressor-Effector T-Lymphocytes; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic; Time; Tuberculosis; United States National Institutes of Health; Viral Load result; Virus Replication; Vitamin D; Vitamin D Deficiency; Work; antiretroviral therapy; cathelicidin; co-infection; cohort; cost effective; cytokine; experience; immune function; insight; interest; mycobacterial; novel; novel diagnostics; pathogen; reconstitution; trafficking; tumor; vacuolar H+-ATPase

PROJECT SUMMARY Human Immunodeficiency Virus-1 (HIV) is an important risk factor for Mycobacterium tuberculosis (Mtb). One third of the world's population has latent tuberculosis infection (LTBI) where the person remains healthy. However, presence of HIV increases the risk of reactivation of LTBI by 30 fold. Although progressive CD4+T cell depletion in chronic, untreated HIV infection increases the risk of co-infection with opportunistic pathogens, it is intriguing that Mtb in HIV infection can reactivate at any disease stage including times when CD4+ T cell numbers are high and viral replication is suppressed. The underlying mechanism for the dysregulated immunity that increases the risk of acquiring Mtb and developing active tuberculosis (TB) in HIV-infected individuals still remains unresolved. There is increasing evidence that untreated HIV infection is associated with the expansion of CD11b+CD33+CD14+HLA DR-/lo myeloid derived suppressor cells (MDSC) and MDSC are mediators of immune suppression. With successful combined antiretroviral therapy (cART), as CD4+ T cells increase and viral replication is suppressed, MDSC numbers decline but are still increased as compared to healthy controls. We hypothesize that in HIV-Mtb co-infected individuals the MDSC are major contributors of defective immunity to Mycobacterium. The significance of this proposal is that we will utilize a multifaceted approach to study the interaction of Mycobacterium with MDSC subset isolated from HIV-Mtb co-infected individuals and compare it to the interaction of Mycobacterium with HLA DRhi subset. We also propose a strategy to control MDSC mediated immune dysfunction. The research proposal combines the experience and knowledge of Dr. Ankita Garg (UCSD, CA, USA) in the pathogenesis and immunological outcomes of HIV and Mtb with the broad experience of Dr Luke Hana on HIV-Mtb co-infection and Dr Gopalan Narendran who is a physician scientist and will provide clinical expertise and specimens (both at NIH/NIRT, ICER, Chennai, India). This will provide us with a unique opportunity to test our hypothesis that MDSC are detrimental for Mycobacterium immunity and are a major factor for the increase in TB disease in HIV-Mtb co-infected individuals. Through this collaboration we will also be able to identify if presence of HIV subtype B (USA cohorts) or subtype C (Indian cohort) differentially regulates MDSC activity and LTBI reactivation. Two specific aims are proposed: in Aim 1) the mechanisms of downregulated innate effector functions and increased Mycobacterial load in MDSC isolated from HIV-Mtb co-infected individuals will be elucidated. In Aim 2) whether Mycobacterium specific T cell function can be augmented by treating MDSC with 1,25 dihydroxyvitamin D3 (vit D3) will be investigated. The long term goal of the proposed research is to investigate novel pathways in immune response to Mtb in the setting of HIV infection. Successful completion of the study will facilitate the development of novel diagnostic and cost-effective therapeutic strategies that can be adopted to decrease the risk for Mtb in HIV-infected persons.

项目概要 人类免疫缺陷病毒-1 (HIV) 是结核分枝杆菌 (Mtb) 的重要危险因素。一 世界上三分之一的人口患有潜伏性结核感染 (LTBI)，但他们仍保持健康。 然而，HIV 的存在会使 LTBI 重新激活的风险增加 30 倍。尽管进行性CD4+T 慢性、未经治疗的艾滋病毒感染中的细胞耗竭会增加机会性病原体共同感染的风险， 有趣的是，HIV 感染中的 Mtb 可以在任何疾病阶段重新激活，包括 CD4+ T 细胞 数量很高，病毒复制受到抑制。免疫失调的潜在机制 这仍然增加了 HIV 感染者感染 Mtb 和发展为活动性结核病 (TB) 的风险 仍未解决。越来越多的证据表明，未经治疗的艾滋病毒感染与艾滋病毒蔓延有关 CD11b+CD33+CD14+HLA DR-/lo 骨髓源性抑制细胞 (MDSC) 和 MDSC 是以下介质的介质 免疫抑制。通过成功的联合抗逆转录病毒治疗 (cART)，随着 CD4+ T 细胞的增加和 病毒复制受到抑制，MDSC 数量下降，但与健康对照相比仍有所增加。 我们假设，在 HIV-Mtb 共感染个体中，MDSC 是免疫缺陷的主要原因 对分枝杆菌。这个建议的意义在于我们将采用多方面的方法来研究 分枝杆菌与从 HIV-Mtb 共感染个体中分离出的 MDSC 亚群的相互作用并进行比较 分枝杆菌与 HLA DRhi 子集的相互作用。我们还提出了控制 MDSC 的策略 介导的免疫功能障碍。该研究提案结合了 Ankita 博士的经验和知识 Garg（加州大学圣地亚哥分校，加利福尼亚州，美国）在 HIV 和 Mtb 的发病机制和免疫学结果方面具有广泛的研究 Luke Hana 博士和医师科学家 Gopalan Narendran 博士在 HIV-Mtb 混合感染方面的经验 并将提供临床专业知识和样本（均在印度钦奈的 NIH/NIRT、ICER）。这将为我们提供 这是一个独特的机会来检验我们的假设，即 MDSC 对分枝杆菌免疫有害，并且 是 HIV-Mtb 合并感染者结核病增加的一个主要因素。通过这次合作 我们还能够确定是否存在 HIV B 亚型（美国队列）或 C 亚型（印度队列） 差异性调节 MDSC 活性和 LTBI 重新激活。提出了两个具体目标：目标 1) 分离的 MDSC 中先天效应功能下调和分枝杆菌负荷增加的机制 将阐明 HIV-Mtb 共同感染者的情况。目标2)是否有分枝杆菌特异性T细胞 将研究用 1,25 二羟基维生素 D3 (vit D3) 治疗 MDSC 来增强功能。这 拟议研究的长期目标是研究 Mtb 免疫反应的新途径 HIV 感染的环境。该研究的成功完成将促进新型诊断方法的开发 以及可用于降低 HIV 感染者感染 Mtb 风险的具有成本效益的治疗策略 人。