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.

项目总结