Monocyte subpopulation in HIV+LTB+ individuals and development of active TB

HIV LTB 个体中的单核细胞亚群与活动性结核病的发展

• 批准号: 9333189
• 负责人: Ramakrishna Vankayalapati
• 金额: $ 17.25万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-16 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333189
• 关键词: Antibodies; Awareness; CD14 gene; Cause of Death; Cells; Cessation of life; Collaborations; Core Facility; Data; Development; Equipment; Freezing; Gene Expression; Growth; HIV; HIV Infections; Health; Health Sciences; Household; Hydroxyl Radical; IL10 gene; Immunity; India; Individual; Infection; Integration Host Factors; Interleukin-10; Investments; Laboratories; Mediating; Microscopy; Mycobacterium tuberculosis; Mycobacterium tuberculosis H37Rv; Nitric Oxide; Peptides; Peripheral Blood Mononuclear Cell; Persons; Phagosomes; Population; Predisposition; Production; Publishing; RNA; Reagent; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Research Personnel; Risk; Sampling; Ships; Site; Small Interfering RNA; T-Lymphocyte; Tuberculosis; United States National Institutes of Health; antimicrobial; base; beta-Defensins; biobank; cathelicidin; cohort; cytokine; extracellular; improved; mRNA Expression; macrophage; monocyte; prevent; response; therapy development; transcription factor

Mycobacterium tuberculosis (Mtb) infects one-third of the world’s population and causes almost 1.3 million deaths per year (1,2). Approximately 90% of infected persons have latent tuberculosis infection (LTBI), have protective immunity and remain well, but 10% develop primary tuberculosis (TB) soon after infection or reactivation TB many years later (3). HIV infection markedly increases susceptibility to TB, and HIV-infected persons with LTBI have an 800-fold greater risk of developing active TB (www.cdc.gov/tb/). TB is the leading cause of death in HIV-infected persons and more than half a million coinfected people die annually (www.avert.org/tuberculosis.htm). Our published studies demonstrate that in healthy donors, Mtb H37Rv grew 5.6-fold more rapidly in CD14hiCD16- MDMs, compared to CD14loCD16+ MDMs. We found increased growth of Mtb in CD14hiCD16- MDMs is due to increased expression of c-Maf, which increases production of IL-10 that promote Mtb H37Rv growth. In preliminary studies we found that in response to Mtb, PBMC from HIV+ and HIV- individuals with LTBI produced equal amounts of T-cell cytokines. In contrast CD14+ monocytes in HIV+ individuals expressed more c-maf and IL-10 in response to Mtb, compared to CD14+ cells from HIV-LTBI+ individuals. Based on our preliminary data we hypothesize that HIV infection increases the number of c- maf and IL-10 expressing CD14+ cells which leads to enhanced Mtb growth, increasing the risk for progression to active TB. Our specific aims are 1. Determine whether HIV infection enhances the growth of Mtb in CD14hiCD16- MDMs. 2. Identify the mechanisms which favor increased growth of Mtb in macrophage subpopulations of HIV+LTBI+ persons.

结核分枝杆菌感染了世界三分之一的人口，导致近130万人死亡 每年死亡人数(1，2)。大约90%的感染者有潜在的结核病感染(LTBI)， 保护性免疫并保持良好，但10%的人在感染或感染后不久就会出现原发结核病(TB) 多年后重新激活结核病(3)。艾滋病毒感染显著增加了结核病的易感性，而艾滋病毒感染者 患有LTBI的人患活动性结核病的风险要高出800倍(www.cdc.gov/tb/)。结核病是最主要的 艾滋病毒感染者的死因，每年有50多万人死于混合感染者 (www.vert.org/tubromosis.htm)。我们发表的研究表明，在健康的捐赠者中，结核分枝杆菌H37Rv生长 与CD14loCD16+MDM相比，CD14hiCD16-MDM的速度快5.6倍。我们发现， CD14hiCD16-MDM中的MTB是由于c-Maf的表达增加，从而增加IL-10的产生，从而 促进Mtb H37Rv增长。在初步研究中，我们发现，在对结核分枝杆菌的应答中，来自HIV+和 HIV-患有LTBI的人产生等量的T细胞细胞因子。相比之下，HIV+中的CD14+单核细胞 与来自HIV-LTBI+的CD14+细胞相比，Mtb诱导的个体表达更多的c-maf和IL-10 个人。根据我们的初步数据，我们假设HIV感染会增加c-DNA的数量。 MAF和IL-10表达CD14+细胞，导致结核分枝杆菌生长增强，增加 进展为活动性结核病。我们的具体目标是1.确定艾滋病毒感染是否促进了 CD14hiCD16-MDM中的MTB。2.确定促进巨噬细胞中结核分枝杆菌生长的机制 HIV+LTBI+人群的亚群。