A Humanized Mouse Model to Study HIV/Mtb Co-infection

研究 HIV/Mtb 合并感染的人源化小鼠模型

• 批准号: 7930463
• 负责人: Janice J Endsley
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-17 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7930463
• 关键词: Acceleration; Animal Model; Animals; Anti-Bacterial Agents; Antigens; Antimycobacterial Agents; Architecture; Automobile Driving; Award; Biological Models; Biology; Blood; CD34 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cations; Cattle; Cell Count; Cell physiology; Cells; Cellular Immunity; Collaborations; Colony-forming units; Confocal Microscopy; Defect; Development; Disease; Disease Outcome; Drug Resistant Tuberculosis; Emergency Situation; Enzyme-Linked Immunosorbent Assay; Extreme drug resistant tuberculosis; Fetal Liver; Granuloma; HIV; HIV-1; Heating; Hepatocyte; Host Defense; Human; Image; Immune; Immune system; Immunology; Infection; Interleukin-10; Intervention; Letters; Leukocytes; Lung; Malaria; Mediating; Memory; Modeling; Monitor; Mus; Mycobacterium bovis; Mycobacterium tuberculosis; Outcome; Pathogenesis; Pathology; Patients; Population; Predisposition; Public Health; Publishing; RNA; Relative (related person); Research; Resource Sharing; Resources; Screening procedure; Severity of illness; Site; Source; Structure of parenchyma of lung; Survival Analysis; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Thymic Tissue; Time; Tissue Survival; Tissues; Tropism; Tuberculosis; Tuberculosis Vaccines; Vaccinated; Vaccination; Vaccines; Viral; Virus Diseases; Virus Replication; Work; cell mediated immune response; cytokine; design; global health; granulysin; human tissue; immune activation; in vivo; innovation; macrophage; man; model development; mouse model; multidisciplinary; novel; pathogen; peripheral blood; prophylactic; public health relevance; reconstitution; research study; synthetic polymer Bioplex; therapeutic vaccine; therapy development; tool; trafficking; vaccination against tuberculosis; vaccine development

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) infection is driving the re-emergence of opportunistic tuberculosis (TB) as a global health emergency, and is strongly associated with the development of multi- or extensively- drug resistant TB (MDR-, XDR-TB). Currently there are no animal models to study HIV/Mtb co-infection due to the human host tropism of HIV. The BLT humanized mouse model is being rapidly applied to study several pathogens where suitable animal models are deficient, including HIV, malaria, and HIV/HCV co-infection. The objective of this proposal is to develop a small animal model of HIV/Mtb co-infection in the humanized mouse for immunological studies critical to Mtb vaccine development. The central hypothesis is that HIV infection will increase the pathogenesis of Mtb and compromise vaccine-induced cell-mediated immunity to Mtb in a humanized mouse model of HIV/Mtb co-infection. The rationale for the proposed research is that a small animal model of human HIV/Mtb co-infection would greatly enhance progress towards understanding these and other mechanisms whereby HIV suppresses CMI to Mtb and accelerate design and screening of TB vaccines for HIV+ populations. The specific aims to test this central hypothesis are 1) To develop a relevant mouse model to study the pathogenesis of Mtb and HIV/Mtb infection and 2) To determine how HIV alters protective CMI to Mtb in M. bovis BCG-vaccinated, humanized mice. These aims will be accomplished by using the NOD-SCID/3cnull mouse engrafted with human fetal liver and thymic tissue, and injected intravenously with CD34+ fetal liver cells from the same tissue source. Differences in Mtb disease severity due to HIV infection will be monitored by in vivo fluorescent quantification (tdTomato Mtb H37Rv), pathology and bacterial load in tissues, and survival. Alterations in CMI in naive and BCG (heat-inactivated)-vaccinated animals due to HIV will be determined by analysis of: cytokine profiles; leukocyte distribution and organization, and T cell effector molecule expression, at sites of Mtb infection; and ex vivo antimycobacterial activity of CD4+ and CD8+ T cells against Mtb-infected macrophages. The proposed work will establish a small animal model of HIV/Mtb co-infection with a defined magnitude, time course, and outcome of disease due to Mtb. Further, specific mechanisms of post-vaccination antimycobacterial T cell function that are impaired by HIV will be identified and assessed relative to protection from Mtb challenge. This co-infection model will be a powerful research tool for discoveries in the basic biology of co-infection and disease intervention. Development of this model is significant, as these results will provide new opportunities to identify the mechanisms whereby HIV compromises the protective CMI response to Mtb. The positive impact of this model system will be greatly enhanced capabilities to design and screen innovative prophylactics and therapeutics for TB to use in populations with HIV-compromised immune systems. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it will significantly advance our fundamental understanding of how HIV dysregulation of the immune system promotes the susceptibility to Mycobacterium tuberculosis. The results of these studies will enable informed guidance for the development of vaccines and therapeutics to protect HIV+ patients from tuberculosis.

描述（由申请人提供）：人类免疫缺陷病毒 (HIV) 感染正在推动机会性结核病 (TB) 重新出现，成为全球性的突发卫生事件，并且与多重或广泛耐药结核病 (MDR) 的发展密切相关-，广泛耐药结核病）。由于HIV具有人类宿主倾向，目前尚无研究HIV/Mtb双重感染的动物模型。 BLT 人源化小鼠模型正被迅速应用于研究几种缺乏合适动物模型的病原体，包括 HIV、疟疾和 HIV/HCV 混合感染。该提案的目的是在人源化小鼠中开发 HIV/Mtb 共同感染的小动物模型，用于对 Mtb 疫苗开发至关重要的免疫学研究。中心假设是，在 HIV/Mtb 共感染的人源化小鼠模型中，HIV 感染会增加 Mtb 的发病机制，并损害疫苗诱导的细胞介导的 Mtb 免疫。拟议研究的基本原理是，人类 HIV/Mtb 混合感染的小动物模型将极大地促进理解 HIV 抑制 CMI 对 Mtb 的这些机制和其他机制的进展，并加速针对 HIV+ 人群的结核疫苗的设计和筛选。检验这一中心假设的具体目标是 1) 开发相关小鼠模型来研究 Mtb 和 HIV/Mtb 感染的发病机制，以及 2) 确定 HIV 如何改变牛分枝杆菌 BCG 疫苗接种的人源化小鼠对 Mtb 的保护性 CMI 。这些目标将通过使用植入人胎儿肝脏和胸腺组织的 NOD-SCID/3cnull 小鼠并静脉注射来自同一组织来源的 CD34+ 胎儿肝细胞来实现。 HIV 感染导致 Mtb 疾病严重程度的差异将通过体内荧光定量 (tdTomato Mtb H37Rv)、组织中的病理学和细菌负荷以及存活率进行监测。未接种疫苗和接种 BCG（热灭活）疫苗的动物中因 HIV 导致的 CMI 变化将通过分析以下内容来确定：细胞因子谱； Mtb 感染部位的白细胞分布和组织以及 T 细胞效应分子表达； CD4+ 和 CD8+ T 细胞对 Mtb 感染的巨噬细胞的体外抗分枝杆菌活性。拟议的工作将建立一个 HIV/Mtb 混合感染的小动物模型，并确定 Mtb 引起的疾病的严重程度、时间进程和结果。此外，将确定和评估与 Mtb 攻击保护相关的疫苗接种后抗分枝杆菌 T 细胞功能被 HIV 损害的具体机制。这种双重感染模型将成为发现双重感染和疾病干预的基础生物学的强大研究工具。该模型的开发具有重要意义，因为这些结果将为确定 HIV 损害 CMI 对 Mtb 的保护性反应的机制提供新的机会。该模型系统的积极影响将大大增强设计和筛选创新的结核病预防和治疗方法的能力，以用于艾滋病毒免疫系统受损的人群。 公共健康相关性：拟议的研究与公共健康相关，因为它将显着增进我们对艾滋病毒免疫系统失调如何促进结核分枝杆菌易感性的基本理解。这些研究的结果将为疫苗和治疗方法的开发提供明智的指导，以保护艾滋病毒+患者免受结核病的侵害。