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）感染推动了机会性结核病（TB）的重新出现，作为全球健康紧急情况，并且与多种或广泛的抗药性TB（MDR-，XDR-TB）的发展密切相关。目前，由于人类宿主的艾滋病毒寄主症状，尚无动物模型来研究HIV/MTB共同感染。 BLT人源化的小鼠模型正在迅速应用于研究合适的动物模型不足的几种病原体，包括HIV，疟疾和HIV/HCV共感染。该提案的目的是开发人源化小鼠中的HIV/MTB共感染的小动物模型，用于对MTB疫苗发育至关重要的免疫学研究。中心假设是，HIV感染将增加MTB的发病机理，并在HIV/MTB共同感染的人源化小鼠模型中损害疫苗诱导的细胞介导的对MTB的免疫。拟议的研究的基本原理是，人类HIV/MTB共同感染的小动物模型将大大提高进步，以理解这些和其他机制，从而使HIV抑制CMI至MTB，并加速了HIV+种群的TB疫苗的设计和筛查。测试该中心假设的具体目的是1）开发相关的小鼠模型，以研究MTB和HIV/MTB感染的发病机理，以及2）确定HIV如何将保护性CMI改变为BCG疫苗接种的M. bcg ventimed M. tbb。这些目标将通过使用植入人类胎儿肝脏和胸腺组织的NOD-SCID/3CNULL小鼠来实现，并从同一组织来源向CD34+胎儿肝细胞静脉注射。通过体内荧光定量（TDTOMATO MTB H37RV），组织中的病理和细菌负荷以及生存率，将监测HIV感染引起的MTB疾病严重程度的差异。 NAIVE和BCG中CMI的改变（热灭活）因HIV引起的动物将通过以下分析来确定：细胞因子谱；白细胞分布和组织，以及在MTB感染部位的T细胞效应分子表达； CD4+和CD8+ T细胞对MTB感染的巨噬细胞的离体抗菌活性。拟议的工作将建立一个小动物模型的HIV/MTB共同感染的小动物模型，并因MTB而定的幅度，时间过程和疾病结果。此外，相对于免于MTB挑战的保护，将发现和评估受HIV损害的疫苗后抗菌T细胞功能的特定机制。这种共同感染模型将成为共同感染和疾病干预基本生物学发现的强大研究工具。该模型的开发非常重要，因为这些结果将为确定HIV损害MTB的保护性CMI反应的机制提供新的机会。该模型系统的积极影响将极大地增强了设计和筛选创新的预防药物和TB的创新性预防疗法的能力，可用于HIV型免疫系统的人群中。 公共卫生相关性：拟议的研究与公共卫生有关，因为它将大大提高我们对免疫系统艾滋病毒失调的基本了解，从而促进对结核分枝杆菌的易感性。这些研究的结果将为疫苗和治疗剂的开发提供知情的指导，以保护HIV+患者免受结核病的影响。