Acquired susceptibility to pulmonary TB

获得性肺结核易感性

• 批准号: 7460497
• 负责人: Hardy Kornfeld
• 金额: $ 20.44万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7460497
• 关键词: 5-(6)-carboxyfluorescein diacetate succinimidyl ester; AIDS/HIV problem; Abbreviations; Acute; Address; Adult; Animal Model; Antibodies; Attention; Bronchus-Associated Lymphoid Tissue; CD4 Positive T Lymphocytes; CD8B1 gene; Calmette-Guerin Bacillus; Candidate Disease Gene; Cause of Death; Cells; Cellular Immunity; Colony-forming units; Communicable Diseases; Cyclophosphamide/Fluorouracil/Prednisone; Data; Defect; Disease; Drug resistance; Esters; Exhibits; Exposure to; Exudate; Fluorescein; Fluoresceins; Funding; Future; General Population; Genes; Genetic; Germ; Growth; Host Defense; Human; Immune; Immune response; Immune system; Immunity; Individual; Infection; Injury; Interferons; Interleukins; Intravenous; Investigation; Lesion; Lung; Lymphocytic choriomeningitis virus; Major Histocompatibility Complex; Memory; Modeling; Monoclonal Antibodies; Murid herpesvirus 1; Mus; Mutation; Mycobacterium tuberculosis; Numbers; Outcome; Patients; Pattern; Phosphate Buffer; Pichinde virus; Play; Population; Predisposition; Proteins; Pulmonary Tuberculosis; Recording of previous events; Research; Resistance; Respiratory Tract Infections; Rifampin; Risk; Risk Factors; Role; Saline; Staining method; Stains; Structure of lymph node of thorax; T memory cell; T-Cell Receptor; T-Lymphocyte; TNF gene; Testing; Therapeutic immunosuppression; Time; Transforming Growth Factors; Tuberculosis; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Upper arm; Vaccinated; Vaccination; Vaccines; Vaccinia virus; Viral; Virus; Virus Diseases; base; cytokine; human TNF protein; immunogenicity; immunopathology; insight; interest; intraperitoneal; isoniazid; latent infection; macrophage; mycobacterial; pathogen; research study; response; subcutaneous; transmission process

DESCRIPTION (provided by applicant): Tuberculosis (TB) remains among the leading causes of death from infectious disease worldwide, and its significance in the developed world may be heightened by the emergence of extreme drug-resistant strains. Most active TB disease in adults arises by reactivation of latent TB infection (LTBI) that may be harbored for decades without illness or risk of transmission. While clear associations exist between TB and HIV/AIDS, immunosuppressive therapies, or certain rare mutations in genes of the immune system, the factors promoting TB susceptibility and the reactivation of LTBI in the general population are not well understood. We discovered that infection of mice with lymphocytic choriomeningitis virus (LCMV), human pathogen, increases TB susceptibility and alters the pattern of immunopathology in the lung. This susceptibility persists for many months after LCMV exposure and at time points when no replication-competent virus or anatomical injury persists in the lung. We believe that this models the potential influence of virus infections on human TB susceptibility. This R21 application seeks funding for experiments testing the hypothesis that crossreactive LCMV-specific CD8+ memory T cells interfere with the expression of adaptive immunity to Mycobacterium tuberculosis (Mtb) in the lung, and experiments testing competing mechanistic hypotheses. We plan to generate data that will support a broader R01 proposal investigating interactions between anti-viral and anti-mycobacterial immunity that impact TB susceptibility. This topic is significant not only in terms of acquired risk factors for TB but also in the investigation of host defense in sequential infection. No human patients are immunologically naive, yet the majority of infectious disease studies in animal models employ naive hosts. PROJECT NARRATIVE. Only about 1 in 20 people infected with a germ that causes tuberculosis go on to become sick with tuberculosis. It remains unknown why some apparently healthy people develop TB while many other do not. This project studies how a particular virus infection might make people more prone to TB.

描述（由申请人提供）：结核病（TB）仍然是全世界传染病的主要死亡原因之一，并且它在发达世界中的重要性可能会因极端耐药菌株的出现而提高。成年人中大多数活跃的结核病是由于潜在的结核病感染（LTBI）的重新激活而产生的，这些感染可能数十年而没有生病或传播风险。尽管TB和HIV/AIDS之间存在明显的关联，免疫抑制疗法或免疫系统基因中某些罕见突变，但促进TB易感性的因素和一般人群中LTBI的重新激活的因素尚不清楚。我们发现，小鼠感染了淋巴细胞绒毛膜炎病毒（LCMV），人类病原体，增加了结核病的敏感性并改变了肺中免疫病理学的模式。 LCMV暴露后的多个月，并且在肺部没有复制能力的病毒或解剖学损伤时，这种敏感性持续了许多月。我们认为，这模拟了病毒感染对人结核病易感性的潜在影响。该R21应用寻求资助实验，以测试以下假设：肺部反应性LCMV特异性CD8+记忆T细胞干扰了肺中对结核分枝杆菌（MTB）的适应性免疫的表达，并且实验测试了竞争机械假设的实验。我们计划生成数据，该数据将支持更广泛的R01提案，以调查影响TB易感性的抗病毒和抗菌免疫之间的相互作用。该主题不仅在结核病的获得的风险因素方面，而且在顺序感染中对宿主防御的研究中也很重要。没有人类患者在免疫学上是幼稚的，但是动物模型中的大多数传染病研究都采用了幼稚的宿主。项目叙述。只有20人中只有大约1人感染了导致结核病的细菌，继续患有结核病。为什么有些人显然健康的人会发展结核病，而许多其他人则尚未知道。该项目研究了特定的病毒感染如何使人们更容易容易结核病。