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死亡的主要原因之一，极端耐药菌株的出现可能会加剧其在发达国家的重要性。大多数成人活动性结核病是由潜伏性结核感染 (LTBI) 重新激活引起的，这种感染可能潜伏数十年而没有疾病或传播风险。虽然结核病与艾滋病毒/艾滋病、免疫抑制治疗或免疫系统基因的某些罕见突变之间存在明显的关联，但在普通人群中促进结核病易感性和 LTBI 重新激活的因素尚不清楚。我们发现，小鼠感染人类病原体淋巴细胞性脉络膜脑膜炎病毒（LCMV）会增加结核病的易感性并改变肺部的免疫病理模式。这种易感性在 LCMV 暴露后持续数月，并且在肺部不存在具有复制能力的病毒或解剖损伤的时间点持续存在。我们认为，这模拟了病毒感染对人类结核病易感性的潜在影响。该 R21 申请为测试交叉反应 LCMV 特异性 CD8+ 记忆 T 细胞干扰肺部结核分枝杆菌 (Mtb) 适应性免疫表达的假设的实验以及测试竞争机制假设的实验寻求资金。我们计划生成数据来支持更广泛的 R01 提案，该提案调查影响结核病易感性的抗病毒和抗分枝杆菌免疫之间的相互作用。该课题不仅在结核病的获得性危险因素方面具有重要意义，而且在连续感染中宿主防御的研究方面也具有重要意义。没有人类患者是免疫原初的，但大多数动物模型传染病研究都使用原初宿主。项目叙述。在感染导致结核病的细菌的人中，只有大约二十分之一会继续患上结核病。目前尚不清楚为什么一些看似健康的人会患上结核病，而其他许多人却不会。该项目研究特定病毒感染如何使人们更容易患结核病。