Acquired susceptibility to pulmonary TB

描述(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，它在发达国家的重要性可能会因极端耐药菌株的出现而得到加强。成人中的大多数活动性结核病是由潜伏的结核病感染(LTBI)重新激活引起的，这种感染可能在没有疾病或传播风险的情况下隐藏了几十年。虽然结核病与艾滋病毒/艾滋病、免疫抑制疗法或免疫系统基因的某些罕见突变之间存在明显的关联，但促进结核病易感性的因素和普通人群中LTBI的重新激活尚不清楚。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。这种易感性在接触LCMV后持续数月，并在肺内没有复制能力的病毒或解剖损伤时持续存在。我们认为，该模型模拟了病毒感染对人类结核病易感性的潜在影响。这项R21申请寻求资金，用于验证交叉反应的LCMV特异性CD8+记忆T细胞干扰肺内结核分枝杆菌(Mtb)适应性免疫表达的假设的实验，以及测试相互竞争的机制假设的实验。我们计划生成数据，以支持更广泛的R01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。这一主题不仅在结核病的获得性危险因素方面具有重要意义，而且在研究连续感染中的宿主防御方面也具有重要意义。没有人类患者在免疫方面是幼稚的，然而大多数动物模型中的传染病研究都使用了幼稚的宿主。项目叙事。在感染了一种导致结核病的细菌的20人中，只有大约1人会继续患上结核病。目前尚不清楚为什么一些表面上健康的人会患上结核病，而其他许多人则不会。这个项目研究一种特定的病毒感染如何可能使人们更容易患上结核病。

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.