Tuberculosis Immunopathogenesis During Superinfection with SARS-CoV2

SARS-CoV2 重复感染期间的结核病免疫发病机制

• 批准号: 10737053
• 负责人: ADEL M TALAAT
• 金额: $ 75.41万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737053
• 关键词: 2019-nCoV; Address; Antitubercular Agents; Authorization documentation; C3HeB/FeJ Mouse; COVID-19; COVID-19 pandemic; Case Management; Cessation of life; Containment; Data; Death Rate; Future; Genes; Goals; Granuloma; Growth; Health; Histologic; Histopathology; Human; Immune response; Immunize; Immunocompetent; Immunologics; Inbred Mouse; Inbreeding; Infection; Inflammation; Influenza; Interferon Type II; Interleukin-10; Knowledge; Lung; Modeling; Mus; Mycobacterium tuberculosis; Organ; Outcome; Pathogenesis; Pathogenicity; Pathologic; Patients; Phase; Population; Public Health; Reporter; Reporting; Role; SARS-CoV-2 B.1.1.529; Structure; Testing; Time; Tissues; Transcript; Transgenic Mice; Tuberculosis; Variant; Viral; authority; cytokine; global health; immunoregulation; improved; in vivo; insight; latent infection; mouse model; mycobacterial; pandemic disease; pathogen; rBCG; respiratory; superinfection; tuberculosis immunity

An estimated 1/3 of the world population is already infected with Mycobacterium tuberculosis (M. tb), the causative agent of tuberculosis (TB), with an almost 5-10% of latent infected patients developing active tuberculosis during their lifetime. In the last three years, infection with severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2, a.k.a. SCV2) the causative agent of COVID-19, has resulted in 6.5 million deaths. According to the WHO Global TB Report 2022, the SCV2 pandemic in 2020-2021 was associated with the reversal of the steady decline in TB death rate for the first time since 2005. Our long-term goal is to better control tuberculosis and manage cases of superinfection with SCV2 as well as gain insight to immunological consequences of SCV2 infection. Preliminary data from our group indicated SCV2 superinfection increased M. tb loads in murine lungs and promoted dissemination to extra-pulmonary organs, which was associated with specific changes in immunomodulatory cytokines (e.g., IFN-g and IL10) and decreased general inflammation in the lungs. These data underpinned our central hypothesis that SCV2 superinfection compromises anti-TB immunity, leading to greater dissemination of M. tb. To address the central hypothesis we plan to I) Characterize the TB/SCV2 superinfection in a latent murine model of TB using C3HeB/FeJ mice in a setup termed Immune Competent TB Model (ICTM); II) Define mechanisms of M. tb dissemination during SCV2 superinfection by targeting IFN-g and IL-10 cytokines using reporter and repletion murine models that are infected with M. tb before superinfection with SCV2 BA.5. Finally, III) Examine M. tb progression in Diversity Outbred (DO) mouse model compared to inbred mice to characterize mycobacterial growth phase associated with pathological and immunological changes during TB/SCV2 superinfection. Outcomes from this project will further improve our understanding of TB immunopathogenesis and how latent infections in humans can convert to active cases of TB including furthering knowledge on the granuloma’s role in containment and pathogenesis. Importantly, gained knowledge could help in understanding TB immunopathogenesis during any future respiratory superinfection, not SCV2 alone. Future research building on outcomes from this project could help in the control of both TB and COVID-19 pandemics that could be tailored for other respiratory emerging infections (e.g. Influenza).

大约1/3的世界人口已经感染了结核分枝杆菌 （M. TB），结核病（TB）的病因，近5-10％的潜在感染患者 在其一生中发展活跃的结核病。在过去三年中，感染严重 急性呼吸道综合征 - 核纳病毒2（SARS-COV-2，又称SCV2） Covid-19，已导致650万死亡。根据世卫组织全球结核病报告，2022年， 2020 - 2021年的SCV2大流行与结核病稳定下降有关 自2005年以来首次死亡率。我们的长期目标是更好地控制结核病和 管理与SCV2超级感染的病例，并洞悉免疫学后果 SCV2感染。来自我们组的初步数据表明SCV2超染料增加了。 鼠肺中的结核病负荷并促进向肺外器官传播 与免疫调节细胞因子（例如IFN-G和IL10）的特定变化有关 肺中的一般炎症减少。这些数据为我们的中心假设提供了基础 SCV2超染料损害了抗TB免疫，导致M. TB的传播更大。 为了解决中心假设，我们计划i）在A中表征TB/SCV2超级感染 使用C3HEB/FEJ小鼠的TB的潜在鼠模型在称为免疫胜任的结核病模型中 （ICTM）; ii）通过靶向定义SCV2超级传染期间M. TB传播的机制 IFN-G和IL-10细胞因子使用报告基因并复制被M. TB感染的鼠模型 在用SCV2 BA.5进行近次感染之前。最后，iii）检查M. TB多样性的进展 与近交小鼠相比，近雌性小鼠模型表征分枝杆菌生长阶段 与TB/SCV2超级感染期间的病理和免疫学变化有关。 该项目的结果将进一步提高我们对结核病免疫病的理解 以及人类的潜在感染如何转化为TB的活性病例，包括进一步 了解颗粒在遏制和发病机理中的作用的知识。重要的是，获得了 知识可以帮助理解任何未来呼吸道期间结核病的免疫病变 超级感染，不是单独的SCV2。关于这个项目结果的未来研究建设 帮助控制TB和COVID-19的Pandemics，可以针对其他呼吸定制 新兴感染（例如流感）。