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).

据估计，世界人口的1/3已经感染了结核分枝杆菌 （M.结核病（TB）的病原体，几乎有5-10%的潜伏感染患者 在他们的一生中患上活动性肺结核。在过去的三年里， 急性呼吸道综合征-冠状病毒-2（SARS-CoV-2，a.k.a. SCV 2）病原体 COVID-19已导致650万人死亡。根据世卫组织《2022年全球结核病报告》， 2020-2021年SCV 2大流行与结核病稳步下降的逆转有关 死亡率自2005年以来首次上升。我们的长期目标是更好地控制结核病， 管理SCV 2双重感染病例，并了解免疫学后果 SCV 2感染。我们组的初步数据表明SCV 2重叠感染增加了M。 肺结核负荷，并促进肺外器官的传播， 与免疫调节细胞因子的特异性变化相关（例如，IFN-g和IL 10）和 减少肺部的一般炎症。这些数据支持了我们的核心假设， SCV 2重叠感染损害抗结核免疫力，导致M. TB. 为了解决中心假设，我们计划I）表征TB/SCV 2重叠感染的特征， 在称为免疫活性TB模型的设置中使用C3 HeB/FeJ小鼠的潜伏性TB鼠模型 （ICTM）; II）定义M. SCV 2双重感染期间结核传播的靶向研究 IFN-γ和IL-10细胞因子使用报告和补充小鼠模型，感染M. TB 在重复感染SCV 2 BA.5之前。第三，检查M。多样性结核病进展 与近交系小鼠相比的远系（DO）小鼠模型，以表征分枝杆菌生长期 与TB/SCV 2重叠感染时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发病机制的理解 以及人类的潜伏感染如何转化为活动性结核病病例，包括进一步 对肉芽肿的遏制作用和发病机制的认识。重要的是， 知识可以帮助理解结核病免疫发病机制，在任何未来的呼吸道疾病， 不是SCV 2单独感染基于该项目成果的未来研究可以 有助于控制结核病和COVID-19大流行，可为其他呼吸道疾病量身定制 新发感染（如流感）。