Tuberculosis Immunopathogenesis During Superinfection with SARS-CoV2

据估计，世界人口的三分之一已经感染了结核分枝杆菌。 (结核)，结核病(TB)的病原体，几乎5%-10%的潜在感染者 在他们有生之年患上活动性肺结核。在过去的三年里，严重的感染 急性呼吸综合征-冠状病毒-2(SARS-CoV-2，又名SCV2)致病因子 新冠肺炎，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SCV2大流行与结核病稳步下降的逆转有关 死亡率自2005年以来首次下降。我们的长期目标是更好地控制结核病和 处理SCV2重叠感染病例并洞察免疫后果 SCV2感染。我们小组的初步数据显示，SCV2重叠感染使M。 小鼠肺部携带结核病，并促进肺外器官的传播，这是 与免疫调节细胞因子(如干扰素-g和白介素10)的特定变化有关 减少肺部的全身炎症。这些数据支持了我们的核心假设 SCV2重叠感染损害了抗结核免疫，导致结核分枝杆菌的更大传播。 为了解决这一中心假设，我们计划：1)描述结核病/SCV2重叠感染在 用C3HeB/FEJ小鼠建立免疫活性结核模型 (ICTM)；二)确定SCV2重叠感染期间结核分枝杆菌的传播机制 干扰素-g和白介素10细胞因子在小鼠结核分枝杆菌感染模型中的应用 在重叠感染SCV2 BA.5之前。最后，三)审查结核分枝杆菌多样性进展情况 近交系小鼠与近交系小鼠比较研究分枝杆菌生长期 与TB/SCV2重叠感染过程中的病理和免疫学变化有关。 该项目的成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 对肉芽肿在遏制和发病机制中的作用的认识。重要的是，获得了 知识可以帮助理解结核病在未来任何呼吸道疾病中的免疫发病机制 重叠感染，而不仅仅是SCV2。以该项目的成果为基础的未来研究可能 帮助控制结核病和新冠肺炎大流行，可以针对其他呼吸道疾病量身定做 新出现的感染(例如流感)。

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).