Impact of SARS-CoV-2 infection on reactivation of latent Mtb infections in a Kenyan Cohort

摘要 2019年的冠状病毒病(新冠肺炎)和肺结核(肺结核)已被报告为 从传染病的角度来看，2020年死亡的主要原因。结核病是由感染引起的。 与结核分枝杆菌(结核分枝杆菌)有关，肯尼亚仍然是艾滋病负担最重的国家之一。 全球结核病发病率。然而，大多数感染结核分枝杆菌的人从未患上活动性结核病，并且 被归类为潜伏感染。然而，病毒感染会增加结核病重新激活的风险， 关于严重急性呼吸系统综合症冠状病毒-2(SARS-2)的影响，人们知之甚少。 CoV-2)对潜伏的结核分枝杆菌感染的重新激活。暴露于SARS-CoV-2会增加病情恶化的风险 通过几种机制从潜伏期结核病转变为活动性结核病。首先，SARS-CoV-2感染可以增加表达 介导全身性炎症的基因，已知与高血压风险增加有关 进展为结核病。第二，SARS-CoV-2感染可促使T细胞分化和耗尽 靶向结核分枝杆菌抗原并提供防止疾病进展的保护。重要的是，尽管推出了 在低收入和中等收入国家的新冠肺炎疫苗中，疫苗接种率仍然缓慢， 该地区出现的SARS-CoV-2变种可能会继续损害这些地区的疫苗效力 地区。第三，新冠肺炎和活动性结核病的混合感染令人担忧，超炎性反应可能 诱发新冠肺炎感染，这有可能加速结核病的发生。因此，共同进化 结核病和新冠肺炎疫情的蔓延将继续成为该地区紧迫的公共卫生问题。在这 研究中，我们将从两个县的三个主要卫生机构招募一组潜伏的结核分枝杆菌感染者 在肯尼亚(内罗毕和基安布)，有和没有SARS-CoV-2感染史。我们会研究 SARS-CoV-2感染对潜伏结核病再激活及结核分枝杆菌抗原免疫的影响 使用生物标记物和免疫学方法的组合。试管中的量子色子-Tb-金 干扰素-伽马释放试验和免疫球蛋白特异性的血清侧向流动试验- G(免疫球蛋白)抗体将用于筛查潜伏感染结核病和接触SARS-CoV-2的参与者， 分别进行了分析。我们将使用流式细胞术来鉴定受联合免疫影响的T细胞群。 感染。这项工作的实际意义将包括识别病理免疫机制。 SARS-CoV-2暴露者潜在筛查中结核病潜伏性疾病再激活的作用 和治疗靶点。这项工作还将在研究网络、基础设施、技能方面奠定坚实的基础 以及肯尼亚新冠肺炎和结核病研究后续工作的数据。

SUMMARY Coronavirus disease of 2019 (COVID-19) and pulmonary tuberculosis (PTB) have been reported as the leading causes of mortality from an infectious disease perspective in 2020. TB disease is caused by infection with Mycobacterium tuberculosis (Mtb), and Kenya remains one of the countries with the highest burden of TB incidence globally. However, the majority of individuals infected with Mtb never develop active TB, and are classified as latent infections. Viral infections can increase the risk of reactivation of TB disease, however, little information is known about the impact of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS- CoV-2) on the reactivation of latent Mtb infection. Exposure to SARS-CoV-2 can increase risk of progression from latent to active TB through several mechanisms. First, SARS-CoV-2 infection can increase expression of genes that mediate systemic inflammation, which are known to be associated with heightened risk of progression to TB disease. Second, SARS-CoV-2 infection can drive differentiation and exhaustion of T cells that target Mtb antigens and confer protection against progression to disease. Importantly, despite the rollout of COVID-19 vaccines in low- and middle-income countries, the rate of vaccination remains slow, and emerging SARS-CoV-2 variants in the region are likely to continue to compromise vaccine efficacy in these regions. Third, co-infection with COVID-19 and active TB is of concern, hyper inflammatory responses may induce COVID-19 infection which has the potential of accelerating TB disease. Therefore, the co-evolution of the TB and COVID-19 pandemics will continue to be a pressing public health concern in the region. In this study, we will recruit a cohort of latently Mtb infected individuals from 3 major health facilities in two counties in Kenya (Nairobi and Kiambu), with and without history of exposure to SARS-CoV-2 infections. We will study the impact of SARS-CoV-2 infections on reactivation of latent TB to TB disease and immunity to Mtb antigens using a combination of biomarkers and immunological approaches. The QuantiFERON-TB-Gold in Tube interferon-gamma release assay and a validated serological lateral flow assay specific for immunoglobulin- G (IgG) antibodies will be used for screening latently infected TB and SARS-CoV-2 exposed participants, respectively. We will use flow cytometry approach for identification of T cell populations impacted by co- infection. The practical implication of this work will include identification of patho-immunological mechanisms at play for TB latent disease reactivation in SARS-CoV-2 exposed individual’s potentially unveiling screening and therapeutic targets. The work will also build a strong foundation in research network, infrastructure, skills and data for follow up work on COVID-19 and TB studies in Kenya.