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

总结 据报道，2019年冠状病毒病（COVID-19）和肺结核（PTB）是 从传染病的角度来看，2020年的主要死亡原因。结核病是由感染引起的 肯尼亚仍然是结核病负担最高的国家之一， 全球结核病发病率。然而，大多数感染Mtb的个体从未发展为活动性结核病， 被归类为潜伏感染然而，病毒感染会增加结核病复发的风险， 关于严重急性呼吸道综合征冠状病毒2型（SARS- CoV-2）对潜伏Mtb感染的再激活的作用。暴露于SARS-CoV-2可增加疾病进展风险 通过几种机制从潜伏性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，这些基因已知与高风险相关， 发展为结核病。其次，SARS-CoV-2感染可驱动T细胞分化和耗竭 其靶向Mtb抗原并赋予针对疾病进展的保护。重要的是，尽管推出了 低收入和中等收入国家的COVID-19疫苗接种率仍然很低， 该地区新出现的SARS-CoV-2变种可能会继续影响疫苗在这些地区的效力， 地区第三，COVID-19和活动性结核病的合并感染令人担忧， 诱发COVID-19感染，这有可能加速结核病。因此，共同进化 结核病和新冠肺炎大流行将继续成为该地区一个紧迫的公共卫生问题。在这 在这项研究中，我们将从两个县的3个主要卫生机构招募一组潜伏性结核病感染者 在肯尼亚（内罗毕和基安布），有或无SARS-CoV-2感染暴露史。我们将研究 SARS-CoV-2感染对结核病潜伏期再激活和对结核分枝杆菌抗原免疫的影响 使用生物标志物和免疫学方法的组合。QuantiFERON-TB-Gold in Tube 干扰素-γ释放测定和经验证的免疫球蛋白特异性血清学侧流测定， G（IgG）抗体将用于筛查潜伏感染的TB和SARS-CoV-2暴露参与者， 分别我们将使用流式细胞术方法鉴定受共刺激影响的T细胞群， 感染这项工作的实际意义将包括确定病理免疫机制 在SARS-CoV-2暴露个体的潜在暴露筛查中， 和治疗靶点。这项工作还将在研究网络、基础设施和技能方面奠定坚实的基础。 以及肯尼亚COVID-19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.