Molecular Basis of Cancer Virus Replication, Transformation, and Innate Defense

冠状病毒病 (COVID-19) 及其病原体严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 是目前最紧迫的健康问题。关于病毒的病理学以及宿主对病毒感染的反应，还需要了解更多。急性呼吸窘迫综合征 (ARDS) 是严重 COVID-19 的最终状态，是由宿主无法控制的免疫反应引起的，即所谓的细胞因子释放综合征 (CRS)。是什么导致一些患者进展为重症 COVID-19 尚不清楚，但某些人群（例如老年人和癌症患者）面临更高的风险。因此，我们正在研究宿主 microRNA (miRNA) 是否可以作为 COVID-19 预后的生物标志物。由于 miRNA 几乎调节每个细胞过程，并且在疾病（包括病毒感染）过程中经常失调，因此 SARS-CoV-2 感染很可能会影响 miRNA 水平。已知病毒感染期间异常的 miRNA 谱是由宿主对抗感染因子的反应和病毒的故意行为引起的，通常是为了抑制免疫系统。我们的研究小组为认识到一些疱疹病毒转录物选择性结合宿主 miRNA 并在称为靶向 miRNA 降解 (TDMD) 的过程中诱导其降解做出了重大贡献。这种选择性的 miRNA 降解对病毒是有益的，例如宿主 miR 27a 水平降低，导致 T 细胞活化延长，从而有助于疱疹病毒 saimiri 的致癌转化。 SARS-CoV-2 可能选择性地影响调节关键细胞因子的 miRNA，因为已知许多 miRNA 可以调节参与抗病毒防御的免疫因子。其中之一是严重 COVID19 期间的关键角色：白细胞介素 6 (IL-6)，它受 miR-146a、miR-142-3p 和 let-7 调节。因此，记录 SARS-CoV-2 感染期间特定 miRNA 的失调具有治疗潜力，并为新冠肺炎进展提供生物标志物。我们将使用最先进的小 RNA 测序以及 TaqMan 逆转录定量 PCR (RT-qPCR) 的 RNA 检测来研究 SARS-CoV-2 感染几种肺细胞系后不同时间的 miRNA 群体。此外，我们正在采用定制的生物信息学预测来搜索可以选择性调节宿主 miRNA 的病毒转录本，并已经确定了几个潜在的候选者。就这些重要的宿主非编码 RNA 提供对 SARS-CoV-2 生物学的基本见解，对于人类应对当前和未来流行病的能力非常重要。

Coronavirus disease (COVID-19) and its causative agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are currently a most pressing health concern. Much more needs to be learned about the pathology of the virus, as well as the host response to viral infection. Acute respiratory distress syndrome (ARDS), the final state of severe COVID-19, is caused by the uncontrollable immune response of the host, so called cytokine release syndrome (CRS). What predisposes some patients to progress to severe COVID-19 is not known, but certain populations – such as the elderly and cancer patients – are at higher risk. Therefore, we are investigating whether host microRNAs (miRNAs) can serve as biomarkers for COVID-19 prognosis. Since miRNAs regulate virtually every cellular process, and are often dysregulated during disease, including viral infections, it is highly likely that SARS-CoV-2 infection impacts miRNA levels. Aberrant miRNA profiles during viral infection are known to be caused both by host responses to counteract the infecting agent and by deliberate actions of the virus, usually to dampen the immune system Our group has contributed significantly to the realization that some herpesviral transcripts selectively bind host miRNAs and induce their degradation in a process known as target-directed miRNA degradation (TDMD). Such selective miRNA degradation is beneficial for the virus, as exemplified by decreased levels of host miR 27a causing prolonged T cell activation that aids oncogenic transformation by herpesvirus saimiri. It is possible that SARS-CoV-2 selectively affects the miRNAs that regulate crucial cytokines, as many miRNAs are known to regulate immune factors involved in antiviral defense. One of these is a key player during severe COVID19: interleukin 6 (IL-6), which is regulated by miR-146a, miR-142-3p and let-7. Documenting the dysregulation of particular miRNAs during infection by SARS-CoV-2 can therefore have therapeutic potential, as well as providing biomarkers for COVID progression. We will use state-of-the art small RNA sequencing, as well as RNA detection by TaqMan reverse transcription quantitative PCR (RT-qPCR) to investigate miRNA populations at various times after infection of several lung cell lines with SARS-CoV-2. In addition, we are employing custom bioinformatic predictions to search for viral transcripts that could selectively regulate host miRNAs and have already identified several potential candidates. Providing fundamental insights into the biology of SARS-CoV-2 as regards these important host noncoding RNAs will be important for mankind’s ability to manage both the current and future pandemics.