Clinical & Experimental Therapeutics Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, New Research Building, 3970 Reservoir Road NW, Washington, DC 20057-1469, United States.
Clinical & Experimental Therapeutics Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, New Research Building, 3970 Reservoir Road NW, Washington, DC 20057-1469, United States.
Virus Res. 2021 Aug;301:198464. doi: 10.1016/j.virusres.2021.198464. Epub 2021 May 29.
The spread of SARS-CoV-2 and the increasing mortality rates of COVID-19 create an urgent need for treatments, which are currently lacking. Although vaccines have been approved by the FDA for emergency use in the U.S., patients will continue to require pharmacologic intervention to reduce morbidity and mortality as vaccine availability remains limited. The rise of new variants makes the development of therapeutic strategies even more crucial to combat the current pandemic and future outbreaks. Evidence from several studies suggests the host immune response to SARS-CoV-2 infection plays a critical role in disease pathogenesis. Consequently, host immune factors are becoming more recognized as potential biomarkers and therapeutic targets for COVID-19. To develop therapeutic strategies to combat current and future coronavirus outbreaks, understanding how the coronavirus hijacks the host immune system during and after the infection is crucial. In this study, we investigated immunological patterns or characteristics of the host immune response to SARS-CoV-2 infection that may contribute to the disease severity of COVID-19 patients. We analyzed large bulk RNASeq and single cell RNAseq data from COVID-19 patient samples to immunoprofile differentially expressed gene sets and analyzed pathways to identify human host protein targets. We observed an immunological profile of severe COVID-19 patients characterized by upregulated cytokines, interferon-induced proteins, and pronounced T cell lymphopenia, supporting findings by previous studies. We identified a number of host immune targets including PERK, PKR, TNF, NF-kB, and other key genes that modulate the significant pathways and genes identified in COVID-19 patients. Finally, we identified genes modulated by COVID-19 infection that are implicated in oncogenesis, including E2F transcription factors and RB1, suggesting a mechanism by which SARS-CoV-2 infection may contribute to oncogenesis. Further clinical investigation of these targets may lead to bonafide therapeutic strategies to treat the current COVID-19 pandemic and protect against future outbreaks and viral escape variants.
SARS-CoV-2 的传播和 COVID-19 死亡率的不断上升，使得人们迫切需要治疗方法，但目前还缺乏这种方法。尽管 FDA 已批准在美国紧急使用疫苗，但由于疫苗供应仍然有限，患者仍将需要药物干预来降低发病率和死亡率。新变种的出现使得制定治疗策略对于应对当前大流行和未来爆发变得更加重要。多项研究的证据表明，宿主对 SARS-CoV-2 感染的免疫反应在疾病发病机制中起着关键作用。因此，宿主免疫因素越来越被认为是 COVID-19 的潜在生物标志物和治疗靶点。为了制定治疗策略来应对当前和未来的冠状病毒爆发，了解冠状病毒在感染期间和之后如何劫持宿主免疫系统至关重要。在这项研究中，我们研究了宿主对 SARS-CoV-2 感染的免疫反应的免疫模式或特征，这些特征可能导致 COVID-19 患者的疾病严重程度。我们分析了来自 COVID-19 患者样本的大量 bulk RNASeq 和单细胞 RNAseq 数据，以免疫分析差异表达基因集，并分析途径以鉴定人类宿主蛋白靶标。我们观察到严重 COVID-19 患者的免疫特征，表现为细胞因子、干扰素诱导蛋白上调和明显的 T 细胞淋巴细胞减少，这与之前的研究结果一致。我们确定了一些宿主免疫靶标，包括 PERK、PKR、TNF、NF-kB 和其他调节 COVID-19 患者中显著途径和基因的关键基因。最后，我们确定了受 COVID-19 感染调节的与肿瘤发生有关的基因，包括 E2F 转录因子和 RB1，表明 SARS-CoV-2 感染可能导致肿瘤发生的机制。对这些靶点的进一步临床研究可能会导致针对当前 COVID-19 大流行的有效治疗策略，并防止未来的爆发和病毒逃逸变种。
