Department of Human Physiology and Pathophysiology, School of Medicine, University of Warmia and Mazury in Olsztyn, 10-082, Olsztyn, Poland.
Department of Botany and Evolutionary Ecology, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland.
Comput Biol Med. 2024 Dec;183:109343. doi: 10.1016/j.compbiomed.2024.109343. Epub 2024 Nov 4.
Although the end of COVID-19 as a public health emergency was declared on May 2023, still new cases of the infection are reported and the risk remains of new variants emerging that may cause new surges in cases and deaths. While clinical symptoms have been rapidly defined worldwide, the basic body responses and pathogenetic mechanisms acting in patients with SARS-CoV-2 infection over time until recovery or death require further investigation. The understanding of the molecular mechanisms underlying the development and course of the disease is essential in designing effective preventive and therapeutic approaches, and ultimately reducing mortality and disease spreading.
The current investigation aimed to identify the key genes engaged in SARS-CoV-2 infection. To achieve this goal high-throughput RNA sequencing of peripheral blood samples collected from healthy donors and COVID-19 patients was performed. The resulting sequence data were processed using a wide range of bioinformatics tools to obtain detailed modifications within five transcriptomic phenomena: expression of genes and long non-coding RNAs, alternative splicing, allel-specific expression and circRNA production. The in silico procedure was completed with a functional analysis of the identified alterations.
The transcriptomic analysis revealed that SARS-CoV-2 has a significant impact on multiple genes encoding ribosomal proteins (RPs). Results show that these genes differ not only in terms of expression but also manifest biases in alternative splicing and ASE ratios. The integrated functional analysis exposed that RPs mostly affected pathways and processes related to infection-COVID-19 and NOD-like receptor signaling pathway, SARS-CoV-2-host interactions and response to the virus. Furthermore, our results linked the multiple intronic ASE variants and exonic circular RNA differentiations with SARS-CoV-2 infection, suggesting that these molecular events play a crucial role in mRNA maturation and transcription during COVID-19 disease.
By elucidating the genetic mechanisms induced by the virus, the current research provides significant information that can be employed to create new targeted therapeutic strategies for future research and treatment related to COVID-19. Moreover, the findings highlight potentially promising therapeutic biomarkers for early risk assessment of critically ill patients.
尽管 2023 年 5 月宣布 COVID-19 作为公共卫生紧急事件结束，但仍有新的感染病例报告，并且仍然存在新的变异株出现的风险，这可能导致病例和死亡人数再次激增。虽然全球范围内已经迅速定义了临床症状，但对于 SARS-CoV-2 感染患者随着时间的推移恢复或死亡的基本身体反应和发病机制仍需要进一步研究。了解疾病发展和病程的分子机制对于设计有效的预防和治疗方法至关重要，最终可以降低死亡率和疾病传播。
本研究旨在确定参与 SARS-CoV-2 感染的关键基因。为了实现这一目标，对来自健康供体和 COVID-19 患者的外周血样本进行了高通量 RNA 测序。使用广泛的生物信息学工具处理得到的序列数据，以获得五个转录组现象（基因和长非编码 RNA 的表达、可变剪接、等位基因特异性表达和 circRNA 产生）内的详细修饰。通过对鉴定出的变化进行功能分析，完成了计算机程序。
转录组分析表明，SARS-CoV-2 对编码核糖体蛋白（RP）的多个基因具有显著影响。结果表明，这些基因不仅在表达方面有所不同，而且在可变剪接和 ASE 比值方面也表现出偏向性。综合功能分析表明，RP 主要影响与感染 COVID-19 相关的途径和过程，以及 NOD 样受体信号通路、SARS-CoV-2 宿主相互作用和对病毒的反应。此外，我们的结果将多个内含子 ASE 变体和外显子环状 RNA 分化与 SARS-CoV-2 感染联系起来，表明这些分子事件在 COVID-19 疾病中对 mRNA 成熟和转录起着至关重要的作用。
通过阐明病毒诱导的遗传机制，本研究提供了重要信息，可用于为未来与 COVID-19 相关的研究和治疗制定新的靶向治疗策略。此外，这些发现强调了潜在有希望的治疗生物标志物，可用于对重症患者进行早期风险评估。
