Recently, the Institute of Brain Science and Brain-like Research of Shandong First Medical University and Peking University Sixth Hospital cooperated in the journal Signal Transduction and Targeted Therapy (STTT, Q1 area, IF=38.) in Nature1) "Non-coding RNAs expression in SARS-CoV-2 infection: pathogenesis, clinical significance and therapeutic targets", *non-coding RNAs (non-coding RNAs, ncRNAs) in SARS-CoV-2 infection, and summarized the potential markers and strategies that are expected to be used in the diagnosis and treatment of new coronavirus, providing new ideas for the prevention and control of new coronavirus infection and future infectious disease pandemics.
More than 90% of the human genome is made up of NCRNAs, among which the mechanisms of microRNAs (miRNAs), long non-coding RNAs (LNCrnas), and circular RNAs (circRNAs) are gradually becoming clear (Fig. 1), and play an important regulatory role in a variety of physiological and pathological processes. and prognosis, it has shown certain clinical application value.
Figure 1 Mechanism of action of nCrRNAs
Changes in the expression of host **ncRNAs after COVID-19 infectionAt present, high-throughput sequencing technology and RT-PCR technology have been widely used in clinical testing, and many studies have carried out whole transcriptome sequencing by collecting blood, saliva, urine, cerebrospinal fluid and other samples of patients infected with the new crown to characterize the transcriptional characteristics of the host** miRNAs, lncRNAs and circRNAs infection responses, among which miRNAs have the largest number of studies. Compared with healthy controls, the expression levels of a large number of miRNAs, LNCrnas and circRNAs were altered in patients with COVID-19 infection. Differentially expressed miRNAs and LNCRNAs were also found in groups of patients of different severity, such as asymptomatic, mild, moderate, and severe disease; In addition, the expression levels of lncRNAs and circRNAs in Fuyang patients were also different from those of healthy controls. More specifically, differentially expressed miRNAs were found in patients with COVID-19 infection compared with patients with influenza virus infection, which may be one of the factors that make COVID-19 infection different from other viral infections. In the temporal dimension, miRNAs and LNCrRNAs showed high sensitivity, and the expression profiles of miRNAs and lncRNAs still changed dynamically within 7 days of viral infection or even at the ** stage. Why does SARS-CoV-2 infection cause changes in host ncrnas expression? The possible mechanism is that SARS-CoV-2 invasion interferes with key factors in the NCRNAs synthesis pathway, such as proteins involved in the mRNA splicing process, resulting in abnormal expression of all or part of NCRNA.
Mechanism of action of host ncrnas in the pathogenic process of new coronavirusHost miRNAs, LNCRNAs, and circRNAs are involved in regulating multiple processes in the occurrence and progression of COVID-19 infection, including viral invasion and replication, immune response, multi-organ damage, and even long-term sequelae (Figure 2). Moreover, the regulatory role of host ncrRNAs in viral infection is bidirectional, which can play both the role of "antiviral infection" and the role of "proviral infection".
Host ncrRNAs are involved in regulating the adsorption and invasion of SARS-CoV-2 into cells. Before SARS-CoV-2 invades the target cell, the Furin protein in the host cell first needs to decompose the viral Spike protein into S1 and S2 subunits. Subsequently, when SARS-CoV-2 invades target cells, it binds to ACE2 receptors and endocytoses into cells mainly under the mediation of TMPrsS2. In this process, many miRNAs and LNCrRNAs can function by targeting ACE2 or TMPrsS2. For example, GATA5 can inhibit the expression of DNA encoding the ACE2 receptor and significantly increase the expression level in patients with new crown infection, especially in severe cases, which may play an antiviral role.
Host**nCrRNAs are involved in the regulation of SARS-CoV-2 genome replication. After the virus invades the target cells, some miRNAs can bind to the coding region of the SARS-CoV-2 genome and inhibit the replication of viral genes, such as miR497-5P, MiR-21-3P, and MiR-195-5P. In addition, some circRNAs, LNCrnas, miRNAs, and mRNAs play a role in inhibiting viral replication by forming regulatory networks.
Host ncrRNAs are involved in regulating the body's immune response. Massive replication of SARS-CoV-2 can lead to abnormalities in the body's innate and adaptive immunity. Among them, host **miRNAs, LNCRNAs, and circRNAs can play a role by regulating the production and function of immune cells such as (1) interferon and inflammatory cytokine signaling pathways and (2) B cells and T cells. For example, the expression of HSA circ 0000479 is elevated in patients with COVID-19 infection, and the expression level of interleukin-6 is increased by promoting the production of retinoic acid-induced gene protein- by binding to miR-149-5p.
Host**ncrRNAs are involved in the regulation of multi-organ damage and even long-term sequelae caused by new crown infection. SARS-CoV-2 infection not only causes abnormalities in the body's respiratory system, but also may damage various organs and tissues such as the nervous system, cardiovascular system, digestive system, reproductive system, etc., and even some symptoms still exist after the patient**, that is, "long COVID". At present, the mainstream view is that viral invasion and residual may be an important cause of multi-organ damage and long-term sequelae. In this process, host ncrRNAs mainly exert their functions by regulating inflammatory cytokine signaling pathways and tissues. For example, MALAT1 and SMC2-AS1 can regulate the regeneration and repair of lung tissue through signaling pathways such as WNT and TGF-. MIR-133A is involved in the process of inflammation-induced cardiomyocyte damage; MiR-15A-5P can regulate the production of a variety of inflammatory cytokines by targeting soluble programmed cell death protein-1 to promote depression, anxiety and phobic behaviors. LET-7B-5P may be involved in the occurrence of symptoms such as fatigue by regulating muscle tissue function.
Fig.2 Function and representative ncRNAs of host** ncRNAs in the occurrence and development of novel coronavirus infection
Potential ncrNAS markersThe severity classification of new crown infection mainly depends on clinical symptoms, and there is a certain lag, which may lead to a delay in the best time. Therefore, the use of host ncrRNAs as biomarkers has important clinical value for long-term monitoring of disease development and timely determination of ** protocols. For example, in the classification of new crown infection, miRNAs and LNCrnas can be used to distinguish between mild, moderate and severe patients, and the effect of distinguishing mild patients from severe patients is better than traditional indicators such as leukocytes and C-reactive protein. In the outcome of COVID-19 infection, the model composed of miRNAs has high sensitivity and specificity in judging the risk of death, and some miRNAs and LNCrnas can be used for long-term symptoms of patients. In addition, compared with the new crown patients who did not respond to the drug**, there was a specific expression of miRNAs in the patients who were effective with the drug**, which provided a potential marker for the precision of the new crown infection** and the condition**. However, the expression of nCRNAs will be affected by factors such as age, gender, and comorbidities, and many considerations need to be considered in practical applications.
Fig.3 Application scenarios of potential ncRNAs markers in COVID-19 infection
Develop a new strategy based on ncrNASAt present, the main ** measures for new crown infection can be divided into three categories: antivirals, monoclonal antibodies, and plasma**. However, these small molecule inhibitors and vaccines cannot directly act on the patient's genome and have certain limitations. With the rapid development of gene editing technology, intervening in ncrRNAs to directly regulate the expression of genes, thereby affecting the invasion and replication of viruses, has a very good clinical application prospect. The existing NCRNAs** strategies are mainly divided into three categories (Figure 4):(1) at the miRNA level, through the use of mimics and other methods to increase the level of specific miRNAs and improve disease symptoms; (2) at the DNA level, use CRISPR interference or activation technology to inhibit or promote the expression of ncrnas, and ** disease by regulating gene expression; (3) At the RNA level, RNA interference technology or antisense oligonucleotides can be used to inhibit ncrnas, so as to silence the expression of related proteins and achieve the purpose of ** disease.
Fig. 4 Existing methods and potential NCRNAS-based strategies for COVID-19 infection
Summary and outlookThe expression of host ncrRNAs is not only affected by COVID-19 infection, but also plays an important regulatory role in viral invasion, immune response and tissue generation. However, the current research on the mechanism of action of host ** nCRNAs is insufficient, and more large-sample cohort studies and more wet experiments are needed in the future to explore the expression changes and regulatory mechanisms of nCRNAs, so as to provide a scientific basis for the prevention of SARS-CoV-2 superinfection and long COVID. In addition, host ncrRNAs can also be used as an evolutionary indicator to observe whether the new crown epidemic will cause evolutionary pressure, which is helpful to understand the long-term impact of major infectious diseases such as the new crown epidemic on humans, and provides a reference for further revealing the mechanism of human life and preventing major public health events such as infectious diseases.
The first authors of this paper are Dr. Liu Xiaoxing from Peking University Sixth Hospital and Dr. Xiong Wandi from Peking University, Academician Lu Lin, Academician of the Chinese Academy of Sciences, President of Shandong First Medical University (Shandong Academy of Medical Sciences), President of Peking University Sixth Hospital, Associate Researcher Bao Yanping of the China Institute of Drug Dependence of Peking University, and Professor Wang Yongxiang of the Institute of Brain Science and Brain-like Research of Shandong First Medical University are the corresponding authors of this paper.
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