SARS-CoV-2 causes host miRNA dysregulation and produces new miRNAs resulting in variable clinical manifestations

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New concerning findings have been discovered from a new study conducted by Chinese researchers from the First Affiliated Hospital of Xi’an Jiaotong University, along with experts from Wuhan University, in which it was found that SARS-CoV-2 causes dysregulation of host miRNAs and also produces novel miRNAs, resulting in varying clinical manifestations.

The study findings also have numerous new implications for the various symptoms and conditions seen in Long COVID.

The study findings were published in the peer reviewed journal: l iSCIENCE (science Direct by Elsevier). https://www.sciencedirect.com/science/article/pii/S2589004222005806

In this study, we identified a large number of DE-miRNAs that were associated with the virus infection, clinical symptoms, disease severity and the viral persistence of the COVID-19 patients as well as a panel of miRNAs that may target the viral sequences of SARS-CoV-2 or the cellular genes associated with the viral life cycle (Figure 1-7).

To our knowledge, this is the first large-scale study of miRNA profiles by high throughput sequencing on the plasma samples from the AS subjects in parallel with the HC individuals and the SM patients with various clinical presentations.

We identified six DE-miRNAs that could be used as biomarkers to distinguish the SARS-CoV-2 infected individuals from the healthy controls, and four of the six biomarkers were suggested to be associated with virus infection, inflammation, immune responses, and lung diseases (Pulati et al., 2019; Ramanathan et al., 2019; Peng et al., 2018).

In particular, hsa-miR-302b-3p_R-2 and hsa-miR- 302a-3p were differentially expressed in COV vs HC, AS vs HC and SM vs HC and significantly down-regulated in the SARS-CoV-2-infeected patients, suggesting that hsa-miR-302 may be used as a potential biomarker to distinguish COVID-19 patients from normal controls.

The hsa-miR-302 family members have been demonstrated to play vital roles in cell proliferation and the regulation of tumour growth (Maadi et al., 2016; Subramanyam et al., 2011; Lin et al., 2011). Previous studies have shown that influenza A virus (IAV) infection may cause down-regulation of miRNA-302a and miR-302c, which may suppress IAV-induced cytokine storm and prevent the translation of nuclear factor-kappa B (NF-κB) from the cytosol to the nucleus, respectively (Gui et al., 2015).

Both hsa-miR-302a and hsa-miR-302b may target on the C-X-C motif chemokine ligand 8 (CXCL8) gene, which was associated with the patients with acute respiratory distress syndrome (ARDS) by promoting neutrophil migration to lung interstitium and alveolar space (Williams et al., 2017).

CXCL8 was also suggested to play a vital role in the inflammatory diseases of the lungs, such as asthma and chronic obstructive pulmonary disease (COPD) (Huang et al., 2017). These findings suggested that miR-302 may have a protective effect in SARS-CoV-2 infected patients through targeting at the CXCL8-linked pathways.

The hsa-miR-146a-3p was significantly up-regulated in AS subjects compared with HC. Previous studies suggested that hsa-miR-146a-3p was a key factor in the regulation of innate immunity, viral infection, inflammation and tumour development (Testa et al., 2017; Fei et al., 2020). Fei et al. found that miR-146a suppresses the NF-κB pathway by down-regulating TLR3 and TRAF6 to alleviate the inflammatory response during coxsackievirus B infection (Fei et al., 2020).

The host’s innate immune system provides the first line of defence against viral invasions so that the body can effectively fight the virus infection. It is conceivable that through the regulatory loop, the inflammation can be controlled to a level adequate to eliminate the invading viruses without causing significant damage to the host.

Our results indicated that hsa-miR-146a-3p may play a protective role in the patients with asymptomatic infection and serve as a biomarker for diagnosis and therapeutic approach for AS.

We also identified a number of De-miRNAs that may help differentiate the SM from AS. In particular, hsa-miR-122-5p, hsa-miR-1246 and hsa-miR-885-5p were suggested to be involved in the virus infection, immune responses and inflammation ((Suo et al., 2018; Lu et al., 2020; Janssen et al., 2013; Hussein et al., 2017). For instance, the stability and propagation of hepatitis C virus (HCV) was dependent on a functional interaction between the HCV genome and liver-expressed miR-122 (Hussein et al., 2017).

The hsa-miR-122 could promote HCV RNA accumulation, and serum miR- 122-5p were significantly higher in patients in different stages of HBV infection than in controls (Lak et al., 2020). HCV infection may lead to dyslipidaemia, and miR-122 can regulate hepatic lipid metabolism and inflammation (Lee et al., 2015).

Targeting miR-122 may be an effective treatment strategy for HCV infection (van der Ree et al., 2014). In addition, miR-122-5p may protect acute lung injury via regulation of DUSP4/ERK signalling in pulmonary microvascular endothelial cells and may help differentiate moderate from severe COVID-19 patents (Lu et al., 2020; Fujita et al., 2021).

Nakao et al. reported that miR-122-5p may target ADAM metallopeptidase domain 17 (ADAM17) and become a promising strategy for hepatocellular carcinoma treatment (Nakao et al., 2014). GO analysis showed that ADAM17 enriched in T cell differentiation in thymus.

There are robust T cell responses against SARS-CoV-2 in COVID-19 patients (Neidleman et al., 2020), suggesting that miR-122-5p may be involved in the immune responses in COVID-19. We observed that hsa-miR-214-3p_L+1R-4 was significantly down-regulated in SD compared with the MD patients, and was associated with the disease severity.

The hsa-miR-214-3p has been suggested to be associated with various cancers, inflammatory diseases and the related signalling pathways (Liu et al., 2019; Yang et al., 2019; Yan et al., 2020; Li and Wang, 2017).

Another important aspect of this study is the identification of 20 DE-miRNAs in the LTNP vs STNP groups, nine of which were significantly correlated with the length of the viral persistence in COVID-19 patients, including hsa-miR-483-5p and hsa-miR-429. The expression level of hsa-miR- 483-5p was significantly higher in the LTNP subjects, indicating that hsa-miR-483-5p was positively correlated with the disease course (Figure 4E). The hsa-miR-483-5p was suggested to be associated with influenza virus infection, acute lung injury, chronic pulmonary obstruction and lung cancer (Hassan et al., 2019; Shen et al., 2017; Wang et al., 2018).

The expression of hsa-miR-483-5p was up- regulated in lung injury tissues and the increase of hsa-miR-483-5p may protect acute lung injury (Leng et al., 2020). In addition, has-miR-429 was previously reported to be antiviral in respiratory diseases (Sardar et al., 2020). Kozak et al have demonstrated that miR-429 may directly target SESN3 (Sestrin 3) (Kozak et al., 2019).

Functional analysis showed that SESN3 enriched in the p53 signalling pathway and could be regulated by p53 (Budanov et al., 2010). SARS-CoV-2 could induce p53 signalling pathway in lymphocytes (Xiong et al., 2020). Therefore, has-miR-429 may target SESN3 through p53 signalling pathway and correlated with the viral persistence.

Moreover, hsa-let- 7b-3p_1ss22CT was up-regulated in LTNP compared with STNP. Since ACE2 is a major cellular receptor for SASR-CoV-2 and Let-7b may downregulate ACE2 expression (Zhang et al., 2019; Zhang et al., 2021), suggesting that the up-regulation of let-7b in the LTNP patients may lead to the downregulation of ACE2 and subsequently prevent the hosts from virus infection.

In this study, we have identified 63 miRNAs that may directly target the viral sequences of SARS- CoV-2 genome and a panel of miRNAs that may target the cellular genes involved in the life cycle of SASR-CoV-2 replication. The exact roles of these miRNA in viral infection, persistence, and pathogenesis of COVID-19 remain unclear at this time, and they warrant additional studies.

In addition, we have successfully established and tested a machine learning model for differentiation of SARS-CoV-2 infected patients from uninfected individuals and classification of COVID-19 patients based on the differentially expressed miRNAs. Currently, detection of viral nucleic acid by RT-PCR is the gold-standard method for clinical diagnosis of SARS-CoV-2 infection.

Since multiple factors may affect the sensitivity and specificity of RT-PCR assays, our machine learning model may become a novel complementary method to RT-PCR for clinical diagnosis of COVID-19.

In conclusion, we identified a large number of DE-miRNAs that were associated with the virus infection, clinical symptoms, disease severity and the viral persistence of the COVID-19 patients, as well as a panel of miRNAs that may target the host genes involved in a variety of pathways or the viral genomic regions of SARS-CoV-2.

Our findings may help us understand the potential contributions of microRNAs to the pathogenesis of COVID-19 and identify novel biomarkers for the diagnosis and treatment of SARS-CoV-2 infection.

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