Epigenetic regulator miRNA pattern differences among SARS-CoV, SARS-CoV-2 and SARS-CoV-2 world-wide isolates delineated the mystery behind the epic pathogenicity and distinct clinical characteristics of pandemic COVID-19

Abstract

Detailed molecular mechanism of SARS-CoV-2 pathogenesis is still elusive to address its deadlier nature and to design effective theraputics. Here, we present our study elucidating the interplay between the SARS-CoV and SARS-CoV-2 viruses’; and host’s miRNAs, an epigenetic regulator, as a mode of pathogenesis, and enlightened how the SARS-CoV and SARS-CoV-2 infections differ in terms of their miRNA mediated interactions with host and its implications in the disease complexity. We have utilized computational approaches to predict potential host and viral miRNAs, and their possible roles in different important functional pathways. We have identified several putative host antiviral miRNAs that can target the SARS viruses, and also SARS viruses’ encoded miRNAs targeting host genes. In silico predicted targets were also integrated with SARS infected human cells microarray and RNA-seq gene expression data. Comparison of the host miRNA binding profiles on 67 different SARS-CoV-2 genomes from 24 different countries with respective country’s normalized death count surprisingly uncovered some miRNA clusters which are associated with increased death rates. We have found that induced cellular miRNAs can be both a boon and a bane to the host immunity, as they have possible roles in neutralizing the viral threat, parallelly, they can also function as proviral factors. On the other hand, from over representation analysis, interestingly our study revealed that although both SARS-CoV and SARS-CoV-2 viral miRNAs could target broad immune signaling pathways; only some of the SARS-CoV-2 miRNAs are found to uniquely target some immune signaling pathways like-autophagy, IFN-I signaling etc, which might suggest their immune-escape mechanisms for prolonged latency inside some hosts without any symptoms of COVID-19. Further, SARS-CoV-2 can modulate several important cellular pathways which might lead to the increased anomalies in patients with comorbidities like-cardiovascular diseases, diabetes, breathing complications, etc. This might suggest that miRNAs can be a key epigenetic modulator behind the overcomplications amongst the COVID-19 patients. Our results support that miRNAs of host and SARS-CoV-2 can indeed play a role in the pathogenesis which can be further concluded with more experiments. These results will also be useful in designing RNA therapeutics to alleviate the complications from COVID-19.

Neurobiology of SARS-CoV-2 interactions with the peripheral nervous system: implications for COVID-19 and pain

“… 23 In the context of SARS-CoV-2, available data and predictive analyses suggest that infection-induced host miRNAs may inhibit some immune surveillance pathways, including IFN-γ signaling, TGF-β signaling, and toll-like receptors, all of which may contribute to immune suppression. 34 The effect miRNAs might have on either disease course or pain processing is (as of yet) unclear. Similarly, although several differentially expressed lncRNAs have been identified in COVID-19 patient-derived lung tissue, 87 their mechanistic role in viral infection and pain processing remain thus far poorly understood and highly speculative.…”

MicroRNAs and SARS-CoV-2 life cycle, pathogenesis, and mutations: biomarkers or therapeutic agents?

“…Furthermore, 10 human miRNAs have been identified to possess binding sites across the SARS-CoV-2 genome. These host cellular miRNAs, by targeting the SARS-CoV-2 genome, produce antiviral effects [23][24][25]. In another study, miRNAs in human lung epithelium were predicted to have potential binding sites in the SARS-CoV-2 genome; 128 human miRNAs had a very low level of expression in lung epithelia, and six of 128 miRNAs exhibited differential expression upon in vitro infection with SARS-CoV-2.…”

“…The work of Khan et al (2020) showed that SARS-CoV-2 miRNAs participate in these complications. For example, brain development, heart development, and insulin signaling pathway were predicted to be targeted by the virus miRNAs.…”

“…For example, brain development, heart development, and insulin signaling pathway were predicted to be targeted by the virus miRNAs. Patients with underlying disorders like cardiovascular diseases, diabetes, or breathing complications are more susceptible to SARS-CoV-2 infection, which suggests an epigenetic modulatory role of virus miRNAs and even targeting host miRNAs [23]. Host miRNAs targeted by the virus are regulated vital functions such as kidney and heart development, neuronal processes, metabolic processes, fatty acid metabolism, insulin resistance, glucagon signaling pathway, and peroxisome proliferator-activated (PPAR) signaling.…”

“…Host miRNAs targeted by the virus are regulated vital functions such as kidney and heart development, neuronal processes, metabolic processes, fatty acid metabolism, insulin resistance, glucagon signaling pathway, and peroxisome proliferator-activated (PPAR) signaling. In COVID-19 patients, dysregulation of these processes follows inhibition of human miRNAs, overcomplicating the condition especially in individuals with comorbidity [23].…”