Abstract
The constant rise of the death toll and cases of COVID-19 has made this pandemic a serious threat to human civilization. Understanding of host-SARS-CoV-2 interaction in viral pathogenesis is still in its infancy. In this study, we utilized a blend of computational and knowledgebase approaches to model the putative virus-host interplay in host signaling pathways by integrating the experimentally validated host interactome proteins and differentially expressed host genes in SARS-CoV-2 infection. While searching for the pathways in which viral proteins interact with host proteins, we discovered various antiviral immune response pathways such as hypoxia-inducible factor 1 (HIF-1) signaling, autophagy, retinoic acid-inducible gene I (RIG-I) signaling, Toll-like receptor signaling, fatty acid oxidation/degradation, and IL-17 signaling. All these pathways can be either hijacked or suppressed by the viral proteins, leading to improved viral survival and life cycle. Aberration in pathways such as HIF-1 signaling and relaxin signaling in the lungs suggests the pathogenic lung pathophysiology in COVID-19. From enrichment analysis, it was evident that the deregulated genes in SARS-CoV-2 infection might also be involved in heart development, kidney development, and AGE-RAGE signaling pathway in diabetic complications. Anomalies in these pathways might suggest the increased vulnerability of COVID-19 patients with comorbidities. Moreover, we noticed several presumed infection-induced differentially expressed transcription factors and epigenetic factors, such as miRNAs and several histone modifiers, which can modulate different immune signaling pathways, helping both host and virus. Our modeling suggests that SARS-CoV-2 integrates its proteins in different immune signaling pathways and other cellular signaling pathways for developing efficient immune evasion mechanisms while leading the host to a more complicated disease condition. Our findings would help in designing more targeted therapeutic interventions against SARS-CoV-2.
Highlights
Though several human coronavirus outbreaks caused severe public health crises over the past few decades, the recent coronavirus disease (COVID-19) outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has beaten the records of the previous ones and the case counts are still on the upswing
Enrichment analysis using these differentially expressed genes exhibited that deregulated genes of SARS-CoV-2 infection can exert biological functions such as regulation of inflammatory response, negative regulation of type I interferon, response to interferon-gamma, interferongamma-mediated signaling, NIK/NF-kappaB signaling, regulation of the apoptotic process, cellular response to hypoxia, angiogenesis, negative regulation of inflammatory response, zinc ion binding, and calcium ion binding; all of these were not enriched for SARS-CoV infection (Figures 2A,B)
Deregulated genes of SARS-CoV-2 infection were involved in pathways such as NF-kappaB signaling, Jak-STAT signaling, retinoic acid-inducible gene I (RIG-I)-like receptor signaling, natural killer cell–mediated cytotoxicity, phagosome, hypoxia-inducible factor 1 (HIF-1) signaling, calcium signaling, GnRH signaling, arachidonic acid metabolism, insulin signaling, adrenergic signaling in cardiomyocytes, and PPAR signaling (Figure 2C; Supplementary Figures S1, Figure 2 | Enrichment analysis and comparison between deregulated genes in SARS-CoV and SARS-CoV-2 infections using (A) Gene Ontology Biological Processes (GOBP) module, (B) GOMF module, and (C) KEGG pathway module
Summary
Though several human coronavirus outbreaks caused severe public health crises over the past few decades, the recent coronavirus disease (COVID-19) outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has beaten the records of the previous ones and the case counts are still on the upswing. About 210 countries and territories around the globe have been affected by this outbreak, ∼24 million people are already infected with SARS-CoV-2, and the number was steadily rising at the time of writing this article (Worldometer, 2020). The genome sequence of SARS-CoV-2 is about 90% similar to bat-derived SARS-like coronavirus, whereas this novel virus is only ∼79 and ∼50% similar to severe acute respiratory syndrome coronavirus (SARSCoV) and Middle East Respiratory Syndrome-related Coronavirus (MERS-CoV), respectively (Lu et al, 2020; Ren et al, 2020). A substantial genomic difference can be observed between SARS-CoV and SARS-CoV-2; as in SARS-CoV-2, there have been 380 amino acids substitution, deletion of ORF8a, elongation of ORF8b, and truncation of ORF3b observed (Lu et al, 2020)
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