COVID-19 pandemic is a global crisis that threatens our way of life. As of April 29, 2020, COVID-19 has claimed more than 200,000 lives, with a global mortality rate of ~7% and recovery rate of ~30%. Understanding the interaction of cellular targets to the SARS-CoV2 infection is crucial for therapeutic development. Therefore, the aim of this study was to perform a comparative analysis of transcriptomic signatures of infection of COVID-19 compared to different respiratory viruses (Ebola, H1N1, MERS-CoV, and SARS-CoV), to determine unique anti-COVID1-19 gene signature. We identified for the first time molecular pathways for Heparin-binding, RAGE, miRNA, and PLA2 inhibitors, to be associated with SARS-CoV2 infection. The NRCAM and SAA2 that are involved in severe inflammatory response, and FGF1 and FOXO1 genes, which are associated with immune regulation, were found to be associated with a cellular gene response to COVID-19 infection. Moreover, several cytokines, most significantly the IL-8, IL-6, demonstrated key associations with COVID-19 infection. Interestingly, the only response gene that was shared between the five viral infections was SERPINB1. The PPI study sheds light on genes with high interaction activity that COVID-19 shares with other viral infections. The findings showed that the genetic pathways associated with Rheumatoid arthritis, AGE-RAGE signaling system, Malaria, Hepatitis B, and Influenza A were of high significance. We found that the virogenomic transcriptome of infection, gene modulation of host antiviral responses, and GO terms of both COVID-19 and Ebola are more similar compared to SARS, H1N1, and MERS. This work compares the virogenomic signatures of highly pathogenic viruses and provides valid targets for potential therapy against COVID-19.
This study mainly aimed to determine the unique host gene expression signature response to COVID-19 infection compared to SARS-CoV, MERS-CoV, Ebola, and H1N1, which will help us to understand the differences and similarities in host responses to various respiratory viruses. To our knowledge, this is the first study to perform such a transcriptomic comparison between these five viral infections. We focused on mapping the potential biological pathways and GO enrichment that are more specific to COVID-19.
The analysis of the host DEGs through COVID-19 infection highlighted the role of SAA2, CCL20, and IL8 genes. Recently, this link between the serum amyloid A 2 (SAA2) gene and the COVID-19 infection has been proposed as a biomarker to differentiate the severity and prognosis of the COVID-19 infection. SAA2 is an inflammation factor that has demonstrated its effectiveness as a sensitive indicator of clinical diagnosis. In addition, we have observed the uniqueness of the SAA2 gene expression in the COVID-19 infection relative to SARS-CoV, MERS-CoV, Ebola, and H1N1 viral infections, which indicates its role in host response. On the other hand, CCL20 gene has been related to lung carcinoma, where it controls proliferation and cell migration via the PI3 K pathway. These mechanisms are among the most important in host defense. Multiple genes belong to the interleukin gene family were identified in this study, such as IL6, CXCL1, 3 and 5, and the IL-17 which have a significant association with the host response of COVID-19. In addition, IL8 gene, which has been related to immune stimulus and a recognized locus of susceptibility to a specific respiratory virus. Such genes serve as key factors for controlling the growth of endothelial cell.
GO-based gene enrichment analysis demonstrated that many biological processes are closely related to the immune responses, including myeloid cell activation and neutrophil activation. Interestingly, miRNAs-related gene pathway was overexpressed as a response to COVID-19 infection, which is known to play an important role against viral infection. Activation of miRNAs as a defense mechanism during lung infection could be related to its important role in physiological and pathological processes in the lung. Studying such a process could open a new way for treatment of COVID-19.
We identified a strong association between COVID-19 infection and GO related to Nuclear Factor Kappa-B (NF-kB) signaling and Tumor Necrosis Factor (TNF) signaling pathways. The NF-kB pathway is closely related to pro-inflammatory and pro-oxidant responses, and is involved in the inflammatory responses in acute lung injuries. The regulation of NF-kB activation was proposed as a potential adjuvant treatment for COVID-19 infection. TNF receptors are mainly involved in the inflammation and apoptosis; interestingly the interactions between viral proteins and intracellular components downstream of the TNF receptors demonstrated viral mechanism to evade the immune response.
Among the genes that are unique in the host response to COVID-19 are CSF2/3, and PTGS2, which known to be involved in the immune responses against Rhinovirus infection. The relation between prostaglandin-endoperoxide synthase 2 (PTGS2/COX-2) gene and host response to COVID-19 infection could be due its role to down-regulate NF-κB mediated transcription, which is a critical element in some virus replication such as HIV-1. It was proposed that this gene is incorporated in the host immune response system against viral infection. The colony-stimulating granulocyte factor (G-CSF) can alter the function of T-cells and induces Th2 immune response. There is also some evidence of a link between elevated G-CSF expression level and the induction of the cellular immune response in H1N1 infected individuals.
The GO-associated molecular function in COVID-19 host response yielded terms such as receptor for advanced glycation endproducts (RAGE) and metal ion binding. RAGE is highly expressed only in the lung, and is rapidly growing at inflammatory sites, primarily in inflammatory and epithelial cells. The triggering and upregulation of RAGE by its ligands correlate with increased survival rates.
Additionally, RAGE has a secretory isoform that can have an independent causative effect on community-acquired pneumonia, such as pandemic influenza (H1N1). Although there is no evidence to link this to COVID-19 infection, it is worth further investigation.
The host response to the five viruses shared the plasminogen activator (SERPINB1) as a common gene signature.This gene is highly correlated with lung chronic airway inflammation such as asthma.The SERPINB1 acts in host-pathogenic interactions and possesses some antiviral activity across infections of rhabdovirus, hepatitis C, and influenza A.
Among the five viral infections, we found that GO terms were mostly enriched between COVID-19 and Ebola. Such overlap suggested certain genes and gene families, which could explain the aggressiveness of COVID-19 infections. Within these GO enriched pathways, the TNIP1, ICAM1, and CFB were most significantly associated with COVID-19 (logpvalue > 40). The TNIP1 gene encodes the A20-binding protein that plays a role in autoimmunity and tissue homeostasis by controlling the activation of the kappa-B nuclear factor. TNIP1 reduction sensitizes keratinocytes to post-receptor signaling after interaction to TLR agonists and has the ability to activate immune cells and induce inflammation. The correlation between TNP1 and COVID-19 could be due to its role in suppressing NF-kB pathway and therefore regulating the overexpression of viral proteins.
The ICAM-1 intercellular adhesion molecule plays a major role in the infectivity and neutralization of the HIV-I and controls the survival of the influenza virus in lung epithelial cells during the early stages of infection. Forkhead Box O1 (FOXO1) is a transcription factor that plays an important role in the regulation of insulin signaling for gluconeogenesis and glycogenolysis. There has been a strong relationship between FOXO1 and viral infections. The FOXO1 binds hepatitis B virus DNA and activates its transcription. The FOXO1 reported to negatively regulate cellular antiviral response by promoting degradation of interferon regulatory transcription factor 3 (IRF3). In addition, it was reported that differentiation of CD8 memory T cells depends on FOXO1, where it plays an intrinsic role in the establishment of a post-effector memory program which is important for the formation of long-lived memory cells capable of immune reactivation.
GO analysis of genes uniquely shared between COVID-19 and Ebola highlighted the activity of the inhibitor of phospholipase, in particular phospholipase A2 (PLA2). Interestingly, synthetic and natural PLA2 inhibitors have been a viable treatment of oxidative stress and neuroinflammation connected with neuropathogenic disorders. Such lipid mediators are considered to play a major role in diseases associated with cancer and inflammation such as arthritis, allergy and asthma. Some reports suggested a potential link between PLA2-generated lipid mediators and viral infection, where these infection alters the lipid mediators of this pathway to initiate infection and pathogenesis . Given the important association between heparin-binding GO and activation of T cells against virus infections like influenza, their interaction with COVID-19 infection has not been documented. In comparison, glycosaminoglycan-binding molecules are essential for the action of certain in vivo chemokines. Some glycosaminoglycans are required for respiratory syncytial viral infection and are important for the entry of a bacterial pathogen into the biological system . Some oncofetal antigens which target such proteins were used to control parasites of malaria (Mette et al., 2019). This might support any of the recent suggestion of using pharmaceuticals derived from glycosaminoglycan to control the infection with COVID-19.
MERS-CoV uniquely shared 51 DEGs with COVID-19. Among the most significant shared genes that are associated with COVID-19 are KRT6B and TNFAIP3. Keratin 6B (KRT6B) is a type II cytokeratin, which is an important biomarker for lung adenocarcinoma. These genes are known as a virus-induced host factors that control the recruitment of T-cells and correlates to chronic virus infections. In addition, the tumor necrosis factor, alpha-induced protein 3 (TNFAIP3), is a central regulator of immunopathology and associated with the maintenance of immune homeostasis and severe viral infections.
We identified many DEGs that are classified as “antiviral genes” that are shared between MERS-CoV and COVID-19. Most of these DEGs are associated with host response to virus infection, and type I interferons. This high number of DEGs could indicate their potential role in host defense against COVID-19 infection. For instance, the regulation of OAS1-3 is highly correlated with host response to viral infections. While genes such as IRF9, PML, IRF7, STAT1 and IFIH1 are related to interferon signaling.
COVID-19, Ebola, and MERS-CoV shared uniquely 31 genes, of which, BIRC3 and MX1 are highly linked to COVID-19. The Baculoviral IAP Repeat Containing 3 (BIRC3) is associated Marginal Zone B-Cell Lymphoma, Lymphoma, and was suggested as a novel NK cell immune checkpoint in cancer. While MX Dynamin Like GTPase 1 (MX1) is an interferon-inducible protein that associated with viral infections of Influenza and Viral Encephalitis. The link between the gene expression of BIRC3 and MX1 have been hypothesized as a part of small group of genes controlling host response against viral infections, including Human Herpes Virus type 6Α (HHV-6Α) infection. Additionally, Mx1 protein contributes to the novel antiviral activity against classical swine fever virus. Among genes that are uniquely shared between COVID-19, Ebola, and MERS-CoV, interferon Induced Protein With Tetratricopeptide Repeats 1 (IFIT1) and DExD/H-Box Helicase 58 (DDX58) which high a significant potentiality. Recently, the uniqueness of DDX58 gene expression under COVID-19 viral infection has been reported. IFIT1 plays a crucial role in some viral infections, where Hepatitis E virus polymerase binds to IFIT1 to shield the viral RNA from translation inhibition mediated by IFIT1 and enhances the interferon response in murine macrophage-like cells.
The COVID-19 gene expression profile demonstrated multiple genes in conjunction with Ebola, H1N1, MERS-CoV, and SARS-CoV. Most of these genes are linked to the viral infection immune response of the host, except for genes such as FGF1 and NRCAM. The Neuronal Cell Adhesion Molecule (NRCAM) is related to neurological diseases such as Alzheimer. Significant NRCAM gene expression has been observed under specific circumstances, such as neuroinflammation triggered by influenza A long-term viral infection. FGF1, also known as acidic fibroblast growth factor (aFGF), is a cellular growth factor and signaling protein encoded by the FGF1 gene. FGF1 is a strong angiogenic factor controls the development of new blood vessels and has been detected through studying endothelial cells infected with influenza virus.
The PPI analysis highlighted the genes COVID-19 shared with other viral infections that have high interaction activity. By selecting high interactive genes, we used an analysis of gene enrichment and PPI to identify more information about the function of these genes. It was clear from the results that the genetic pathways associated with Rheumatoid arthritis, AGE-RAGE signaling pathway, Malaria, Hepatitis B, and Influenza A were of high significance. The correlation between host response to Rheumatoid arthritis, Malaria and COVID-19 has been mysterious to date. Despite the fact that several Rheumatoid arthritis and malaria drugs are available, with some efficacy against COVID-19 infection. Our results suggest that the link between these diseases and the infection with COVID-19 is more related to PPI interactions. In addition, the PPI network has shown that these genes are highly significant across other infectious diseases such as Ebola, MERS-CoV and SARS-CoV.
We compared five transcriptomic profiles for cell host infection with COVID-19, Ebola, H1N1, MERS-CoV and SARS-CoV. Our analysis identified several key aspects of host response to COVID-19 infection where essential immunity genes and biological pathways could be used for understanding the pathogenesis of COVID-19 infection. Common and specific genetic factors and pathways have been identified that characterize the immune pathology of COVID-19 infection. Our research outlined the relationship between Ebola's cellular host response and COVID-19, where many genes and GO words are enriched. Genes related to immune regulation, including FGF1 and FOXO1, and those associated with extreme inflammation, such as NRCAM and SAA2, have been closely associated with cellular response to COVID-19 infection. In addition, common interleukin family members, in particular IL-8, IL-6, demonstrated a special relationship with COVID-19 infection, indicating their key importance. The GO evaluation highlighted pathways for RAGE, miRNA and PLA2 inhibitors, which were first identified in this study as possible pathways highly associated with the host response to COVID-19 infection. Some of these pathways, such as PLA2 inhibitors, may hold the key for potential drugs to manage COVID-19 infections. The PPI study sheds light on genes with high interaction activity that COVID-19 shares with other viral infections, where the findings showed that the genetic pathways associated with Rheumatoid arthritis, AGE-RAGE signaling system, Malaria, Hepatitis B, and Influenza A were of high significance. Our work also shows that the combination of different types of experimental methods and parameters have been effective in studying the etiology of COVID-19 immunopathology compared to similar viral infections. In this regard, further research in this direction will be promising for characterizing new diagnostic biomarkers in the future or as surrogates for assessing the effectiveness of potential innovative therapies.
Reference & source information: https://www.biorxiv.org/
Read More on: