Abstract
Background: Severe coronavirus disease 2019 (COVID-19) is associated with multiple comorbidities and is characterized by an auto-aggressive inflammatory state leading to massive collateral damage. To identify preventive and therapeutic strategies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is important to ascertain the molecular interactions between virus and host, and how they translate into disease pathophysiology. Methods: We matched virus-human protein interactions of human coronaviruses and other respiratory viruses with lists of genes associated with autoimmune diseases and comorbidities associated to worse COVID-19 course. We then selected the genes included in the statistically significant intersection between SARS-CoV-2 network and disease associated gene sets, identifying a meta-interactome. We analyzed the meta-interactome genes expression in samples derived from lungs of infected humans, and their regulation by IFN-β. Finally, we performed a drug repurposing screening to target the network's most critical nodes. Results: We found a significant enrichment of SARS-CoV-2 interactors in immunological pathways and a strong association with autoimmunity and three prognostically relevant conditions (type 2 diabetes, coronary artery diseases, asthma), that present more independent physiopathological subnetworks. We observed a reduced expression of meta-interactome genes in human lungs after SARS-CoV-2 infection, and a regulatory potential of type I interferons. We also underscored multiple repurposable drugs to tailor the therapeutic strategies. Conclusions: Our data underscored a plausible genetic background that may contribute to the distinct observed pathophysiologies of severe COVID-19. Also, these results may help identify the most promising therapeutic targets and treatments for this condition.
Highlights
The severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) is responsible for the current coronavirus disease 2019 (COVID-19) pandemic
We extended the experimentally determined SARS-CoV-2-host interactions[9] by including second neighbors, i.e. molecules directly interacting with the host proteins engaged by the virus extracted from Human Integrated Protein-Protein Interaction rEference (HIPPIE)
We looked for an enrichment of human proteins interacting with SARS-CoV-2 within sets of genes mapped in genome-wide studies of immune-mediated conditions and comorbidities impacting on COVID-19 prognosis
Summary
The severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) is responsible for the current coronavirus disease 2019 (COVID-19) pandemic. Since the early phases of the pandemic, comorbidities such as hypertension, diabetes, cardiovascular disease, and obesity were readily identified as conditions associated with the severity of COVID-19 and the most aggressive collateral damage[1,2]. SARS-CoV-2 displays an overall 79% genome similarity with SARS-CoV, reaching a 99.7% homology within the Spike protein (S) gene, the major determinant of viral tropism[5] In both viruses, the Spike protein binds the membrane protein angiotensin-converting-enzyme 2 (ACE2) and engages the serine protease TMPRSS2 to infect human cells[6]. To identify preventive and therapeutic strategies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is important to ascertain the molecular interactions between virus and host, and how they translate into disease pathophysiology. Results: We found a significant enrichment of SARS-CoV-2 interactors in immunological pathways and a strong association with autoimmunity and three prognostically relevant conditions (type 2 diabetes, coronary artery diseases, asthma), that present more
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