ABSTRACT
The current pandemic is already a third coronavirus spillover in the span of 20years. This recurrency meant that there was some information available about person-to-person transmission, cell entry, and host-pathogen interactions. The choice to target the Spike viral structural protein was easy, given its importance and specificity, together with a relatively low mutational rate. However, early in the pandemic, before any vaccines were ready, the scientific community was concerned with a lack of effective treatments against COVID-19. As soon as the viral genome was posted online, the race to identify potential host and viral targets gained pace, especially in the form of in silico "multi-omics.” Protein-protein interaction networks help identify key hub genes and proteins, as well as existing approved drugs whose mechanisms of action might be useful against this novel threat. To this end, several approaches have been devised: using influenza virus as a proxy;comparing SARS, MERS, and a common cold coronavirus to SARS-CoV-2;gene ontology matching;and the search for vulnerable proteins (VPs) and their perturbators. The algorithms deployed to perform the task have included a random walk with restart (RWR), degree of centrality, enrichment analysis, and weighted networks, backed up by experimental methods: cloning, tagging, and expressing viral proteins, affinity purification mass spectrometry, biotin labeling, and time-based transcriptomics, among others. Some of the proposed proteins and their genes reveal important pathways. Existing drugs available for repurposing encompass some interesting mechanisms of action: mRNA inhibitors, regulators of sigma receptors, and protease inhibitors. Candidate meds need to be further evaluated in clinical trials. Interestingly, most approaches give different results, and some of the insights and drugs do not make much sense. These studies, however, already make for a wealth of data to be revisited during gene discovery and drug repurposing. © 2023 Elsevier Inc. All rights reserved.
ABSTRACT
The COVID-19 pandemic reached five waves in three years, with over 6.5 million deaths across the globe. Knowing the differential susceptibility to the novel betacoronavirus has allowed us to better understand the pathophysiology and inflammatory complications and dissect the response against the virus. As in other viral infections, CD8+ T lymphocytes and NK cells stand out as key players, together with viral sensors, type 1 interferons, an exaggerated inflammatory response by NLRP3, and a storm that includes cytokines IL-6 and IL-8. Whole-exome sequencing has identified several genes with pathogenic germline variants in patients with severe COVID-19;said genes would account for around 5% of all severe cases. In addition, up to 20% of hospitalized adults harbor autoantibodies against type-I and III interferons. These findings translate into novel genetic etiologies, whereas autoantibodies explain the worse prognosis of the elderly, linked to the inflammaging phenomenon. In general, patients with known primary immune deficiencies who acquired COVID-19 fared well, with global survival rates over 80% and a predominance of mild courses. The exceptions were patients with severe-combined immune deficiency, and with the autoimmune polyglandular syndrome 1, the latter because they develop autoantibodies against interferon. Neither have there been reports of greater severity in patients with autoimmune or autoinflammatory disorders. However, those receiving immunosuppressant treatments usually have a more protracted course. Patients with NLRP3 or STAT1 gain of function might be especially susceptible to systemic inflammatory complications. In this review, we summarize the global experience in the caretaking of patients with immune alterations who were infected by SARS-CoV-2. © 2022 Instituto Nacional de Pediatria. All rights reserved.