SARS-CoV-2 infection: molecular mechanisms of severe outcomes to suggest therapeutics

Abstract

Introduction: The year 2020 was defined by the 29,903 base pairs of RNA that codes for the SARS-CoV-2 genome. SARS-CoV-2 infects humans to cause COVID-19, spreading from patient-to-patient yet impacts patients very divergently. Areas covered: Within this review, we address the known molecular mechanisms and supporting data for COVID-19 clinical course and pathology, clinical risk factors and molecular signatures, therapeutics of severe COVID-19, and reinfection/vaccination. Literature and published datasets were reviewed using PubMed, Google Scholar, and NCBI SRA tools. The combination of exaggerated cytokine signaling, pneumonia, NETosis, pyroptosis, thrombocytopathy, endotheliopathy, multiple organ dysfunction syndrome (MODS), and acute respiratory distress syndrome (ARDS) create a positive feedback loop of severe damage in patients with COVID-19 that impacts the entire body and may persist for months following infection. Understanding the molecular pathways of severe COVID-19 opens the door for novel therapeutic design. We summarize the current insights into pathology, risk factors, secondary infections, genetics, omics, and drugs being tested to treat severe COVID-19. Expert opinion : A growing level of support suggests the need for stronger integration of biomarkers and precision medicine to guide treatment strategies of severe COVID-19, where each patient has unique outcomes and thus require guided treatment.

Performance of SARS-CoV-2 Antigens in a Multiplex Bead Assay for Integrated Serological Surveillance of Neglected Tropical and Other Diseases

“…This assay adds to the growing number of multiplexed assays that can simultaneously test for antibodies against multiple SARS-CoV-2 antigens with routinely high sensitivity and specificity 13,[32][33][34][35][36] and high repeatability. 37 While increased sensitivity was achieved using a multi-antigen for many assays, 13,[32][33][34][35]37 we found no significant improvement in PPA or NPA using any combination of the four antigens compared with using only the S protein alone. We will continue evaluate in other populations, particularly in those with malaria exposure, for which cross-reactivity with SARS-CoV-2 antigens has been documented.…”

The fatal contribution of serine protease-related genetic variants to COVID-19 outcomes

“…SARS-CoV-2 uses the ACE2 receptor and TMPRSS2 to promote cellular entry by cleaving the S protein into S1 and S2 ( 27 – 29 ). TMPRSS2 is used by diverse viruses to infect humans, and it has been associated with physiological processes such as digestion, tissue remodeling, blood coagulation, fertility, inflammatory responses, and pain, among others, and the expression of TMPRSS2 is regulated by aging ( 30 ).…”

Regulated necrosis in COVID-19: A double-edged sword

“…Although the appropriate phage for patients with COVID-19 to accept pharmacological interventions is worth exploring, much remains obscure regarding potential agonists to provide a host for pyroptosis Downstream cytokine antagonists may have advantages in treating COVID-19, given that the overexpression of IL-1β, specifically in the lungs, is sufficient to recapitulate many of the ARDS phenotypes ( 90 ). Anakinra, an inhibitor of IL-1, and canakinumab, a half-life-prolonged IL-1β, may have potential benefits in the treatment of COVID-19, for which prospective randomized controlled trials are currently underway ( 90 ). RNA sequencing of the early recovery stage of COVID-19 showed that classical CD14 ++ and CD14 ++ IL-1β +; monocytes are of greater abundance with high expression of inflammatory genes, indicating that IL-1β may be a potential target for the COVID-19 intervention ( 105 ).…”