Immunopathogenesis and Immunogenetic Variants in COVID-19.

Coronavirus disease 2019 (COVID-19) continues to spread globally despite the discovery of vaccines. Many people die due to COVID-19 as a result of catastrophic consequences, such as acute respiratory distress syndrome, pulmonary embolism, and disseminated intravascular coagulation caused by a cytokine storm. Immunopathology and immunogenetic research may assist in diagnosing, predicting, and treating severe COVID-19 and the cytokine storm associated with COVID-19. This paper reviews the immunopathogenesis and immunogenetic variants that play a role in COVID-19. Although various immune-related genetic variants have been investigated in relation to severe COVID-19, the NOD-like receptor protein 3 (NLRP3) and interleukin 18 (IL-18) have not been assessed for their potential significance in the clinical outcome. Here, we a) summarize the current understanding of the immunogenetic etiology and pathophysiology of COVID-19 and the associated cytokine storm; and b) construct and analyze protein-protein interaction (PPI) networks (using enrichment and annotation analysis) based on the NLRP3 and IL18 variants and all genes, which were established in severe COVID-19. Our PPI network and enrichment analyses predict a) useful drug targets to prevent the onset of severe COVID-19, including key antiviral pathways such as Toll-Like-Receptor cascades, NOD-like receptor signaling, RIG-induction of interferon (IFN) α/ß, and interleukin (IL)-1, IL-6, IL-12, IL-18, and tumor necrosis factor signaling; and b) SARS-CoV-2 innate immune evasion and the participation of MYD88 and MAVS in the pathophysiology of severe COVID-19. The PPI network genetic variants may be used to predict more severe COVID-19 outcomes, thereby opening the door for targeted preventive treatments.

New Drug Targets to Prevent Death Due to Stroke: A Review Based on Results of Protein-Protein Interaction Network, Enrichment, and Annotation Analyses.

This study used established biomarkers of death from ischemic stroke (IS) versus stroke survival to perform network, enrichment, and annotation analyses. Protein-protein interaction (PPI) network analysis revealed that the backbone of the highly connective network of IS death consisted of IL6, ALB, TNF, SERPINE1, VWF, VCAM1, TGFB1, and SELE. Cluster analysis revealed immune and hemostasis subnetworks, which were strongly interconnected through the major switches ALB and VWF. Enrichment analysis revealed that the PPI immune subnetwork of death due to IS was highly associated with TLR2/4, TNF, JAK-STAT, NOD, IL10, IL13, IL4, and TGF-ß1/SMAD pathways. The top biological and molecular functions and pathways enriched in the hemostasis network of death due to IS were platelet degranulation and activation, the intrinsic pathway of fibrin clot formation, the urokinase-type plasminogen activator pathway, post-translational protein phosphorylation, integrin cell-surface interactions, and the proteoglycan-integrin extracellular matrix complex (ECM). Regulation Explorer analysis of transcriptional factors shows: (a) that NFKB1, RELA and SP1 were the major regulating actors of the PPI network; and (b) hsa-mir-26-5p and hsa-16-5p were the major regulating microRNA actors. In conclusion, prevention of death due to IS should consider that current IS treatments may be improved by targeting VWF, the proteoglycan-integrin-ECM complex, TGF-ß1/SMAD, NF-κB/RELA and SP1.

The role of zinc, copper, manganese and iron in neurodegenerative diseases.

Metals are involved in different pathophysiological mechanisms associated with neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD) and multiple sclerosis (MS). The aim of this study was to review the effects of the essential metals zinc (Zn), copper (Cu), manganese (Mn) and iron (Fe) on the central nervous system (CNS), as well as the mechanisms involved in their neurotoxicity. Low levels of Zn as well as high levels of Cu, Mn, and Fe participate in the activation of signaling pathways of the inflammatory, oxidative and nitrosative stress (IO&NS) response, including nuclear factor kappa B and activator protein-1. The imbalance of these metals impairs the structural, regulatory, and catalytic functions of different enzymes, proteins, receptors, and transporters. Neurodegeneration occurs via association of metals with proteins and subsequent induction of aggregate formation creating a vicious cycle by disrupting mitochondrial function, which depletes adenosine triphosphate and induces IO&NS, cell death by apoptotic and/or necrotic mechanisms. In AD, at low levels, Zn suppresses ß-amyloid-induced neurotoxicity by selectively precipitating aggregation intermediates; however, at high levels, the binding of Zn to ß-amyloid may enhance formation of fibrillar ß-amyloid aggregation, leading to neurodegeneration. High levels of Cu, Mn and Fe participate in the formation α-synuclein aggregates in intracellular inclusions, called Lewy Body, that result in synaptic dysfunction and interruption of axonal transport. In PD, there is focal accumulation of Fe in the substantia nigra, while in AD a diffuse accumulation of Fe occurs in various regions, such as cortex and hippocampus, with Fe marginally increased in the senile plaques. Zn deficiency induces an imbalance between T helper (Th)1 and Th2 cell functions and a failure of Th17 down-regulation, contributing to the pathogenesis of MS. In MS, elevated levels of Fe occur in certain brain regions, such as thalamus and striatum, which may be due to inflammatory processes disrupting the blood-brain barrier and attracting Fe-rich macrophages. Delineating the specific mechanisms by which metals alter redox homeostasis is essential to understand the pathophysiology of AD, PD, and MS and may provide possible new targets for their prevention and treatment of the patients affected by these NDDs.