IL-17A Orchestrates Reactive Oxygen Species/HIF1α-Mediated Metabolic Reprogramming in Psoriasis.

Immune cell-derived IL-17A is one of the key pathogenic cytokines in psoriasis, an immunometabolic disorder. Although IL-17A is an established regulator of cutaneous immune cell biology, its functional and metabolic effects on nonimmune cells of the skin, particularly keratinocytes, have not been comprehensively explored. Using multiomics profiling and systems biology-based approaches, we systematically uncover significant roles for IL-17A in the metabolic reprogramming of human primary keratinocytes (HPKs). High-throughput liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance spectroscopy revealed IL-17A-dependent regulation of multiple HPK proteins and metabolites of carbohydrate and lipid metabolism. Systems-level MitoCore modeling using flux-balance analysis identified IL-17A-mediated increases in HPK glycolysis, glutaminolysis, and lipid uptake, which were validated using biochemical cell-based assays and stable isotope-resolved metabolomics. IL-17A treatment triggered downstream mitochondrial reactive oxygen species and HIF1α expression and resultant HPK proliferation, consistent with the observed elevation of these downstream effectors in the epidermis of patients with psoriasis. Pharmacological inhibition of HIF1α or reactive oxygen species reversed IL-17A-mediated glycolysis, glutaminolysis, lipid uptake, and HPK hyperproliferation. These results identify keratinocytes as important target cells of IL-17A and reveal its involvement in multiple downstream metabolic reprogramming pathways in human skin.

Genetic alterations and oxidative stress in T cell lymphomas.

T cell lymphomas encompass a diverse group of Non-Hodgkin lymphomas with a wide spectrum of clinical, immunological and pathological manifestations. In the last two decades there has been a progress in our understanding of the cell of origin, genetic abnormalities and their impact on behaviour in T cell lymphomas. Genetic alterations are one of the critical drivers of the pathogenesis of T cell lymphoma. Disease progression has been correlated with multiple genetic abnormalities where malignant clones arise primarily out of the host immune surveillance arsenal. There are many cellular processes involved in disease development, and some of them are T cell signaling, differentiation, epigenetic modifications, and immune regulation. Modulation of these crucial pathways via genetic mutations and chromosomal abnormalities possessing either point or copy number mutations helps tumor cells to develop a niche favourable for their growth via metabolic alterations. Several metabolic pathways especially regulation of redox homeostasis is critical in pathogenesis of lymphoma. Disruption of redox potential and induction of oxidative stress renders malignant cells vulnerable to mitochondrial damage and triggers apoptotic pathways causing cell death. Targeting genetic abnormalities and oxidative stress along with current treatment regime have the potential for improved therapeutics and presents new combination approaches towards selective treatment of T cell lymphomas.

Pathogenic perspective of missense mutations of ORF3a protein of SARS-CoV-2.

One of the most important proteins for COVID-19 pathogenesis in SARS-CoV-2 is the ORF3a which is the largest accessory protein among others coded by the SARS-CoV-2 genome. The major roles of the protein include virulence, infectivity, ion channel activity, morphogenesis, and virus release. The coronavirus, SARS-CoV-2 is mutating rapidly, therefore, critical study of mutations in ORF3a is certainly important from the pathogenic perspective. Here, a sum of 175 non-synonymous mutations in the ORF3a of SARS-CoV-2 were identified from 7194 complete genomes of SARS-CoV-2 available from NCBI database. Effects of these mutations on structural stability, and functions of ORF3a were also studied. Broadly, three different classes of mutations, such as neutral, disease, and mixed (neutral and disease) types of mutations were observed. Consecutive phenomena of mutations in ORF3a protein were studied based on the timeline of detection of the mutations. Considering the amino acid compositions of the ORF3a protein, twenty clusters were detected using the K-means clustering method. The present findings on 175 novel mutations of ORF3a proteins will extend our knowledge on ORF3a, a vital accessory protein in SARS-CoV-2, to enlighten the pathogenicity of this life-threatening virus.

Urgent Need for Field Surveys of Coronaviruses in Southeast Asia to Understand the SARS-CoV-2 Phylogeny and Risk Assessment for Future Outbreaks.

Phylogenetic analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is focused on a single isolate of bat coronaviruses (bat CoVs) which does not adequately represent genetically related coronaviruses (CoVs) [...].

Notable sequence homology of the ORF10 protein introspects the architecture of SARS-CoV-2.

The current Coronavirus Disease 19 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) shows similar pathology to MERS and SARS-CoV, with a current estimated fatality rate of 1.4%. Open reading frame 10 (ORF10) is a unique SARS-CoV-2 accessory protein, which contains eleven cytotoxic T lymphocyte (CTL) epitopes each of nine amino acids in length. Twenty-two unique SARS-CoV-2 ORF10 variants have been identified based on missense mutations found in sequence databases. Some of these mutations are predicted to decrease the stability of ORF10 in silico physicochemical and structural comparative analyses were carried out on SARS-CoV-2 and Pangolin-CoV ORF10 proteins, which share 97.37% amino acid (aa) homology. Though there is a high degree of ORF10 protein similarity of SARS-CoV-2 and Pangolin-CoV, there are differences of these two ORF10 proteins related to their sub-structure (loop/coil region), solubility, antigenicity and shift from strand to coil at aa position 26 (tyrosine). SARS-CoV-2 ORF10, which is apparently expressed in vivo since reactive T cell clones are found in convalescent patients should be monitored for changes which could correlate with the pathogenesis of COVID-19.

A unique view of SARS-CoV-2 through the lens of ORF8 protein.

Immune evasion is one of the unique characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) attributed to its ORF8 protein. This protein modulates the adaptive host immunity through down-regulation of MHC-1 (Major Histocompatibility Complex) molecules and innate immune responses by surpassing the host's interferon-mediated antiviral response. To understand the host's immune perspective in reference to the ORF8 protein, a comprehensive study of the ORF8 protein and mutations possessed by it have been performed. Chemical and structural properties of ORF8 proteins from different hosts, such as human, bat, and pangolin, suggest that the ORF8 of SARS-CoV-2 is much closer to ORF8 of Bat RaTG13-CoV than to that of Pangolin-CoV. Eighty-seven mutations across unique variants of ORF8 in SARS-CoV-2 can be grouped into four classes based on their predicted effects (Hussain et al., 2021) [1]. Based on the geo-locations and timescale of sample collection, a possible flow of mutations was built. Furthermore, conclusive flows of amalgamation of mutations were found upon sequence similarity analyses and consideration of the amino acid conservation phylogenies. Therefore, this study seeks to highlight the uniqueness of the rapidly evolving SARS-CoV-2 through the ORF8.

The structural basis of accelerated host cell entry by SARS-CoV-2†.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the pandemic coronavirus disease 2019 (COVID-19) that exhibits an overwhelming contagious capacity over other human coronaviruses (HCoVs). This structural snapshot describes the structural bases underlying the pandemic capacity of SARS-CoV-2 and explains its fast motion over respiratory epithelia that allow its rapid cellular entry. Based on notable viral spike (S) protein features, we propose that the flat sialic acid-binding domain at the N-terminal domain (NTD) of the S1 subunit leads to more effective first contact and interaction with the sialic acid layer over the epithelium, and this, in turn, allows faster viral 'surfing' of the epithelium and receptor scanning by SARS-CoV-2. Angiotensin-converting enzyme 2 (ACE-2) protein on the epithelial surface is the primary entry receptor for SARS-CoV-2, and protein-protein interaction assays demonstrate high-affinity binding of the spike protein (S protein) to ACE-2. To date, no high-frequency mutations were detected at the C-terminal domain of the S1 subunit in the S protein, where the receptor-binding domain (RBD) is located. Tight binding to ACE-2 by a conserved viral RBD suggests the ACE2-RBD interaction is likely optimal. Moreover, the viral S subunit contains a cleavage site for furin and other proteases, which accelerates cell entry by SARS-CoV-2. The model proposed here describes a structural basis for the accelerated host cell entry by SARS-CoV-2 relative to other HCoVs and also discusses emerging hypotheses that are likely to contribute to the development of antiviral strategies to combat the pandemic capacity of SARS-CoV-2.

Non-histone substrates of histone deacetylases as potential therapeutic targets in epilepsy.

Introduction: Epilepsy is a network-level neurological disorder characterized by unprovoked recurrent seizures and associated comorbidities. Aberrant activity and localization of histone deacetylases (HDACs) have been reported in epilepsy and HDAC inhibitors (HDACi) have been used for therapeutic purposes. Several non-histone targets of HDACs have been recognized whose reversible acetylation can modulate protein functions and can contribute to disease pathology. Areas covered: This review provides an overview of HDACs in epilepsy and reflects its action on non-histone substrates involved in the pathogenesis of epilepsy and explores the effectiveness of HDACi as anti-epileptic drugs (AEDs). It also covers the efforts undertaken to target the interaction of HDACs with their substrates. We have further discussed non-deacetylase activity possessed by specific HDACs that might be essential in unraveling the molecular mechanism underlying the disease. For this purpose, relevant literature from 1996 to 2020 was derived from PubMed. Expert opinion: The interaction of HDACs and their non-histone substrates can serve as a promising therapeutic target for epilepsy. Pan-HDACi offers limited benefits to the epileptic patients. Thus, identification of novel targets of HDACs contributing to the disease and designing inhibitors targeting these complexes would be more effective and holds a greater potential as an anti-epileptogenic therapy.

Possible Transmission Flow of SARS-CoV-2 Based on ACE2 Features.

Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that is engendering the severe coronavirus disease 2019 (COVID-19) pandemic. The spike (S) protein receptor-binding domain (RBD) of SARS-CoV-2 binds to the three sub-domains viz. amino acids (aa) 22-42, aa 79-84, and aa 330-393 of ACE2 on human cells to initiate entry. It was reported earlier that the receptor utilization capacity of ACE2 proteins from different species, such as cats, chimpanzees, dogs, and cattle, are different. A comprehensive analysis of ACE2 receptors of nineteen species was carried out in this study, and the findings propose a possible SARS-CoV-2 transmission flow across these nineteen species.