SARS-CoV-2 structural coverage map reveals viral protein assembly, mimicry, and hijacking mechanisms

Abstract We modeled 3D structures of all SARS‐CoV‐2 proteins, generating 2,060 models that span 69% of the viral proteome and provide details not available elsewhere. We found that ˜6% of the proteome mimicked human proteins, while ˜7% was implicated in hijacking mechanisms that reverse post‐translational modifications, block host translation, and disable host defenses; a further ˜29% self‐assembled into heteromeric states that provided insight into how the viral replication and translation complex forms. To make these 3D models more accessible, we devised a structural coverage map, a novel visualization method to show what is—and is not—known about the 3D structure of the viral proteome. We integrated the coverage map into an accompanying online resource (https://aquaria.ws/covid) that can be used to find and explore models corresponding to the 79 structural states identified in this work. The resulting Aquaria‐COVID resource helps scientists use emerging structural data to understand the mechanisms underlying coronavirus infection and draws attention to the 31% of the viral proteome that remains structurally unknown or dark

SARS-CoV-2 structural coverage map reveals viral protein assembly, mimicry, and hijacking mechanisms

We modeled 3D structures of all SARS-CoV-2 proteins, generating 2,060 models that span 69% of the viral proteome and provide details not available elsewhere. We found that ˜6% of the proteome mimicked human proteins, while ˜7% was implicated in hijacking mechanisms that reverse post-translational modifications, block host translation, and disable host defenses; a further ˜29% self-assembled into heteromeric states that provided insight into how the viral replication and translation complex forms. To make these 3D models more accessible, we devised a structural coverage map, a novel visualization method to show what is-and is not-known about the 3D structure of the viral proteome. We integrated the coverage map into an accompanying online resource (https://aquaria.ws/covid) that can be used to find and explore models corresponding to the 79 structural states identified in this work. The resulting Aquaria-COVID resource helps scientists use emerging structural data to understand the mechanisms underlying coronavirus infection and draws attention to the 31% of the viral proteome that remains structurally unknown or dark

The Role of Molecular Chaperones in Virus Infection and Implications for Understanding and Treating COVID-19

The COVID-19 pandemic made imperative the search for means to end it, which requires a knowledge of the mechanisms underpinning the multiplication and spread of its cause, the coronavirus SARS-CoV-2. Many viruses use members of the hosts' chaperoning system to infect the target cells, replicate, and spread, and here we present illustrative examples. Unfortunately, the role of chaperones in the SARS-CoV-2 cycle is still poorly understood. In this review, we examine the interactions of various coronaviruses during their infectious cycle with chaperones in search of information useful for future research on SARS-CoV-2. We also call attention to the possible role of molecular mimicry in the development of autoimmunity and its widespread pathogenic impact in COVID-19 patients. Viral proteins share highly antigenic epitopes with human chaperones, eliciting anti-viral antibodies that crossreact with the chaperones. Both, the critical functions of chaperones in the infectious cycle of viruses and the possible role of these molecules in COVID-19 autoimmune phenomena, make clear that molecular chaperones are promising candidates for the development of antiviral strategies. These could consist of inhibiting-blocking those chaperones that are necessary for the infectious viral cycle, or those that act as autoantigens in the autoimmune reactions causing generalized destructive effects on human tissues

Structural similarity between thyroid peroxidase [Homo sapiens] and SARS-CoV-2 spike glycoprotein: An autoimmune thyroiditis triggering mechanism in COVID-19 carriers?

Introduction: there are reports of autoimmune disease related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) such neurological syndromes and hematological syndromes, and more recently autoimmune thyroid dysfunctions have been described. These reports suggest that SARS-CoV-2 acts as a probable trigger for triggering the autoimmunity process. Aim: to evaluate structural similarity between thyroid peroxidase [Homo sapiens] (TPO) and SARS-CoV-2 spike glycoprotein (COVID-19), and to propose this similarity as a likely trigger for autoimmune thyroiditis. Methodology: using bioinformatics tools, we compare the amino acids (AA) sequences between protein structure of TPO and chain A COVID-19, chain B COVID-19, and chain C COVID-19, accessible in the National Center for Biotechnology Information database, by Basic Local Alignment Search Tool in order to locate the homologous regions between the sequences of AA. Results: the homology sequence between the TPO and COVID-19 ranged from 27.0 % (10 identical residues out of 37 AA in the sequence) to 56.0% (5 identical residues out of 9 AA in the sequence). The similar alignments demonstrated relatively high E values in function of short alignment. Conclusion: data suggest a possible pathological link between TPO and COVID-19. The structural similarity of AA sequences between TPO and COVID-19 may present a molecular mimicry suggesting the possibility of antigen crossover between TPO and COVID-19 that might represent an immunological basis for autoimmune thyroiditis associated with COVID-19

Peptide Mimicrying Between SARS Coronavirus Spike Protein and Human Proteins Reacts with SARS Patient Serum

Molecular mimicry, defined as similar structures shared by molecules from dissimilar genes or proteins, is a general strategy used by pathogens to infect host cells. Severe acute respiratory syndrome (SARS) is a new human respiratory infectious disease caused by SARS coronavirus (SARS-CoV). The spike (S) protein of SARS-CoV plays an important role in the virus entry into a cell. In this study, eleven synthetic peptides from the S protein were selected based on its sequence homology with human proteins. Two of the peptides D07 (residues 927–937) and D08 (residues 942–951) were recognized by the sera of SARS patients. Murine hyperimmune sera against these peptides bound to proteins of human lung epithelial cells A549. Another peptide D10 (residues 490–502) stimulated A549 to proliferate and secrete IL-8. The present results suggest that the selected S protein regions, which share sequence homology with human proteins, may play important roles in SARS-CoV infection

Insights to Protein Pathogenicity from the Lens of Protein Evolution

As protein sequences evolve, differences in selective constraints may lead to outcomes ranging from sequence conservation to structural and functional divergence. Evolutionary protein family analysis can illuminate which protein regions are likely to diverge or remain conserved in sequence, structure, and function. Moreover, nonsynonymous mutations in pathogens may result in the emergence of protein regions that affect the behavior of pathogenic proteins within a host and host response. I aimed to gain insight on pathogenic proteins from cancer and viruses using an evolutionary perspective. First, I examined p53, a conformationally flexible, multifunctional protein mutated in ~50% of human cancers. Multifunctional proteins may experience rapid sequence divergence given trade-offs between functions, while proteins with important functions may be more constrained. How, then, does a protein like p53 evolve? I assessed the evolutionary dynamics of structural and regulatory properties in the p53 family, revealing paralog-specific patterns of functional divergence. I also studied flaviviruses, like Dengue and Zika virus, whose conformational flexibility contributes to antibody-dependent enhancement (ADE). ADE has long complicated vaccine development for these viruses, making antiviral drug development an attractive alternative. I identified fitness-critical sites conserved in sequence and structure in the proteome of flaviviruses with the potential to act as broadly neutralizing antiviral drug target sites. I later developed Epitopedia, a computational method for epitope-based prediction of molecular mimicry. Molecular mimicry occurs when regions of antigenic proteins resemble protein regions from the host or other pathogens, leading to antibody cross-reactivity at these sites which can result in autoimmunity or have a protective effect. I applied Epitopedia to the antigenic Spike protein from SARS-CoV-2, the causative agent of COVID-19. Molecular mimicry may explain the varied symptoms and outcomes seen in COVID-19 patients. I found instances of molecular mimicry in Spike associated with COVID-19-related blood-clotting disorders and cardiac disease, with implications on disease treatment and vaccine design

Does sars-cov-2 trigger stress-induced autoimmunity by molecular mimicry? A hypothesis

Viruses can generate molecular mimicry phenomena within their hosts. Why should severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) not be considered one of these? Information in this short review suggests that it might be so and, thus, encourages research aiming at testing this possibility. We propose, as a working hypothesis, that the virus induces antibodies and that some of them crossreact with host’s antigens, thus eliciting autoimmune phenomena with devasting consequences in various tissues and organs. If confirmed, by in vitro and in vivo tests, this could drive researchers to find effective treatments against the virus

Endothelial Cell Contributions to COVID-19

Understanding of the clinical, histological and molecular features of the novel coronavirus 2019 (Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)) has remained elusive. Coronavirus disease 2019 (COVID-19) caused by this virus has unusual clinical presentation with regard to other related coronaviruses. Recent reports suggest that SARS-CoV-2, unlike other related viruses, infects and replicates within endothelial cells, which may explain a significant portion of the observed clinical pathology. Likewise, mounting evidence associates vascular and endothelial cell dysfunction with increased mortality. This review focuses on understanding how endothelial cell pathology is caused by SARS-CoV-2 at the molecular and cellular levels and how these events relate to COVID-19. A detailed examination of current knowledge regarding canonical inflammatory reaction pathways as well as alteration of endothelial cell-derived exosomes and transdifferentiation by SARS-CoV-2 is included in this assessment. Additionally, given an understanding of endothelial contributions to COVID-19, potential therapeutic aims are discussed, particularly as would affect endothelial function and pathology

Differential patterns of cross-reactive antibody response against SARS-CoV-2 spike protein detected for chronically ill and healthy COVID-19 naive individuals

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