scholarly journals Genetic alteration of human MYH6 is mimicked by SARS-CoV-2 polyprotein: mapping viral variants of cardiac interest

2021 ◽  
Author(s):  
Praveen Anand ◽  
Patrick J. Lenehan ◽  
Michiel Niesen ◽  
Unice Yoo ◽  
Dhruti Patwardhan ◽  
...  
Keyword(s):  
Molecular Mimicry ◽  
Clinical Phenotype ◽  
South Asians ◽  
Viral Evolution ◽  
Cardiac Injury ◽  
Protein Coding ◽  
Cardiac Inflammation ◽  
Splicing Variants ◽  
Human Proteins ◽  
Low Prevalence

AbstractAcute cardiac injury has been observed in a subset of COVID-19 patients, but the molecular basis for this clinical phenotype is unknown. It has been hypothesized that molecular mimicry may play a role in triggering an autoimmune inflammatory reaction in some individuals after SARS-CoV-2 infection. Here we investigate if linear peptides contained in proteins that are primarily expressed in the heart also occur in the SARS-CoV-2 proteome. Specifically, we compared the library of 136,704 8-mer peptides from 144 human proteins (including splicing variants) to 9,926 8-mers from all 17 viral proteins in the reference SARS-CoV-2 proteome. No 8-mers were exactly identical between the reference human proteome and the reference SARS-CoV-2 proteome. However, there were 45 8-mers that differed by only one amino acid when compared to the reference SARS-CoV-2 proteome. Interestingly, analysis of protein-coding mutations from 141,456 individuals showed that one of these 8-mers from the SARS-CoV-2 Replicase polyprotein 1a/1ab (KIALKGGK) is identical to a MYH6 peptide encoded by the c.5410C>A (Q1804K) genetic variation, which has been observed at low prevalence in Africans/African Americans (0.08%), East Asians (0.3%), South Asians (0.06%) and Latino/Admixed Americans (0.003%). Furthermore, analysis of 4.85 million SARS-CoV-2 genomes from over 200 countries shows that viral evolution has already resulted in 20 additional 8-mer peptides that are identical to human heart-enriched proteins encoded by reference sequences or genetic variants. Whether such mimicry contributes to cardiac inflammation during or after COVID-19 illness warrants further experimental evaluation. We suggest that SARS-CoV-2 variants harboring peptides identical to human cardiac proteins should be investigated as ‘viral variants of cardiac interest’.

scholarly journals Ivabradine Induces Cardiac Protection against Myocardial Infarction by Preventing Cyclophilin-A Secretion in Pigs under Coronary Ischemia/Reperfusion

2021 ◽  
Vol 22 (6) ◽  
pp. 2902
Author(s):  
Ignacio Hernandez ◽  
Laura Tesoro ◽  
Rafael Ramirez-Carracedo ◽  
Javier Diez-Mata ◽  
Sandra Sanchez ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Cyclophilin A ◽  
Cardiac Ischemia ◽  
Cardiac Protection ◽  
Cardiac Inflammation ◽  
Risk Areas ◽  
Lysosome Degradation ◽  
Cardiac Necrosis

In response to cardiac ischemia/reperfusion, proteolysis mediated by extracellular matrix metalloproteinase inducer (EMMPRIN) and its secreted ligand cyclophilin-A (CyPA) significantly contributes to cardiac injury and necrosis. Here, we aimed to investigate if, in addition to the effect on the funny current (I(f)), Ivabradine may also play a role against cardiac necrosis by reducing EMMPRIN/CyPA-mediated cardiac inflammation. In a porcine model of cardiac ischemia/reperfusion (IR), we found that administration of 0.3 mg/kg Ivabradine significantly improved cardiac function and reduced cardiac necrosis by day 7 after IR, detecting a significant increase in cardiac CyPA in the necrotic compared to the risk areas, which was inversely correlated with the levels of circulating CyPA detected in plasma samples from the same subjects. In testing whether Ivabradine may regulate the levels of CyPA, no changes in tissue CyPA were found in healthy pigs treated with 0.3 mg/kg Ivabradine, but interestingly, when analyzing the complex EMMPRIN/CyPA, rather high glycosylated EMMPRIN, which is required for EMMPRIN-mediated matrix metalloproteinase (MMP) activation and increased CyPA bonding to low-glycosylated forms of EMMPRIN were detected by day 7 after IR in pigs treated with Ivabradine. To study the mechanism by which Ivabradine may prevent secretion of CyPA, we first found that Ivabradine was time-dependent in inhibiting co-localization of CyPA with the granule exocytosis marker vesicle-associated membrane protein 1 (VAMP1). However, Ivabradine had no effect on mRNA expression nor in the proteasome and lysosome degradation of CyPA. In conclusion, our results point toward CyPA, its ligand EMMPRIN, and the complex CyPA/EMMPRIN as important targets of Ivabradine in cardiac protection against IR.

scholarly journals Whole Transcriptome Analysis of Hypertension Induced Cardiac Injury Using Deep Sequencing

2016 ◽  
Vol 38 (2) ◽  
pp. 670-682 ◽  
Author(s):  
Tao-Tao Li ◽  
Xiao-Yan Li ◽  
Li-Xin Jia ◽  
Jing Zhang ◽  
Wen-Mei Zhang ◽  
...  
Keyword(s):  
Transcriptome Analysis ◽  
Cell Activation ◽  
Critical Role ◽  
Cardiac Injury ◽  
Interaction Network ◽  
Receptor Interaction ◽  
Rna Seq ◽  
Cardiac Inflammation ◽  
Molecular Events ◽  
Focal Adhesion Protein

Background/Aims: Hypertension plays a critical role in the cardiac inflammation and injury. However, the mechanism of how hypertension causes the cardiac injury at a molecular level remains to be elucidated. Methods: RNA-Seq has been demonstrated to be an effective approach for transcriptome analysis, which is essential to reveal the molecular constituents of cells and tissues. In this study, we investigated the global molecular events associated with the mechanism of hypertension induced cardiac injury using RNA-Seq analysis. Results: Our results showed that totally 1,801 genes with different expression variations were identified after Ang II infusion at 1, 3 and 7 days. Go analysis showed that the top 5 high enrichment Go terms were response to stress, response to wounding, cellular component organization, cell activation and defense response. KEGG pathway analysis revealed the top 5 significantly overrepresented pathways were associated with ECM-receptor interaction, focal adhesion, protein digestion and absorption, phagosome and asthma. Moreover, protein-protein interaction network analysis indicated that ubiquitin C may play a key role in the processes of hypertension-induced cardiac injury. Conclusion: Our study provides a comprehensive understanding of the transcriptome events in hypertension-induced cardiac pathology.

scholarly journals Benchmarking evolutionary tinkering underlying human–viral molecular mimicry shows multiple host pulmonary–arterial peptides mimicked by SARS-CoV-2

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
A. J. Venkatakrishnan ◽  
Nikhil Kayal ◽  
Praveen Anand ◽  
Andrew D. Badley ◽  
George M. Church ◽  
...  
Keyword(s):  
Molecular Mimicry ◽  
Herd Immunity ◽  
Computational Framework ◽  
Human Lungs ◽  
Human Proteins ◽  
Peptide Mimicry ◽  
Pulmonary Arterial ◽  
Binding Peptides ◽  
Human Viruses

Abstract The hand of molecular mimicry in shaping SARS-CoV-2 evolution and immune evasion remains to be deciphered. Here, we report 33 distinct 8-mer/9-mer peptides that are identical between SARS-CoV-2 and the human reference proteome. We benchmark this observation against other viral–human 8-mer/9-mer peptide identity, which suggests generally similar extents of molecular mimicry for SARS-CoV-2 and many other human viruses. Interestingly, 20 novel human peptides mimicked by SARS-CoV-2 have not been observed in any previous coronavirus strains (HCoV, SARS-CoV, and MERS). Furthermore, four of the human 8-mer/9-mer peptides mimicked by SARS-CoV-2 map onto HLA-B*40:01, HLA-B*40:02, and HLA-B*35:01 binding peptides from human PAM, ANXA7, PGD, and ALOX5AP proteins. This mimicry of multiple human proteins by SARS-CoV-2 is made salient by single-cell RNA-seq (scRNA-seq) analysis that shows the targeted genes significantly expressed in human lungs and arteries; tissues implicated in COVID-19 pathogenesis. Finally, HLA-A*03 restricted 8-mer peptides are found to be shared broadly by human and coronaviridae helicases in functional hotspots, with potential implications for nucleic acid unwinding upon initial infection. This study presents the first scan of human peptide mimicry by SARS-CoV-2, and via its benchmarking against human–viral mimicry more broadly, presents a computational framework for follow-up studies to assay how evolutionary tinkering may relate to zoonosis and herd immunity.

scholarly journals A Novel Approach To Display Structural Proteins of Hepatitis C Virus Quasispecies in Patients Reveals a Key Role of E2 HVR1 in Viral Evolution

2020 ◽  
Vol 94 (17) ◽  
Author(s):  
Yimin Tong ◽  
Qingchao Li ◽  
Rui Li ◽  
Yongfen Xu ◽  
Yu Pan ◽  
...  
Keyword(s):  
Reverse Genetics ◽  
Vaccine Development ◽  
Viral Evolution ◽  
Hcv Infection ◽  
Clinical Isolates ◽  
Structural Proteins ◽  
Structural Protein ◽  
Protein Coding ◽  
Viral Structural Proteins

ABSTRACT Hepatitis C virus (HCV) infection remains a major worldwide health problem despite development of highly effective direct-acting antivirals. HCV rapidly evolves upon acute infection and generates multiple viral variants (quasispecies), leading to immune evasion and persistent viral infection. Identification of epitopes of broadly neutralizing anti-HCV antibodies (nAbs) is critical to guide HCV vaccine development. In this study, we developed a new reverse genetics system for HCV infection based on trans-complementation of viral structural proteins. The HCV genome (JFH1 strain) lacking the structural protein-coding sequence can be efficiently rescued by ectopic expression of core-E1-E2-p7-NS2 (core-NS2) or core-E1-E2-p7 (core-p7) in trans, leading to production of single-round infectious virions designated HCVΔS. JFH1-based HCVΔS can be also rescued by expressing core-NS2 of other HCV genotypes, rendering it an efficient tool to display the structural proteins of HCV strains of interests. Furthermore, we successfully rescued HCVΔS with structural proteins from clinical isolates. Multiple viral structural proteins with different sensitivities to nAbs were identified from a same patient serum, demonstrating the genetic diversity of HCV quasispecies in vivo. Interestingly, the structural protein-coding sequences of highly divergent viral quasispecies from the same patient can be clustered based on their hypervariable region 1 (HVR1) in viral envelope protein E2, which critically dictates the sensitivity to neutralizing antibodies. In summary, we developed a novel reverse genetics system that efficiently displays viral structural proteins from HCV clinical isolates, and analysis of quasispecies from the same patient using this system demonstrated that E2 HVR1 is the major determinant of viral evolution in vivo. IMPORTANCE A cell culture model that can recapitulate the diversity of HCV quasispecies in patients is important for analysis of neutralizing epitopes and HCV vaccine development. In this study, we developed a new reverse genetics system for HCV infection based on trans-complementation of viral structural proteins (HCVΔS). This system can be used to display structural proteins of HCV strains of multiple genotypes as well as clinical isolates. By using this system, we showed that multiple different HCV structural proteins from a same patient were displayed on HCVΔS. Interestingly, these variant structural proteins within the same patient can be classified according to the sequence of HVR1in E2, which dictates viral sensitivity to nAbs and viral evolution in vivo. Our work provided a new tool to study highly divergent HCV quasispecies and shed light on underlying mechanisms driving HCV evolution.

scholarly journals Cardiac inflammation associated with a Western diet is mediated via activation of RAGE by AGEs

2008 ◽  
Vol 295 (2) ◽  
pp. E323-E330 ◽  
Author(s):  
Christos Tikellis ◽  
Merlin C. Thomas ◽  
Brooke E. Harcourt ◽  
Melinda T. Coughlan ◽  
Josepha Pete ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Hypertrophy ◽  
Fast Food ◽  
Cardiac Injury ◽  
Western Diet ◽  
Cardiomyocyte Hypertrophy ◽  
Standard Diet ◽  
Wild Type ◽  
Cardiac Inflammation ◽  
And Oxidative Stress

A diet high in fat induces cardiac hypertrophy, inflammation, and oxidative stress. Although such actions have largely been ascribed to fat deposition, the accumulation of advanced glycation end products (AGEs) and subsequent activation of the receptor for AGEs (RAGE) may also represent important mediators of cardiac injury following exposure to a Western diet. In this study, male C57BL6J and RAGE knockout mice were placed on either a standard diet (7% fat) or a Western “fast-food” diet (21% fat). Animals receiving a high-fat diet were further randomized to receive the AGE inhibitor alagebrium chloride (1 mg·kg−1·day−1) and followed for 16 wk. A Western diet was associated with cardiac hypertrophy, inflammation, mitochondrial-dependent superoxide production, and cardiac AGE accumulation in wild-type mice. Although RAGE-KO mice fed a Western diet also became obese and accumulated intramyocardial lipid, cardiomyocyte hypertrophy, inflammation, and oxidative stress were attenuated compared with wild-type mice. Similarly, mice of both strains receiving alagebrium chloride had reduced levels of inflammation and oxidative stress, in association with a reduction in cardiac AGEs and RAGE. This study suggests that AGEs represent important mediators of cardiac injury associated with a Western fast-food diet. These data point to the potential utility of AGE-reducing strategies in the prevention and management of cardiac disease.

scholarly journals Revealing missing isoforms encoded in the human genome by integrating genomic, transcriptomic and proteomic data

2014 ◽  
Author(s):  
Zhiqiang Hu ◽  
Hamish S. Scott ◽  
Guangrong Qin ◽  
Guangyong Zheng ◽  
Xixia Chu ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Shotgun Proteomics ◽  
Proteomics Data ◽  
Protein Coding ◽  
Novel Proteins ◽  
Proteomic Data ◽  
Human Genes ◽  
Human Proteins ◽  
Novel Transcripts ◽  
Coding Potential

Biological and biomedical research relies on comprehensive understanding of protein-coding transcripts. However, the total number of human proteins is still unknown due to the prevalence of alternative splicing and is much larger than the number of human genes. In this paper, we detected 31,566 novel transcripts with coding potential by filtering our ab initio predictions with 50 RNA-seq datasets from diverse tissues/cell lines. PCR followed by MiSeq sequencing showed that at least 84.1% of these predicted novel splice sites could be validated. In contrast to known transcripts, the expression of these novel transcripts were highly tissue-specific. Based on these novel transcripts, at least 36 novel proteins were detected from shotgun proteomics data of 41 breast samples. We also showed L1 retrotransposons have a more significant impact on the origin of new transcripts/genes than previously thought. Furthermore, we found that alternative splicing is extraordinarily widespread for genes involved in specific biological functions like protein binding, nucleoside binding, neuron projection, membrane organization and cell adhesion. In the end, the total number of human transcripts with protein-coding potential was estimated to be at least 204,950.

scholarly journals Human to yeast pathway transplantation: cross-species dissection of the adenine de novo pathway regulatory node

2017 ◽  
Author(s):  
Neta Agmon ◽  
Jasmine Temple ◽  
Zuojian Tang ◽  
Tobias Schraink ◽  
Maayan Baron ◽  
...  
Keyword(s):  
Yeast Strain ◽  
Transcriptional Control ◽  
De Novo ◽  
Enzyme Level ◽  
Yeast Cells ◽  
Protein Coding ◽  
Coding Regions ◽  
Human Proteins ◽  
Human Ortholog ◽  
Yeast Genes

AbstractPathway transplantation from one organism to another represents a means to a more complete understanding of a biochemical or regulatory process. The purine biosynthesis pathway, a core metabolic function, was transplanted from human to yeast. We replaced the entireSaccharomyces cerevisiaeadenine de novo pathway with the cognate human pathway components. A yeast strain was “humanized” for the full pathway by deleting all relevant yeast genes completely and then providing the human pathway in trans using a neochromosome expressing the human protein coding regions under the transcriptional control of their cognate yeast promoters and terminators. The “humanized” yeast strain grows in the absence of adenine, indicating complementation of the yeast pathway by the full set of human proteins. While the strain with the neochromosome is indeed prototrophic, it grows slowly in the absence of adenine. Dissection of the phenotype revealed that the human ortholog ofADE4, PPAT, shows only partial complementation. We have used several strategies to understand this phenotype, that point toPPAT/ADE4as the central regulatory node. Pathway metabolites are responsible for regulatingPPAT’sprotein abundance through transcription and proteolysis as well as its enzymatic activity by allosteric regulation in these yeast cells. Extensive phylogenetic analysis of PPATs from diverse organisms hints at adaptations of the enzyme-level regulation to the metabolite levels in the organism. Finally, we isolated specific mutations in PPAT as well as in other genes involved in the purine metabolic network that alleviate incomplete complementation byPPATand provide further insight into the complex regulation of this critical metabolic pathway.

scholarly journals Selectively expressing SARS-CoV-2 Spike protein S1 subunit in cardiomyocytes induces cardiac hypertrophy in mice.

2021 ◽  
Author(s):  
Steven G. Negron ◽  
Chase W. Kessinger ◽  
Bing Xu ◽  
William T. Pu ◽  
Zhiqiang Lin
Keyword(s):  
Immune Responses ◽  
Cardiac Injury ◽  
Innate Immune ◽  
Spike Protein ◽  
Innate Immune Responses ◽  
Toll Like Receptor 4 ◽  
Cardiac Inflammation ◽  
Leucine Rich Repeats ◽  
Recognition Receptor

Cardiac injury is common in hospitalized COVID-19 patients and portends poorer prognosis and higher mortality. To better understand how SARS-CoV-2 (CoV-2) damages the heart, it is critical to elucidate the biology of CoV-2 encoded proteins, each of which may play multiple pathological roles. For example, CoV-2 Spike glycoprotein (CoV-2-S) not only engages ACE2 to mediate virus infection, but also directly impairs endothelial function and can trigger innate immune responses in cultured murine macrophages. Here we tested the hypothesis that CoV-2-S damages the heart by activating cardiomyocyte (CM) innate immune responses. HCoV-NL63 is another human coronavirus with a Spike protein (NL63-S) that also engages ACE2 for virus entry but is known to only cause moderate respiratory symptoms. We found that CoV-2-S and not NL63-S interacted with Toll-like receptor 4 (TLR4), a crucial pattern recognition receptor that responsible for detecting pathogen and initiating innate immune responses. Our data show that the S1 subunit of CoV-2-S (CoV-2-S1) interacts with the extracellular leucine rich repeats-containing domain of TLR4 and activates NF-kB. To investigate the possible pathological role of CoV-2-S1 in the heart, we generated a construct that expresses membrane-localized CoV-2-S1 (S1-TM). AAV9-mediated, selective expression of the S1-TM in CMs caused heart dysfunction, induced hypertrophic remodeling, and elicited cardiac inflammation. Since CoV-2-S does not interact with murine ACE2, our study presents a novel ACE2-independent pathological role of CoV-2-S, and suggests that the circulating CoV-2-S1 is a TLR4-recognizable alarmin that may harm the CMs by triggering their innate immune responses.

scholarly journals Molecular Mimicry Map (3M) of SARS-CoV-2: Prediction of potentially immunopathogenic SARS-CoV-2 epitopes via a novel immunoinformatic approach

2020 ◽  
Author(s):  
Hyunsu An ◽  
Jihwan Park
Keyword(s):  
T Cell ◽  
Autoimmune Diseases ◽  
Web Application ◽  
Molecular Mimicry ◽  
Sequence Similarity ◽  
Protein Structures ◽  
Cross Reactivity ◽  
T Cell Epitopes ◽  
B Cell Epitopes ◽  
Human Proteins

ABSTRACTCurrently, more than 33 million peoples have been infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and more than a million people died from coronavirus disease 2019 (COVID-19), a disease caused by the virus. There have been multiple reports of autoimmune and inflammatory diseases following SARS-CoV-2 infections. There are several suggested mechanisms involved in the development of autoimmune diseases, including cross-reactivity (molecular mimicry). A typical workflow for discovering cross-reactive epitopes (mimotopes) starts with a sequence similarity search between protein sequences of human and a pathogen. However, sequence similarity information alone is not enough to predict cross-reactivity between proteins since proteins can share highly similar conformational epitopes whose amino acid residues are situated far apart in the linear protein sequences. Therefore, we used a hidden Markov model-based tool to identify distant viral homologs of human proteins. Also, we utilized experimentally determined and modeled protein structures of SARS-CoV-2 and human proteins to find homologous protein structures between them. Next, we predicted binding affinity (IC50) of potentially cross-reactive T-cell epitopes to 34 MHC allelic variants that have been associated with autoimmune diseases using multiple prediction algorithms. Overall, from 8,138 SARS-CoV-2 genomes, we identified 3,238 potentially cross-reactive B-cell epitopes covering six human proteins and 1,224 potentially cross-reactive T-cell epitopes covering 285 human proteins. To visualize the predicted cross-reactive T-cell and B-cell epitopes, we developed a web-based application “Molecular Mimicry Map (3M) of SARS-CoV-2” (available at https://ahs2202.github.io/3M/). The web application enables researchers to explore potential cross-reactive SARS-CoV-2 epitopes alongside custom peptide vaccines, allowing researchers to identify potentially suboptimal peptide vaccine candidates or less ideal part of a whole virus vaccine to design a safer vaccine for people with genetic and environmental predispositions to autoimmune diseases. Together, the computational resources and the interactive web application provide a foundation for the investigation of molecular mimicry in the pathogenesis of autoimmune disease following COVID-19.

scholarly journals Protective Effect of miR-204 on Doxorubicin-Induced Cardiomyocyte Injury via HMGB1

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Youyou Du ◽  
Guanghui Liu ◽  
Luosha Zhao ◽  
Rui Yao
Keyword(s):  
Myocardial Injury ◽  
Cardiac Injury ◽  
Protective Effects ◽  
Cardiac Inflammation ◽  
Hmgb1 Expression ◽  
Adenoassociated Virus ◽  
New Treatment ◽  
Virus System

The toxicity of doxorubicin (DOX) limits its clinical application. Nevertheless, at present, there is no effective drug to prevent DOX-induced cardiac injury. miR-204 is a newly discovered miRNA with many protective effects on cardiovascular diseases. However, little research has been done on the effects of miR-204 on DOX-induced cardiac injury. Our study is aimed at investigating the effect of miR-204 on DOX-induced myocardial injury. An adenoassociated virus system was used to achieve cardiac-specific overexpression of miR-204. Two weeks later, the mice were intraperitoneally injected with DOX (15 mg/kg) to induce cardiac injury. H9c2 myocardial cells were used to validate the role of miR-204 in vitro. Our study showed that miR-204 expression was decreased in DOX-treated hearts. miR-204 overexpression improved cardiac function and alleviated cardiac inflammation, apoptosis, and autophagy induced by DOX. In addition, our results showed that miR-204 prevented DOX-induced injury in cardiomyocytes by directly decreasing HMGB1 expression. Moreover, the overexpression of HMGB1 could offset the protective effects of miR-204 against DOX-induced cardiac injury. In summary, our study showed that miR-204 protected against DOX-induced cardiac injury via the inhibition of HMGB1, and increasing miR-204 expression may be a new treatment option for patients with DOX-induced cardiac injury.

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