scholarly journals Multi-pronged human protein mimicry by SARS-CoV-2 reveals bifurcating potential for MHC detection and immune evasion

2020 ◽  
Author(s):  
AJ Venkatakrishnan ◽  
Nikhil Kayal ◽  
Praveen Anand ◽  
Andrew D. Badley ◽  
George M. Church ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Immune Cells ◽  
Molecular Mimicry ◽  
Human Proteome ◽  
Human Coronavirus ◽  
Human Proteins ◽  
Peptide Mimicry ◽  
Binding Peptides ◽  
Viral Mimicry

The hand of molecular mimicry in shaping SARS-CoV-2 evolution and immune evasion remains to be deciphered. We identify 33 distinct 8-mer/9-mer peptides that are identical between SARS-CoV-2 and human proteomes, along similar extents of viral mimicry observed in other viruses. Interestingly, 20 novel peptides have not been observed in any previous human coronavirus (HCoV) strains. Four of the total mimicked 8-mers/9-mers 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 the targeted genes being focally expressed in arteries, lungs, esophagus, pancreas, and macrophages. Further, HLA-A*03 restricted 8-mer peptides are shared broadly by human and coronaviridae helicases with primary expression of the mimicked human proteins in the neurons and immune cells. This study presents the first comprehensive scan of peptide mimicry by SARS-CoV-2 of the human proteome and motivates follow-up research into its immunological consequences.

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 computational interactome and functional annotation for the human proteome

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
José Ignacio Garzón ◽  
Lei Deng ◽  
Diana Murray ◽  
Sagi Shapira ◽  
Donald Petrey ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Complexes ◽  
Enrichment Analysis ◽  
Human Proteome ◽  
Gene Set Enrichment Analysis ◽  
Protein Protein Interactions ◽  
Functional Relationships ◽  
Structural Relationships ◽  
Human Proteins ◽  
Validation Tests

We present a database, PrePPI (Predicting Protein-Protein Interactions), of more than 1.35 million predicted protein-protein interactions (PPIs). Of these at least 127,000 are expected to constitute direct physical interactions although the actual number may be much larger (~500,000). The current PrePPI, which contains predicted interactions for about 85% of the human proteome, is related to an earlier version but is based on additional sources of interaction evidence and is far larger in scope. The use of structural relationships allows PrePPI to infer numerous previously unreported interactions. PrePPI has been subjected to a series of validation tests including reproducing known interactions, recapitulating multi-protein complexes, analysis of disease associated SNPs, and identifying functional relationships between interacting proteins. We show, using Gene Set Enrichment Analysis (GSEA), that predicted interaction partners can be used to annotate a protein’s function. We provide annotations for most human proteins, including many annotated as having unknown function.

scholarly journals Extracellular Vesicles and Ebola Virus: A New Mechanism of Immune Evasion

Viruses ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 410 ◽  
Author(s):  
Michelle L. Pleet ◽  
Catherine DeMarino ◽  
Spencer W. Stonier ◽  
John M. Dye ◽  
Steven Jacobson ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Immune Evasion ◽  
Immune Cells ◽  
Ebola Virus ◽  
Acute Infection ◽  
Hemorrhagic Fever ◽  
Lymphocyte Apoptosis ◽  
Current Field ◽  
Future Directions ◽  
Pro Inflammatory Cytokines

Ebola virus (EBOV) disease can result in a range of symptoms anywhere from virtually asymptomatic to severe hemorrhagic fever during acute infection. Additionally, spans of asymptomatic persistence in recovering survivors is possible, during which transmission of the virus may occur. In acute infection, substantial cytokine storm and bystander lymphocyte apoptosis take place, resulting in uncontrolled, systemic inflammation in affected individuals. Recently, studies have demonstrated the presence of EBOV proteins VP40, glycoprotein (GP), and nucleoprotein (NP) packaged into extracellular vesicles (EVs) during infection. EVs containing EBOV proteins have been shown to induce apoptosis in recipient immune cells, as well as contain pro-inflammatory cytokines. In this manuscript, we review the current field of knowledge on EBOV EVs including the mechanisms of their biogenesis, their cargo and their effects in recipient cells. Furthermore, we discuss some of the effects that may be induced by EBOV EVs that have not yet been characterized and highlight the remaining questions and future directions.

Advanced Non Small Cell Lung Cancer Patients with Fewer Numbers of Blood Myeloid Dendritic Cells and CD4 Cells Prior to Treatment Have Inferior Progression-Free Survival: Implications for Cancer Immunotherapy

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4837-4837
Author(s):  
Nutan J. DeJoubner ◽  
Qunna Li ◽  
Wayne A.C. Harris ◽  
Zhibo Wang ◽  
Yuan Liu ◽  
...  
Keyword(s):  
Disease Progression ◽  
Progenitor Cells ◽  
Immune Cells ◽  
Advanced Nsclc ◽  
Progression Free Survival ◽  
Study Entry ◽  
Free Survival ◽  
Neutrophil Lymphocyte Ratio ◽  
Lymphocyte Ratio

Abstract Abstract 4837 Background: The tumor microenvironment includes tumor cells, and host-derived endothelial cells, fibroblasts, innate and adaptive immune cells. Tumors may induce neo-vascularization that supports local tumor growth or immune suppression and tolerance that facilitates tumor metastasis. We hypothesized that the patients with higher numbers of circulating CD34+ endothelial progenitor cells (CD34+/CD146+/CD45-, CEC), a cellular bio-marker for vasculogenesis, would have worse post-treatment outcomes and patients with more hematopoietic progenitor cells (CD34+/CD45+/CD45dim/CD133+, HPC) and Immune cells including T-cells would have better outcomes. Methods: We analyzed blood samples from sixty-two patients with advanced NSCLC at 3 time points: before chemotherapy, after cycle one, and at completion of treatment or progression of disease, in an IRB-approved protocol. CEC, HPC, and immune subsets were measured by high throughput multi-parameter flow cytometry, 2.5,000,000 events were acquired using a lyse, no-wash method optimized for rare event detection. Primary outcomes were progression free survival(PFS) and Overall Survival(OS) from the time of study entry. The patient population was stratified into groups based on optimum cut-off point for each cell subset of interest. Statistical analysis was done with log-rank test and Cox regression. Results: Mean age at diagnosis was 64 (37–87 years), 30 events (death) occurred with median follow-up of 9.3 months. Forty-six patients (74%) had disease progression with a median follow-up of 4.7 months. At baseline lower numbers of WBC, Neutrophil lymphocyte ratio(NLR), CEC, HPC were associated with better PFS, while only WBC and Neutrophil lymphocyte ratio (NLR) were associated with a favorable OS. While lower numbers of Immune cells were associated with worse PFS and OS (increased HR death or relapse) in univariate analysis as noted in the Table. Only covariates that were significant and non collinear were entered in the Multivariable model adjusted for age, gender, smoking, race, TNM stage, pathology, and performance status at diagnosis. This showed that baseline numbers of CD4+ T-cell (HR 0.46; 95% CI 0.33–0.98; p= 0.045), Myeloid DC (HR 0.38; 95% CI 0.39–0.81; p=0.012), HPC (continuous variable) (HR 0.78; 95% CI 0.64–0.93; p= 0.008) were significant for disease progression, while NLR was significant for death after study entry (Figure; HR 3; 95% CI 1.45–6.25; p=0 0.003). Conclusions: In patients with advanced NSCLC, lower numbers of HPC and NLR were associated with improved PFS and OS respectively. Lower numbers of immune subsets at diagnosis were associated with inferior outcomes to treatment, supporting the role for immune-mediated disease control. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Poxvirus Targeting of E3 Ligase β-TrCP by Molecular Mimicry: A Mechanism to Inhibit NF-κB Activation and Promote Immune Evasion and Virulence

2013 ◽  
Vol 9 (2) ◽  
pp. e1003183 ◽  
Author(s):  
Daniel S. Mansur ◽  
Carlos Maluquer de Motes ◽  
Leonie Unterholzner ◽  
Rebecca P. Sumner ◽  
Brian J. Ferguson ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Molecular Mimicry ◽  
E3 Ligase

scholarly journals Bioinformatics analysis reveals biophysical and evolutionary insights into the 3-nitrotyrosine post-translational modification in the human proteome

Open Biology ◽  
2013 ◽  
Vol 3 (2) ◽  
pp. 120148 ◽  
Author(s):  
John Y. Ng ◽  
Lies Boelen ◽  
Jason W. H. Wong
Keyword(s):  
Protein Function ◽  
Bioinformatics Analysis ◽  
Proteome Analysis ◽  
Human Proteome ◽  
Prediction Algorithm ◽  
Post Translational Modification ◽  
Tyrosine Residues ◽  
Cellular Processes ◽  
Wide Range ◽  
Human Proteins

Protein 3-nitrotyrosine is a post-translational modification that commonly arises from the nitration of tyrosine residues. This modification has been detected under a wide range of pathological conditions and has been shown to alter protein function. Whether 3-nitrotyrosine is important in normal cellular processes or is likely to affect specific biological pathways remains unclear. Using GPS-YNO2, a recently described 3-nitrotyrosine prediction algorithm, a set of predictions for nitrated residues in the human proteome was generated. In total, 9.27 per cent of the proteome was predicted to be nitratable (27 922/301 091). By matching the predictions against a set of curated and experimentally validated 3-nitrotyrosine sites in human proteins, it was found that GPS-YNO2 is able to predict 73.1 per cent (404/553) of these sites. Furthermore, of these sites, 42 have been shown to be nitrated endogenously, with 85.7 per cent (36/42) of these predicted to be nitrated. This demonstrates the feasibility of using the predicted dataset for a whole proteome analysis. A comprehensive bioinformatics analysis was subsequently performed on predicted and all experimentally validated nitrated tyrosine. This found mild but specific biophysical constraints that affect the susceptibility of tyrosine to nitration, and these may play a role in increasing the likelihood of 3-nitrotyrosine to affect processes, including phosphorylation and DNA binding. Furthermore, examining the evolutionary conservation of predicted 3-nitrotyrosine showed that, relative to non-nitrated tyrosine residues, 3-nitrotyrosine residues are generally less conserved. This suggests that, at least in the majority of cases, 3-nitrotyrosine is likely to have a deleterious effect on protein function and less likely to be important in normal cellular function.

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 Immune Evasion Strategies of Schistosomes

2021 ◽  
Vol 11 ◽  
Author(s):  
Jacob R. Hambrook ◽  
Patrick C. Hanington
Keyword(s):  
Immune Evasion ◽  
Immune Cell ◽  
Molecular Mimicry ◽  
Life Cycles ◽  
Host Responses ◽  
Immune Recognition ◽  
Factors Affecting ◽  
Cell Functions ◽  
Treatment Plans ◽  
Host Parasite

Human schistosomes combat the unique immune systems of two vastly different hosts during their indirect life cycles. In gastropod molluscs, they face a potent innate immune response composed of variable immune recognition molecules and highly phagocytic hemocytes. In humans, a wide variety of innate and adaptive immune processes exist in proximity to these parasites throughout their lifespan. To survive and thrive as the second most common parasitic disease in humans, schistosomes have evolved many techniques to avoid and combat these targeted host responses. Among these techniques are molecular mimicry of host antigens, the utilization of an immune resistant outer tegument, the secretion of several potent proteases, and targeted release of specific immunomodulatory factors affecting immune cell functions. This review seeks to describe these key immune evasion mechanisms, among others, which schistosomes use to survive in both of their hosts. After diving into foundational observational studies of the processes mediating the establishment of schistosome infections, more recent transcriptomic and proteomic studies revealing crucial components of the host/parasite molecular interface are discussed. In order to combat this debilitating and lethal disease, a comprehensive understanding of schistosome immune evasion strategies is necessary for the development of novel therapeutics and treatment plans, necessitating the discussion of the numerous ways in which these parasitic flatworms overcome the immune responses of both hosts.

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.

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