Human molecular chaperones share with SARS-CoV-2 antigenic epitopes potentially capable of eliciting autoimmunity against endothelial cells: possible role of molecular mimicry in COVID-19.
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ABSTRACT:
SUBMITTER: Marino Gammazza A
PROVIDER: S-EPMC7402394 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe gut microbiota profile is unique for each individual and are composed by different bacteria species according to individual birth-to-infant transitions. In the last years, the local and systemic effects of microbiota on cancer onset, progression and response to treatments, such as immunotherapies, has been extensively described. Here we offer a new perspective, proposing a role for the microbiota based on the molecular mimicry of tumor associated antigens by microbiome-associated antigens.MethodsIn the present study we looked for homology between published TAAs and non-self microbiota-derived epitopes. Blast search for sequence homology was combined with extensive bioinformatics analyses.ResultsSeveral evidences for homology between TAAs and microbiota-derived antigens have been found. Strikingly, three cases of 100% homology between the paired sequences has been identified. The predicted average affinity to HLA molecules of microbiota-derived antigens is very high (< 100 nM). The structural conformation of the microbiota-derived epitopes is, in general, highly similar to the corresponding TAA. In some cases, it is identical and contact areas with both HLA and TCR chains are indistinguishable. Moreover, the spatial conformation of TCR-facing residues can be identical in paired TAA and microbiota-derived epitopes, with exactly the same values of planar as well as dihedral angles.ConclusionsThe data reported in the present study show for the first time the high homology in the linear sequence as well as in structure and conformation between TAAs and peptides derived from microbiota species of the Firmicutes and the Bacteroidetes phyla, which together account for 90% of gut microbiota. Cross-reacting CD8+ T cell responses are very likely induced. Therefore, the anti-microbiota T cell memory may turn out to be an anti-cancer T cell memory, able to control the growth of a cancer developed during the lifetime if the expressed TAA is similar to the microbiota epitope. This may ultimately represent a relevant selective advantage for cancer patients and may lead to a novel preventive anti-cancer vaccine strategy.
| S-EPMC9281086 | biostudies-literature
Project description:BackgroundPeople living with HIV/AIDS (PLWHA) show a reduced incidence for three cancer types, namely breast, prostate and colon cancers. In the present study, we assessed whether a molecular mimicry between HIV epitopes and tumor associated antigens and, consequently, a T cell cross-reactivity could provide an explanation for such an epidemiological evidence.MethodsHomology between published TAAs and non-self HIV-derived epitopes have been assessed by BLAST homology. Structural analyses have been performed by bioinformatics tools. Immunological validation of CD8+ T cell cross-reactivity has been evaluated ex vivo by tetramer staining.FindingsSequence homologies between multiple TAAs and HIV epitopes have been found. High structural similarities between the paired TAAs and HIV epitopes as well as comparable patterns of contact with HLA and TCR α and β chains have been observed. Furthermore, cross-reacting CD8+ T cells have been identified.InterpretationThis is the first study showing a molecular mimicry between HIV antigens an TAAs identified in breast, prostate and colon cancers. Therefore, it is highly reasonable that memory CD8+ T cells elicited during the HIV infection may play a key role in controlling development and progression of such cancers in the PLWHA lifetime. This represents the first demonstration ever that a viral infection may induce a natural "preventive" anti-cancer memory T cells, with highly relevant implications beyond the HIV infection.
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Project description:Type 1 narcolepsy (T1N) is caused by hypocretin/orexin (HCRT) neuronal loss. Association with the HLA DQB1*06:02/DQA1*01:02 (98% vs. 25%) heterodimer (DQ0602), T cell receptors (TCR) and other immune loci suggest autoimmunity but autoantigens are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1) infection and vaccination (Pandemrix). Peptides derived from HCRT and influenza A, including pH1N1, were screened for DQ0602 binding and presence of cognate DQ0602 tetramer-peptide-specific CD4+ T cells tested in 35 T1N cases and 22 DQ0602 controls. Higher reactivity to influenza pHA273-287 (pH1N1 specific), PR8 (H1N1 pre-2009 and H2N2)-specific NP17-31 and C-amidated but not native version of HCRT54-66 and HCRT86-97 (HCRTNH2) were observed in T1N. Single-cell TCR sequencing revealed sharing of CDR3? TRBV4-2-CASSQETQGRNYGYTF in HCRTNH2 and pHA273-287-tetramers, suggesting molecular mimicry. This public CDR3? uses TRBV4-2, a segment modulated by T1N-associated SNP rs1008599, suggesting causality. TCR-?/? CDR3 motifs of HCRT54-66-NH2 and HCRT86-97-NH2 tetramers were extensively shared: notably public CDR3?, TRAV2-CAVETDSWGKLQF-TRAJ24, that uses TRAJ24, a chain modulated by T1N-associated SNPs rs1154155 and rs1483979. TCR-?/? CDR3 sequences found in pHA273-287, NP17-31, and HCRTNH2 tetramer-positive CD4+ cells were also retrieved in single INF-?-secreting CD4+ sorted cells stimulated with Pandemrix, independently confirming these results. Our results provide evidence for autoimmunity and molecular mimicry with flu antigens modulated by genetic components in the pathophysiology of T1N.
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Project description:Alphaviral infections are foremost in causing debilitating clinical outcomes in humans characterized by rheumatic arthritis like conditions. Though the presence of virus in joints and associated inflammation has been implicated as one of the reasons for the acute and chronic polyarthritis post alphaviral infections, the basis for rheumatic like outcomes is not clear. Through an in silico analysis, we have investigated the possibility of an autoimmune process mediated through molecular mimicry in alphaviral infection induced pathogenicity. Interestingly, sequence alignment of the structural polyproteins belonging to arthritogenic alphaviruses revealed conserved regions which share homology with human proteins implicated in rheumatoid arthritis (RA). These conserved regions were predicted to exhibit binding to HLA class II alleles, showcasing their potential to incite T cell help. Molecular docking of the viral peptide and the corresponding homologous region in the human protein onto HLA-DRB1 revealed strong similarities in their binding patterns. Linear and conformational B cell epitope prediction analyses showed that these potential mimics have high propensity to elicit an efficient B cell response. We thus propose that the origin of polyarthritis post-arthritogenic alphaviral infections may also be mediated through a hitherto unknown autoimmune response due to the presence of cross-reactive epitopes between viral and human proteins.
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Project description:The association of immune thrombocytopenia (ITP) with cancer has been reported, but the causality of tumor cells in paraneoplastic ITP pathogenesis and maintenance has never been established. We analyzed the unusual case of refractory ITP and coincident urothelial tumor of the kidney with circulating high titer anti-GPIIBIIIA autoantibodies. Intriguingly, after nephrectomy, the patient recovered fully and her anti-GPIIBIIIA autoantibodies disappeared. Proteomic and immunohistochemistry analyses revealed erratic GPIIB expression by the tumor cells, suggesting possible antigenic mimicry chronically stimulating the immune system and leading to this patient's refractory ITP. Such previously unreported findings provide proof-of-concept that requires further confirmation with the prospective study of a larger number of patients.
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Project description:Molecular mimicry between viral antigens and host proteins can produce cross-reacting antibodies leading to autoimmunity. The coronavirus SARS-CoV-2 causes COVID-19, a disease curiously resulting in varied symptoms and outcomes, ranging from asymptomatic to fatal. Autoimmunity due to cross-reacting antibodies resulting from molecular mimicry between viral antigens and host proteins may provide an explanation. Thus, we computationally investigated molecular mimicry between SARS-CoV-2 Spike and known epitopes. We discovered molecular mimicry hotspots in Spike and highlight two examples with tentative high autoimmune potential and implications for understanding COVID-19 complications. We show that a TQLPP motif in Spike and thrombopoietin shares similar antibody binding properties. Antibodies cross-reacting with thrombopoietin may induce thrombocytopenia, a condition observed in COVID-19 patients. Another motif, ELDKY, is shared in multiple human proteins, such as PRKG1 involved in platelet activation and calcium regulation, and tropomyosin, which is linked to cardiac disease. Antibodies cross-reacting with PRKG1 and tropomyosin may cause known COVID-19 complications such as blood-clotting disorders and cardiac disease, respectively. Our findings illuminate COVID-19 pathogenesis and highlight the importance of considering autoimmune potential when developing therapeutic interventions to reduce adverse reactions.
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Project description:In Escherichia coli, the molecular chaperones DnaK and DnaJ cooperate to assist the folding of newly synthesized or unfolded polypeptides. DnaK and DnaJ bind to hydrophobic motifs in these proteins and they also bind to each other. Together, this system is thought to be sufficiently versatile to act on the entire proteome, which creates interesting challenges in understanding the interactions between DnaK, DnaJ and their thousands of potential substrates. To address this question, we computationally predicted the number and frequency of DnaK- and DnaJ-binding motifs in the E. coli proteome, guided by free energy-based binding consensus motifs. This analysis revealed that nearly every protein is predicted to contain multiple DnaK- and DnaJ-binding sites, with the DnaJ sites occurring approximately twice as often. Further, we found that an overwhelming majority of the DnaK sites partially or completely overlapped with the DnaJ-binding motifs. It is well known that high concentrations of DnaJ inhibit DnaK-DnaJ-mediated refolding. The observed overlapping binding sites suggest that this phenomenon may be explained by an important balance in the relative stoichiometry of DnaK and DnaJ. To test this idea, we measured the chaperone-assisted folding of two denatured substrates and found that the distribution of predicted DnaK- and DnaJ-binding sites was indeed a good predictor of the optimal stoichiometry required for folding. These studies provide insight into how DnaK and DnaJ might cooperate to maintain global protein homeostasis.
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Project description:Understanding etiology of autoimmune diseases has been a great challenge for designing drugs and vaccines. The pathophysiology of many autoimmune diseases may be attributed to molecular mimicry provoked by microbes. Molecular mimicry hypothesizes that a sequence homology between foreign and self-peptides leads to cross-activation of autoreactive T cells. Different microbial proteins are implicated in various autoimmune diseases, including multiple sclerosis, human type 1 diabetes, primary biliary cirrhosis and rheumatoid arthritis. It may be imperative to identify the microbial epitopes that initiate the activation of autoreactive T cells. Consequently, in the present study, we employed immunoinformatics tools to delineate homologous antigenic regions between microbes and human proteins at not only the sequence level but at the structural level too. Interestingly, many cross-reactive MHC class II binding epitopes were detected from an array of microbes. Further, these peptides possess a potential to skew immune response toward Th1-like patterns. The present study divulges many microbial target proteins, their putative MHC-binding epitopes, and predicted structures to establish the fact that both sequence and structure are two important aspects for understanding the relationship between molecular mimicry and autoimmune diseases. Such findings may enable us in designing potential immunotherapies to tolerize autoreactive T cells.
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Project description:Immunoglobulin molecules specifically recognize particular areas on the surface of proteins. These areas are commonly dubbed B-cell epitopes. The identification of epitopes in proteins is important both for the design of experiments and vaccines. Additionally, the interactions between epitopes and antibodies have often served as a model for protein-protein interactions. One of the main obstacles in creating a database of antigen-antibody interactions is the difficulty in distinguishing between antigenic and non-antigenic interactions. Antigenic interactions involve specific recognition sites on the antibody's surface, while non-antigenic interactions are between a protein and any other site on the antibody. To solve this problem, we performed a comparative analysis of all protein-antibody complexes for which structures have been experimentally determined. Additionally, we developed a semi-automated tool that identified the antigenic interactions within the known antigen-antibody complex structures. We compiled those interactions into Epitome, a database of structure-inferred antigenic residues in proteins. Epitome consists of all known antigen/antibody complex structures, a detailed description of the residues that are involved in the interactions, and their sequence/structure environments. Interactions can be visualized using an interface to Jmol. The database is available at http://www.rostlab.org/services/epitome/.
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Project description:Epidemiological studies and meta-analyses have shown a strong association between high seroprevalence of Toxoplasma gondii (T. gondii) and schizophrenia. Schizophrenic patients showed higher levels of anti-Toxoplasma immunoglobulins M and G (IgM and IgG) when compared to healthy controls. Previously, in a rat model, we demonstrated that the progeny of mothers immunized with T. gondii lysates before gestation had behavioral and social impairments during adulthood. Therefore, we suggested that T. gondii infection can trigger autoreactivity by molecularly mimicking host brain proteins. Here, we aimed to identify the occurrence of antigenic mimicry between T. gondii epitopes and host brain proteins. Using a bioinformatic approach, we predicted T. gondii RH-88 B cell epitopes and compared them to human cell-surface proteins involved in brain development and differentiation (BrainS). Five different algorithms for B-cell-epitope prediction were used and compared, resulting in 8584 T. gondii epitopes. We then compared T. gondii predicted epitopes to BrainS proteins by local sequence alignments using BLASTP. T. gondii immunogenic epitopes significantly overlapped with 42 BrainS proteins. Among these overlapping proteins essential for brain development and differentiation, we identified HSP90 and NOTCH receptors as the proteins most likely to be targeted by the maternally generated pathogenic antibodies due to their topological overlap at the extracellular region of their sequence. This analysis highlights the relevance of pregestational clinical surveillance and screening for potential pathogenic anti-T. gondii antibodies. It also identifies potential targets for the design of vaccines that could prevent behavioral and cognitive impairments associated with pre-gestational T. gondii exposure.
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