ABSTRACT
The SARS-CoV-2 P.1 variant, responsible for an outbreak in Manaus, Brazil, is distinguished by 12 amino acid differences in the S protein, potentially increasing its ACE-2 affinity and immune evasion capability. We investigated the innate immune response of this variant compared to the original B.1 strain, particularly concerning cytokine production. Blood samples from three severe COVID-19 patients were analyzed post-infection with both strains. Results showed no significant difference in cytokine production of mononuclear cells and neutrophils for either variant. While B.1 had higher cytopathogenicity, neither showed viral replication in mononuclear cells. Structural analyses of the S protein highlighted physicochemical variations, which might be linked to the differences in infectivity between the strains. Our studies point to the increased infectivity of P.1 could stem from altered immunogenicity and receptor-binding affinity.
Subject(s)
Alleles , Alopecia , HLA-B Antigens , T-Lymphocytes , Humans , Alopecia/genetics , Brazil , T-Lymphocytes/immunology , HLA-B Antigens/genetics , Female , Fibrosis , MaleABSTRACT
OBJECTIVE: Describe the development, implementation, and utilization of dashboards for epidemiological analysis through open data research during the COVID-19 pandemic. METHODS: The dashboards were designed to analyze COVID-19 related public data from various sources, including official government data and social media, at world level. Data processing and cleaning techniques were used to join datasets. We calculated Spearman correlation coefficient between the COVID-like symptoms data of the University of Maryland and Facebook Health research, called COVID Trends and Impacts Survey (CTIS) and the official data of notified COVID-19 cases by the Brazilian Health Ministry. RESULTS: The dashboards were successful in predicting the onset of new waves of COVID-19 in Brazil. The data analysis revealed a correlation between the CTIS and the official number of cases the country. This article shows the potential of interactive dashboards as a decision-making tool in the context of public health emergencies, as it was used by the official communication of the Rio Grande do Sul state government. CONCLUSION: The use of dashboards for predicting the spread of COVID-19 in Brazil was a useful tool for decision-making. To anticipate waves of the disease gives time so that these decisions can be potentially more assertive. This drafts the need of more interdisciplinary actions of this nature, with visualization tools on epidemiologic research.
Subject(s)
COVID-19 , Dashboard Systems , Humans , Brazil/epidemiology , COVID-19/epidemiology , Government , Pandemics , Public HealthABSTRACT
ABSTRACT Objective: Describe the development, implementation, and utilization of dashboards for epidemiological analysis through open data research during the COVID-19 pandemic. Methods: The dashboards were designed to analyze COVID-19 related public data from various sources, including official government data and social media, at world level. Data processing and cleaning techniques were used to join datasets. We calculated Spearman correlation coefficient between the COVID-like symptoms data of the University of Maryland and Facebook Health research, called COVID Trends and Impacts Survey (CTIS) and the official data of notified COVID-19 cases by the Brazilian Health Ministry. Results: The dashboards were successful in predicting the onset of new waves of COVID-19 in Brazil. The data analysis revealed a correlation between the CTIS and the official number of cases the country. This article shows the potential of interactive dashboards as a decision-making tool in the context of public health emergencies, as it was used by the official communication of the Rio Grande do Sul state government. Conclusion: The use of dashboards for predicting the spread of COVID-19 in Brazil was a useful tool for decision-making. To anticipate waves of the disease gives time so that these decisions can be potentially more assertive. This drafts the need of more interdisciplinary actions of this nature, with visualization tools on epidemiologic research.
RESUMO Objetivo: Descrever o desenvolvimento, a implementação e o uso de painéis para a análise epidemiológica de dados abertos durante a pandemia de COVID-19. Métodos: Os painéis foram criados para analisar dados públicos relacionados á COVID-19 de várias fontes, incluindo dados oficiais dos governos e de redes sociais, a nível global. Técnicas de processamento e limpeza foram utilizadas para aglutinar os bancos de dados. Calculamos o coeficiente de correlação de Spearman entre as curvas de sintomas gripais da pesquisa da Universidade de Maryland em conjunto com o Facebook, chamada COVID Trends and Impacts Survey (CTIS), e a curva de casos notificados pelo Ministério da Saúde no Brasil. Resultados: Os painéis obtiveram sucesso em antecipar a chegada de novas ondas de COVID-19 no Brasil. A análise do dado revelou a correlação entre a pesquisa CTIS e o número oficial de casos no país. O artigo destaca o potencial de painéis interativos como uma ferramenta de tomada de decisão no contexto de emergências de saúde pública, como, por exemplo, no uso destes para a comunicação oficial do governo do Rio Grande do Sul. Conclusão: O uso de painéis para prever o avanço da COVID-19 no Brasil foi uma ferramenta útil para a tomada de decisão. A antecipação de ondas da doença possibilita tempo oportuno para que essas decisões sejam potencialmente mais assertivas. Isso esboça a necessidade de mais ações interdisciplinares dessa natureza, com ferramentas de visualização nas pesquisas epidemiológicas.
ABSTRACT
The therapeutic targeting of the immune system, for example in vaccinology and cancer treatment, is a challenging task and the subject of active research. Several in silico tools used for predicting immunogenicity are based on the analysis of peptide sequences binding to the Major Histocompatibility Complex (pMHC). However, few of these bioinformatics tools take into account the pMHC three-dimensional structure. Here, we describe a new bioinformatics tool, MatchTope, developed for predicting peptide similarity, which can trigger cross-reactivity events, by computing and analyzing the electrostatic potentials of pMHC complexes. We validated MatchTope by using previously published data from in vitro assays. We thereby demonstrate the strength of MatchTope for similarity prediction between targets derived from several pathogens as well as for indicating possible cross responses between self and tumor peptides. Our results suggest that MatchTope can enhance and speed up future studies in the fields of vaccinology and cancer immunotherapy.
Subject(s)
Major Histocompatibility Complex , Peptides , Histocompatibility Antigens , Cross Reactions , Amino Acid SequenceABSTRACT
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disclose the variants of concern (VOC) including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P1), Delta (B.1.617.2), and Omicron (B.1.1.529). Its spike protein (S) present on the surface of the virus is recognized by the host cell receptor, the angiotensin-2 converting enzyme (ACE2) which promotes their entry into the cell. The mutations presented by VOCs are found in RBD and the N-terminal region of S protein. Therefore, mutations occurring in RBD can modify the biological and immunogenic characteristics of the virus, such as modifying the spike affinity for ACE2, increasing the virus transmissibility, or conferring the ability to escape the immune responses. The raise of a potential new SARS-CoV-2 variant capable of evading the host defenses at the same time maintaining its fitness justifies the importance of continued genetic monitoring of the pandemic coronavirus.
Subject(s)
COVID-19 , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/genetics , Humans , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/geneticsABSTRACT
COVID-19 brought scenes from sci-fi movies into real life. Infected individuals include asymptomatic cases to severe disease leading to death, suggesting the involvement of the genetic constitution of populations and pathogens contributing to differential individuals' outcomes. To investigate shared immunogenic features between SARS-CoV-2 targets and other coronaviruses, we modeled their peptides in 3D structures of HLA-A*02:01 (pMHC), comparing their molecular surfaces These structures were also compared with a panel of epitopes from unrelated viruses, looking for potential triggers conferring cross-protection in uninfected individuals. As expected, SARS-CoV 1 and 2 peptides share molecular and physicochemical features, providing an explanation for the verified experimental immunogenicity among them. Surprisingly, even discordant sequences from human coronaviruses 229E, OC43 and epitopes from unrelated viruses involved in endemic human infections exhibit similar fingerprints of immunogenicity with SARS-CoV-2 peptides. The same approach indicates a conserved CD8+ T cell recognition between Wuhan SARS-CoV-2 sequences and altered peptides from Variants of Concern. Examination of structural data over epitope sequence analysis here could explain how previous infections may produce a heterologous immunity response in a global scale against emergent diseases such as Covid-19, mitigating its full lethal potential, and paves the way for the development of wide spectrum vaccine development.
Subject(s)
COVID-19 , SARS-CoV-2 , Antigens, Viral , Epitopes , Humans , PeptidesABSTRACT
We aimed to describe the SARS-CoV-2 lineages circulating early pandemic among samples with S gene dropout and characterize the receptor-binding domain (RBD) of viral spike protein. Adults and children older than 2 months with signs and symptoms of COVID-19 were prospectively enrolled from May to October in Porto Alegre, Brazil. All participants performed RT-PCR assay, and samples with S gene dropout and cycle threshold < 30 were submitted to high-throughput sequencing (HTS). 484 out of 1,557 participants tested positive for SARS-CoV-2. The S gene dropout was detected in 7.4% (36/484) and a peak was observed in August. The B.1.1.28, B.1.91 and B.1.1.33 lineages were circulating in early pandemic. The RBD novel mutation (Y380Q) was found in one sample occurring simultaneously with C379W and V395A, and the B.1.91 lineage in the spike protein. The Y380Q and C379W may interfere with the binding of neutralizing antibodies (CR3022, EY6A, H014, S304).
Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Antibodies, Monoclonal , Antibodies, Neutralizing , Antibodies, Viral , Child , Humans , Infant , Mutation , Protein Binding , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/geneticsABSTRACT
The interaction of HIV-1, human leukocyte antigen (HLA), and elite controllers (EC) compose a still intricate triad. Elite controllers maintain a very low viral load and a normal CD4 count, even without antiretrovirals. There is a lot of diversity in HIV subtypes and HLA alleles. The most common subtype in each country varies depending on its localization and epidemiological history. As we know EC appears to maintain an effective CD8 response against HIV. In this phenomenon, some alleles of HLAs are associated with a slow progression of HIV infection, others with a rapid progression. This relationship also depends on the virus subtype. Epitopes of Gag protein-restricted by HLA-B*57 generated a considerable immune response in EC. However, some mutations allow HIV to escape the CD8 response, while others do not. HLA protective alleles, like HLA-B*27, HLA-B*57 and HLA-B*58:01, that are common in Caucasians infected with HIV-1 Clade B, do not show the same protection in sub-Saharan Africans infected by HIV-1 Clade C. Endogenous pathway of antigen processing and presentation is used to present intracellular synthesized cellular peptides as well as viral protein fragments via the MHC class I molecule to the cytotoxic T-lymphocytes (CTLs). Some epitopes are immunodominant, which means that they drive the immune reaction to some virus. Mutation on an anchor residue of epitope necessary for binding on MHC class I is used by HIV to escape the immune system. Mutations inside or flanking an epitope may lead to T cell lack of recognition and CTL escape. Studying how immunodominance at epitopes drives the EC in a geographically dependent way with genetics and immunological elements orchestrating it may help future research on vaccines or immunotherapy for HIV.
Subject(s)
HIV Infections , HIV-1 , CD8-Positive T-Lymphocytes , HIV Infections/drug therapy , HIV Infections/genetics , HIV-1/genetics , Humans , T-Lymphocytes, Cytotoxic , Viral Load , gag Gene Products, Human Immunodeficiency VirusABSTRACT
The interaction of HIV-1, human leukocyte antigen (HLA), and elite controllers (EC) compose a still intricate triad. Elite controllers maintain a very low viral load and a normal CD4 count, even without antiretrovirals. There is a lot of diversity in HIV subtypes and HLA alleles. The most common subtype in each country varies depending on its localization and epidemiological history. As we know EC appears to maintain an effective CD8 response against HIV. In this phenomenon, some alleles of HLAs are associated with a slow progression of HIV infection, others with a rapid progression. This relationship also depends on the virus subtype. Epitopes of Gag protein-restricted by HLA-B*57 generated a considerable immune response in EC. However, some mutations allow HIV to escape the CD8 response, while others do not. HLA protective alleles, like HLA-B*27, HLA-B*57 and HLA-B*58:01, that are common in Caucasians infected with HIV-1 Clade B, do not show the same protection in sub-Saharan Africans infected by HIV-1 Clade C. Endogenous pathway of antigen processing and presentation is used to present intracellular synthesized cellular peptides as well as viral protein fragments via the MHC class I molecule to the cytotoxic T-lymphocytes (CTLs). Some epitopes are immunodominant, which means that they drive the immune reaction to some virus. Mutation on an anchor residue of epitope necessary for binding on MHC class I is used by HIV to escape the immune system. Mutations inside or flanking an epitope may lead to T cell lack of recognition and CTL escape. Studying how immunodominance at epitopes drives the EC in a geographically dependent way with genetics and immunological elements orchestrating it may help future research on vaccines or immunotherapy for HIV. 2021 Sociedade Brasileira de Infectologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license
Subject(s)
HIV Infections/genetics , HIV Infections/drug therapy , HIV-1/genetics , T-Lymphocytes, Cytotoxic , CD8-Positive T-Lymphocytes , Viral Load , gag Gene Products, Human Immunodeficiency VirusABSTRACT
Esophageal squamous cell carcinoma (ESCA) exhibits high intratumoral molecular heterogeneity posing a challenge to cancer therapy. Immune checkpoint blockade therapy has been approved for this disease, but with modest results. RNA-Seq data from paired tumor and surrounding nonmalignant tissue from 14 patients diagnosed with ESCA without previous treatment and from The Cancer Genome Atlas-ESCA cohort were analyzed. Herein, we investigated ESCA immune landscape including mutation-derived neoantigens and immune cell subpopulations. Tumor-associated antigen expression was determined by in silico analyses and confirmed by immunohistochemistry showing that PRAME, CEACAM4, and MAGEA11 proteins are expressed on tumors. Immune checkpoint molecules gene expression was higher in the tumor compared with surrounding nonmalignant tissue, but its expression varies greatly among patients. TCR repertoire and BCR transcripts analysis evidenced low clonal diversity with one TCR clone predicted to be specific for a MAGEA11-derived peptide. A high number of B-cell clones infiltrating the tumors and the abundance of these cells in tertiary lymphoid structures observed in ESCA tumors support B cells as a potential immune modulator in this tumor.
Subject(s)
Antigens, Neoplasm/immunology , B-Lymphocytes/immunology , Esophageal Neoplasms/immunology , Esophageal Squamous Cell Carcinoma/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Receptors, Antigen, T-Cell/immunology , Tertiary Lymphoid Structures/immunology , Tumor Microenvironment/immunology , B-Lymphocytes/pathology , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma/pathology , Female , Humans , Lymphocytes, Tumor-Infiltrating/pathology , Male , RNA-Seq , Tertiary Lymphoid Structures/pathologyABSTRACT
The world is dealing with one of the worst pandemics ever. SARS-CoV-2 is the etiological agent of COVID-19 that has already spread to more than 200 countries. However, infectivity, severity, and mortality rates do not affect all countries equally. Here we consider 140 HLA alleles and extensively investigate the landscape of 3,723 potential HLA-I A and B restricted SARS-CoV-2-derived antigens and how 37 countries in the world are predicted to respond to those peptides considering their HLA-I distribution frequencies. The clustering of HLA-A and HLA-B allele frequencies partially separates most countries with the lowest number of deaths per million inhabitants from the other countries. We further correlated the patterns of in silico predicted population coverage and epidemiological data. The number of deaths per million inhabitants correlates to the predicted antigen coverage of S and N derived peptides and its module is influenced if a given set of frequent or rare HLA alleles are analyzed in a given population. Moreover, we highlighted a potential risk group carrying HLAs associated with an elevated number of deaths per million inhabitants. In addition, we identified three potential antigens bearing at least one amino acid of the four-length insertion that differentiates SARS-CoV-2 from previous coronavirus strains. We believe these data can contribute to the search for peptides with the potential to be used in vaccine strategies considering the role of herd immunity to hamper the spread of the disease. Importantly, to the best of our knowledge, this work is the first to use a populational approach in association with COVID-19 outcome.
Subject(s)
Antigens, Viral , COVID-19 , Coronavirus Nucleocapsid Proteins , HLA-A Antigens , HLA-B Antigens , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Antigens, Viral/genetics , Antigens, Viral/immunology , COVID-19/genetics , COVID-19/immunology , COVID-19/mortality , Computer Simulation , Coronavirus Nucleocapsid Proteins/immunology , Female , Gene Frequency , HLA-A Antigens/genetics , HLA-A Antigens/immunology , HLA-B Antigens/genetics , HLA-B Antigens/immunology , Humans , Male , Phosphoproteins/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunologyABSTRACT
The amino acid sequence of DNMT2 is very similar to the catalytic domains of bacterial and eukaryotic proteins. However, there is great variability in the region of recognition of the target sequence. While bacterial DNMT2 acts as a DNA methyltransferase, previous studies have indicated low DNA methylation activity in eukaryotic DNMT2, with preference by tRNA methylation. Drosophilids are known as DNMT2-only species and the DNA methylation phenomenon is a not elucidated case yet, as well as the ontogenetic and physiologic importance of DNMT2 for this species group. In addition, more recently study showed that methylation in the genome in Drosophila melanogaster is independent in relation to DNMT2. Despite these findings, Drosophilidae family has more than 4,200 species with great ecological diversity and historical evolution, thus we, therefore, aimed to examine the drosophilids DNMT2 in order to verify its conservation at the physicochemical and structural levels in a functional context. We examined the twenty-six DNMT2 models generated by molecular modelling and five crystallographic structures deposited in the Protein Data Bank (PDB) using different approaches. Our results showed that despite sequence and structural similarity between species close related, we found outstanding differences when they are analyzed in the context of surface distribution of electrostatic properties. The differences found in the electrostatic potentials may be linked with different affinities and processivity of DNMT2 for its different substrates (DNA, RNA or tRNA) and even for interactions with other proteins involved in the epigenetic mechanisms.
Subject(s)
DNA (Cytosine-5-)-Methyltransferases/chemistry , Drosophila Proteins/chemistry , Epigenesis, Genetic , Protein Conformation , Static Electricity , Amino Acid Sequence , Animals , DNA (Cytosine-5-)-Methyltransferases/metabolism , Drosophila Proteins/metabolism , Drosophila melanogaster , Kinetics , Models, Molecular , PhylogenyABSTRACT
The immune system is constantly challenged, being required to protect the organism against a wide variety of infectious pathogens and, at the same time, to avoid autoimmune disorders. One of the most important molecules involved in these events is the Major Histocompatibility Complex class I (MHC-I), responsible for binding and presenting small peptides from the intracellular environment to CD8(+) T cells. The study of peptide:MHC-I (pMHC-I) molecules at a structural level is crucial to understand the molecular mechanisms underlying immunologic responses. Unfortunately, there are few pMHC-I structures in the Protein Data Bank (PDB) (especially considering the total number of complexes that could be formed combining different peptides), and pMHC-I modelling tools are scarce. Here, we present DockTope, a free and reliable web-based tool for pMHC-I modelling, based on crystal structures from the PDB. DockTope is fully automated and allows any researcher to construct a pMHC-I complex in an efficient way. We have reproduced a dataset of 135 non-redundant pMHC-I structures from the PDB (Cα RMSD below 1 Å). Modelling of pMHC-I complexes is remarkably important, contributing to the knowledge of important events such as cross-reactivity, autoimmunity, cancer therapy, transplantation and rational vaccine design.
Subject(s)
CD8-Positive T-Lymphocytes/metabolism , Computational Biology/methods , Histocompatibility Antigens Class I/metabolism , Internet , Peptides/metabolism , Algorithms , Amino Acid Sequence , Databases, Protein , Epitopes/chemistry , Epitopes/genetics , Epitopes/metabolism , Histocompatibility Antigens Class I/chemistry , Histocompatibility Antigens Class I/genetics , Humans , Models, Molecular , Peptides/chemistry , Protein Binding , Protein Domains , Reproducibility of ResultsABSTRACT
Oxytocin is a nonapeptide involved in a wide range of physiologic and behavioral functions. Until recently, it was believed that an unmodified oxytocin sequence was present in all placental mammals. This study analyzed oxytocin (OXT) in 29 primate species and the oxytocin receptor (OXTR) in 21 of these species. We report here three novel OXT forms in the New World monkeys, as well as a more extensive distribution of a previously described variant (Leu8Pro). In structural terms, these OXTs share the same three low-energy conformations in solution during molecular dynamic simulations, with subtle differences in their side chains. A consistent signal of positive selection was detected in the Cebidae family, and OXT position 8 showed a statistically significant (P = 0.013) correlation with litter size. Several OXTR changes were identified, some of them promoting gain or loss of putative phosphorylation sites, with possible consequences for receptor internalization and desensitization. OXTR amino acid sites are under positive selection, and intramolecular and intermolecular coevolutionary processes with OXT were also detected. We suggest that some New World monkey OXT-OXTR forms can be correlated to male parental care through the increase of cross-reactivity with its correlated vasopressin system.
Subject(s)
Evolution, Molecular , Oxytocin/genetics , Primates/genetics , Receptors, Oxytocin/genetics , Selection, Genetic , Amino Acid Sequence , Animals , Base Sequence , Male , Molecular Sequence Data , Oxytocin/chemistryABSTRACT
The CrossTope is a highly curate repository of three-dimensional structures of peptide:major histocompatibility complex (MHC) class I complexes (pMHC-I). The complexes hosted by this databank were obtained in protein databases and by large-scale in silico construction of pMHC-I structures, using a new approach developed by our group. At this moment, the database contains 182 'non-redundant' pMHC-I complexes from two human and two murine alleles. A web server provides interface for database query. The user can download (i) structure coordinate files and (ii) topological and charges distribution maps images from the T-cell receptor-interacting surface of pMHC-I complexes. The retrieved structures and maps can be used to cluster similar epitopes in cross-reactivity approaches, to analyse viral escape mutations in a structural level or even to improve the immunogenicity of tumour antigens. Database URL: http://www.crosstope.com.br.
Subject(s)
Databases, Protein , Major Histocompatibility Complex/immunology , Models, Molecular , Peptides/chemistry , Peptides/immunology , Animals , Cross Reactions/immunology , Crystallography, X-Ray , Humans , Information Storage and Retrieval , Mice , Multivariate Analysis , Software Design , User-Computer InterfaceABSTRACT
The Bunyaviridae virus family is composed by five genera, of which the Hantavirus genus is one of the most important representatives. Occasionally, these viruses can be transmitted to humans, giving rise to severe diseases that present high mortality rates. We analyzed the amino acid sequences of the nucleocapsid (N) proteins of 34 different hantaviruses to investigate the potential mechanisms involved in immunogenicity against hantaviruses. Immunogenic epitopes described in the literature through experimental analyses for Sin Nombre (SNV), Puumala (PUUV), and Hantaan (HTNV) viruses' species were retrieved. We identified and characterized the regions believed to be responsible for the induction of immune response in hosts. We found that N protein epitopes described in the literature for PUUV, SNV and HTNV viruses are all located in highly conserved regions of the protein. The high conservation of these regions suggests that a cross-reactive immune response among different hantaviruses can be induced.