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1.
Cell Stress Chaperones ; 25(5): 701-705, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32889638

RESUMO

Near the end of 2019, SARS-CoV-2, a novel highly contagious coronavirus phylogenetically related to the SARS virus, entered the human population with lethal consequences. This special issue devoted to the resulting disease COVID-19 was not planned but instead the articles accumulated organically as researchers in the cell stress response field noticed similarities among the pathophysiology of COVID-19 infections and the responses that they studied in contexts unrelated to viral infection. We preface the issue with an introductory article which begins with a brief review of the structure and biology of SARS-CoV-2. As we collected and compared the COVID-19 articles, several shared themes emerged. In the second part of the introduction, each article is summarized briefly and the common themes that link each into a spontaneously arising chain of ideas and hypotheses are emphasized. These themes include growing evidence of molecular mimicry among the viral proteins and the proteins of patients. The realization that much of the consequences of such immune mimicry may play out on the plasma membrane of vascular endothelial cells raised the specter of autoimmune-induced vascular endothelial damage in multiple organs. Proposals of new therapeutic approaches have coalesced around the theme of inducing protection of the vascular endothelium. New chemical treatments that are proposed include stannous chloride, inducers of the gasotransmitter hydrogen sulfide such as sodium thiosulfate and inducers of the cytoprotective stress protein heme oxygenase. Oxygen delivered by ventilators is already in extensive use to provide life support for patients with severe COVID-19. Two articles propose to advance the use of oxygen to the level of a therapeutic treatment early in the detection of the virus in infected patients by delivering oxygen under elevated pressure in hyperbaric chambers. At elevated blood plasma concentrations, hyperbaric oxygen is capable of achieving results far beyond the capability of ventilators as it promotes the activation of transcription factors that control the establishment of inducible cellular defense systems.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Coronavirus , Células Endoteliais/imunologia , Oxigênio/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Proteínas Virais/imunologia , Coronavirus/classificação , Coronavirus/imunologia , Células Endoteliais/citologia , Humanos , Pandemias
2.
Proc Natl Acad Sci U S A ; 117(39): 24384-24391, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32913053

RESUMO

An improved understanding of human T cell-mediated immunity in COVID-19 is important for optimizing therapeutic and vaccine strategies. Experience with influenza shows that infection primes CD8+ T cell memory to peptides presented by common HLA types like HLA-A2, which enhances recovery and diminishes clinical severity upon reinfection. Stimulating peripheral blood mononuclear cells from COVID-19 convalescent patients with overlapping peptides from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the clonal expansion of SARS-CoV-2-specific CD8+ and CD4+ T cells in vitro, with CD4+ T cells being robust. We identified two HLA-A*02:01-restricted SARS-CoV-2-specfic CD8+ T cell epitopes, A2/S269-277 and A2/Orf1ab3183-3191 Using peptide-HLA tetramer enrichment, direct ex vivo assessment of A2/S269 +CD8+ and A2/Orf1ab3183 +CD8+ populations indicated that A2/S269 +CD8+ T cells were detected at comparable frequencies (∼1.3 × 10-5) in acute and convalescent HLA-A*02:01+ patients. These frequencies were higher than those found in uninfected HLA-A*02:01+ donors (∼2.5 × 10-6), but low when compared to frequencies for influenza-specific (A2/M158) and Epstein-Barr virus (EBV)-specific (A2/BMLF1280) (∼1.38 × 10-4) populations. Phenotyping A2/S269 +CD8+ T cells from COVID-19 convalescents ex vivo showed that A2/S269 +CD8+ T cells were predominantly negative for CD38, HLA-DR, PD-1, and CD71 activation markers, although the majority of total CD8+ T cells expressed granzymes and/or perforin. Furthermore, the bias toward naïve, stem cell memory and central memory A2/S269 +CD8+ T cells rather than effector memory populations suggests that SARS-CoV-2 infection may be compromising CD8+ T cell activation. Priming with appropriate vaccines may thus be beneficial for optimizing CD8+ T cell immunity in COVID-19.


Assuntos
Betacoronavirus/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/imunologia , Antígeno HLA-A2/imunologia , Pneumonia Viral/imunologia , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T , Feminino , Humanos , Memória Imunológica , Imunofenotipagem , Leucócitos Mononucleares/imunologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Pandemias , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Proteínas Virais/química , Proteínas Virais/imunologia
3.
J Med Microbiol ; 69(9): 1183-1196, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32812860

RESUMO

Introduction. PCV2 is a DNA virus that exists widely in pigs and has caused great economic losses to the pig industry worldwide. In the existing commercial PCV2 enzyme-linked immunosorbent assay (ELISA) kits both natural infection with PCV2 and vaccine immunization produce results that are positive for PCV2 Cap antibodies and therefore they cannot diagnose PCV2 infection in immunized pig farms.Aim. To establish a PCV2 non-structural protein antibody detection method that distinguishes between antibodies resulting from natural prior exposure (infection) and those induced by subunit vaccine immunization.Methodology. Based on the non-structural Rep' protein, we established an indirect ELISA (iELISA) using sera from guinea pigs and piglets.Results. The results for iELISA for guinea pig serum showed that animals vaccinated with a whole-virus inactivated PCV2 vaccine had 100 % (10/10) Cap antibody positivity and 100 % (10/10) Rep' antibody positivity. Guinea pigs vaccinated with a recombinant subunit PCV2 vaccine had 100 % (10/10) Cap antibody positivity, while no (0/10) guinea pigs were Rep' antibody-positive. The combined detection results for the Rep' iELISA and a PCV2 Antibody Test kit (Commercial) showed that pigs vaccinated with a whole-virus inactivated PCV2 vaccine or PCV2 SD/2017 had 100 % (5/5) Cap antibody positivity and 100 % (5/5) Rep' antibody positivity. Pigs vaccinated with a recombinant subunit PCV2 vaccine had 100 % (5/5) Cap antibody positivity, while no (0/10) pigs were Rep' antibody-positive.Conclusion. This paper describes an effective iELISA method that can distinguish natural infection with PCV2 (Cap and Rep positive) or inoculation with a whole-virus inactivated vaccine (Cap and Rep positive) from subunit vaccine immunization (Cap-positive, Rep-negative). These comparative assays could be very useful in the control of PCV2 in pig herds.


Assuntos
Anticorpos Antivirais/imunologia , Infecções por Circoviridae/sangue , Infecções por Circoviridae/veterinária , Circovirus/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Doenças dos Suínos/sangue , Proteínas Virais/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/análise , Infecções por Circoviridae/imunologia , Circovirus/genética , Imunização , Suínos , Doenças dos Suínos/imunologia , Doenças dos Suínos/virologia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/genética , Vacinas de Subunidades/imunologia , Proteínas Virais/administração & dosagem , Proteínas Virais/genética , Vacinas Virais/administração & dosagem , Vacinas Virais/genética
4.
PLoS Pathog ; 16(8): e1008703, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776994

RESUMO

Herpes simplex virus type 1 (HSV1) is a complicated structural agent with a sophisticated transcription process and a high infection rate. A vaccine against HSV1 is urgently needed. As multiple viral-encoded proteins, including structural and nonstructural proteins, contribute to immune response stimulation, an attenuated or deficient HSV1 vaccine may be relatively reliable. Advances in genomic modification technologies provide reliable means of constructing various HSV vaccine candidates. Based on our previous work, an M6 mutant with mutations in the UL7, UL41, LAT, Us3, Us11 and Us12 genes was established. The mutant exhibited low proliferation in cells and an attenuated phenotype in an animal model. Furthermore, in mice and rhesus monkeys, the mutant can induce remarkable serum neutralizing antibody titers and T cell activation and protect against HSV1 challenge by impeding viral replication, dissemination and pathogenesis.


Assuntos
Vacinas contra o Vírus do Herpes Simples/imunologia , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Animais , Feminino , Herpes Simples/prevenção & controle , Herpes Simples/virologia , Vacinas contra o Vírus do Herpes Simples/administração & dosagem , Vacinas contra o Vírus do Herpes Simples/genética , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Mutação , Fenótipo , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Proteínas Virais/administração & dosagem , Proteínas Virais/genética , Proteínas Virais/imunologia
5.
J Immunol ; 205(6): 1564-1579, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32747502

RESUMO

Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic human coronavirus causing severe disease and mortality. MERS-CoV infection failed to elicit robust IFN response, suggesting that the virus might have evolved strategies to evade host innate immune surveillance. In this study, we identified and characterized type I IFN antagonism of MERS-CoV open reading frame (ORF) 8b accessory protein. ORF8b was abundantly expressed in MERS-CoV-infected Huh-7 cells. When ectopically expressed, ORF8b inhibited IRF3-mediated IFN-ß expression induced by Sendai virus and poly(I:C). ORF8b was found to act at a step upstream of IRF3 to impede the interaction between IRF3 kinase IKKε and chaperone protein HSP70, which is required for the activation of IKKε and IRF3. An infection study using recombinant wild-type and ORF8b-deficient MERS-CoV further confirmed the suppressive role of ORF8b in type I IFN induction and its disruption of the colocalization of HSP70 with IKKε. Ectopic expression of HSP70 relieved suppression of IFN-ß expression by ORF8b in an IKKε-dependent manner. Enhancement of IFN-ß induction in cells infected with ORF8b-deficient virus was erased when HSP70 was depleted. Taken together, HSP70 chaperone is important for IKKε activation, and MERS-CoV ORF8b suppresses type I IFN expression by competing with IKKε for interaction with HSP70.


Assuntos
Ativação Enzimática/imunologia , Quinase I-kappa B/imunologia , Interferon Tipo I/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Proteínas Virais/imunologia , Betacoronavirus , Linhagem Celular , Infecções por Coronavirus , Proteínas de Choque Térmico HSP70/imunologia , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Quinase I-kappa B/metabolismo , Interferon Tipo I/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/metabolismo , Pandemias , Pneumonia Viral , Proteínas Virais/metabolismo
6.
Clin Immunol ; 219: 108572, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32810602

RESUMO

Human Leukocyte Antigen (HLA) includes a large set of genes with important actions in immune response against viral infection. Numerous studies have revealed the existence of significant associations between certain HLA alleles and the susceptibility and prognosis of different infectious diseases. In this pilot study we analyse the binding affinity between 66 class I HLA alleles and SARS-CoV-2 viral peptides, and its association with the severity of the disease. A total of 45 Spanish patients with mild, moderate and severe SARS-CoV-2 infection were typed for HLA class I; after that, we analysed if an in silico model of HLA I-viral peptide binding affinity and classical HLA supertypes could be correlated to the severity of the disease. Our results suggest that patients with mild disease present Class I HLA molecules with a higher theoretical capacity for binding SARS-Cov-2 peptides and showed greater heterozygosity when comparing them with moderate and severe groups. In this regard, identifying HLA-SARS-CoV-2 peptides binding differences between individuals would help to clarify the heterogeneity of clinical responses to the disease and will also be useful to guide a personalized treatment according to its particular risk.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/genética , Antígenos de Histocompatibilidade Classe I/genética , Interações Hospedeiro-Patógeno/imunologia , Pneumonia Viral/genética , Proteínas Virais/genética , Adulto , Idoso , Alelos , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Progressão da Doença , Feminino , Expressão Gênica , Frequência do Gene , Antígenos de Histocompatibilidade Classe I/classificação , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunidade Inata , Masculino , Pessoa de Meia-Idade , Pandemias , Peptídeos/genética , Peptídeos/imunologia , Projetos Piloto , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Ligação Proteica , Índice de Gravidade de Doença , Espanha , Proteínas Virais/imunologia
7.
Sci Rep ; 10(1): 14179, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843695

RESUMO

A novel coronavirus (SARS-CoV-2) emerged from China in late 2019 and rapidly spread across the globe, infecting millions of people and generating societal disruption on a level not seen since the 1918 influenza pandemic. A safe and effective vaccine is desperately needed to prevent the continued spread of SARS-CoV-2; yet, rational vaccine design efforts are currently hampered by the lack of knowledge regarding viral epitopes targeted during an immune response, and the need for more in-depth knowledge on betacoronavirus immunology. To that end, we developed a computational workflow using a series of open-source algorithms and webtools to analyze the proteome of SARS-CoV-2 and identify putative T cell and B cell epitopes. Utilizing a set of stringent selection criteria to filter peptide epitopes, we identified 41 T cell epitopes (5 HLA class I, 36 HLA class II) and 6 B cell epitopes that could serve as promising targets for peptide-based vaccine development against this emerging global pathogen. To our knowledge, this is the first study to comprehensively analyze all 10 (structural, non-structural and accessory) proteins from SARS-CoV-2 using predictive algorithms to identify potential targets for vaccine development.


Assuntos
Betacoronavirus/imunologia , Biologia Computacional , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/imunologia , Interações Hospedeiro-Patógeno/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Proteínas Virais/imunologia , Sequência de Aminoácidos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Betacoronavirus/classificação , Betacoronavirus/genética , Betacoronavirus/metabolismo , Biologia Computacional/métodos , Infecções por Coronavirus/metabolismo , Epitopos de Linfócito B/química , Epitopos de Linfócito T/química , Genoma Viral , Genômica/métodos , Humanos , Modelos Moleculares , Pandemias , Peptídeos/química , Peptídeos/imunologia , Filogenia , Pneumonia Viral/metabolismo , Relação Estrutura-Atividade , Linfócitos T/imunologia , Linfócitos T/metabolismo , Vacinas de Subunidades/imunologia , Proteínas Virais/química , Vacinas Virais/imunologia
8.
Cell Stress Chaperones ; 25(5): 737-741, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32754823

RESUMO

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), the cause of COVID-19 disease, has the potential to elicit autoimmunity because mimicry of human molecular chaperones by viral proteins. We compared viral proteins with human molecular chaperones, many of which are heat shock proteins, to determine if they share amino acid-sequence segments with immunogenic-antigenic potential, which can elicit cross-reactive antibodies and effector immune cells with the capacity to damage-destroy human cells by a mechanism of autoimmunity. We identified the chaperones that can putatively participate in molecular mimicry phenomena after SARS-CoV-2 infection, focusing on those for which endothelial cell plasma-cell membrane localization has already been demonstrated. We also postulate that post-translational modifications, induced by physical (shear) and chemical (metabolic) stress caused respectively by the risk factors hypertension and diabetes, might have a role in determining plasma-cell membrane localization and, in turn, autoimmune-induced endothelial damage.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/virologia , Proteínas de Choque Térmico , Pneumonia Viral/virologia , Proteínas Virais , Sequência de Aminoácidos , Autoantígenos , Autoimunidade , Bases de Dados de Proteínas , Células Endoteliais/metabolismo , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/imunologia , Humanos , Epitopos Imunodominantes , Mimetismo Molecular , Pandemias , Proteínas Virais/química , Proteínas Virais/imunologia
9.
Front Immunol ; 11: 1784, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849643

RESUMO

COVID-19 has recently become the most serious threat to public health, and its prevalence has been increasing at an alarming rate. The incubation period for the virus is ~1-14 days and all age groups may be susceptible to a fatality rate of about 5.9%. COVID-19 is caused by a novel single-stranded, positive (+) sense RNA beta coronavirus. The development of a vaccine for SARS-CoV-2 is an urgent need worldwide. Immunoinformatics approaches are both cost-effective and convenient, as in silico predictions can reduce the number of experiments needed. In this study, with the aid of immunoinformatics tools, we tried to design a multi-epitope vaccine that can be used for the prevention and treatment of COVID-19. The epitopes were computed by using B cells, cytotoxic T lymphocytes (CTL), and helper T lymphocytes (HTL) base on the proteins of SARS-CoV-2. A vaccine was devised by fusing together the B cell, HTL, and CTL epitopes with linkers. To enhance the immunogenicity, the ß-defensin (45 mer) amino acid sequence, and pan-HLA DR binding epitopes (13aa) were adjoined to the N-terminal of the vaccine with the help of the EAAAK linker. To enable the intracellular delivery of the modeled vaccine, a TAT sequence (11aa) was appended to C-terminal. Linkers play vital roles in producing an extended conformation (flexibility), protein folding, and separation of functional domains, and therefore, make the protein structure more stable. The secondary and three-dimensional (3D) structure of the final vaccine was then predicted. Furthermore, the complex between the final vaccine and immune receptors (toll-like receptor-3 (TLR-3), major histocompatibility complex (MHC-I), and MHC-II) were evaluated by molecular docking. Lastly, to confirm the expression of the designed vaccine, the mRNA of the vaccine was enhanced with the aid of the Java Codon Adaptation Tool, and the secondary structure was generated from Mfold. Then we performed in silico cloning. The final vaccine requires experimental validation to determine its safety and efficacy in controlling SARS-CoV-2 infections.


Assuntos
Betacoronavirus/química , Biologia Computacional/métodos , Infecções por Coronavirus/prevenção & controle , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/imunologia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Proteínas Virais/imunologia , Vacinas Virais/imunologia , Sequência de Aminoácidos , Infecções por Coronavirus/virologia , Antígenos HLA-DR/imunologia , Humanos , Imunogenicidade da Vacina , Simulação de Acoplamento Molecular , Pneumonia Viral/virologia , Dobramento de Proteína , Estrutura Terciária de Proteína , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Vacinas de Subunidades/imunologia , beta-Defensinas/imunologia
10.
Arch Virol ; 165(10): 2165-2176, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32740830

RESUMO

The PI3K/Akt signalling pathway is a crucial signalling cascade that regulates transcription, protein translation, cell growth, proliferation, cell survival, and metabolism. During viral infection, viruses exploit a variety of cellular pathways, including the well-known PI3K/Akt signalling pathway. Conversely, cells rely on this pathway to stimulate an antiviral response. The PI3K/Akt pathway is manipulated by a number of viruses, including DNA and RNA viruses and retroviruses. The aim of this review is to provide up-to-date information about the role of the PI3K-Akt pathway in infection with members of five different families of negative-sense ssRNA viruses. This pathway is hijacked for viral entry, regulation of endocytosis, suppression of premature apoptosis, viral protein expression, and replication. Although less common, the PI3K/Akt pathway can be downregulated as an immunomodulatory strategy or as a mechanism for inducing autophagy. Moreover, the cell activates this pathway as an antiviral strategy for interferon and cytokine production, among other strategies. Here, we present new data concerning the role of this pathway in infection with the paramyxovirus Newcastle disease virus (NDV). Our data seem to indicate that NDV uses the PI3K/Akt pathway to delay cell death and increase cell survival as a means of improving its replication. The interference of negative-sense ssRNA viruses with this essential pathway might have implications for the development of antiviral therapies.


Assuntos
Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Fosfatidilinositol 3-Quinase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Infecções por Vírus de RNA/genética , Apoptose/genética , Autofagia/genética , Autofagia/imunologia , Citocinas/genética , Citocinas/imunologia , Endocitose/genética , Endocitose/imunologia , Filoviridae/genética , Filoviridae/metabolismo , Filoviridae/patogenicidade , Interações Hospedeiro-Patógeno/imunologia , Interferons/genética , Interferons/imunologia , Orthomyxoviridae/genética , Orthomyxoviridae/metabolismo , Orthomyxoviridae/patogenicidade , Paramyxoviridae/genética , Paramyxoviridae/metabolismo , Paramyxoviridae/patogenicidade , Fosfatidilinositol 3-Quinase/imunologia , Pneumovirinae/genética , Pneumovirinae/metabolismo , Pneumovirinae/patogenicidade , Biossíntese de Proteínas , Proteínas Proto-Oncogênicas c-akt/imunologia , Infecções por Vírus de RNA/imunologia , Infecções por Vírus de RNA/virologia , Rhabdoviridae/genética , Rhabdoviridae/metabolismo , Rhabdoviridae/patogenicidade , Transdução de Sinais , Proteínas Virais/genética , Proteínas Virais/imunologia , Internalização do Vírus , Replicação Viral
11.
PLoS Pathog ; 16(8): e1008685, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32745153

RESUMO

Smallpox and monkeypox pose severe threats to human health. Other orthopoxviruses are comparably virulent in their natural hosts, including ectromelia, the cause of mousepox. Disease severity is linked to an array of immunomodulatory proteins including the B22 family, which has homologs in all pathogenic orthopoxviruses but not attenuated vaccine strains. We demonstrate that the ectromelia B22 member, C15, is necessary and sufficient for selective inhibition of CD4+ but not CD8+ T cell activation by immunogenic peptide and superantigen. Inhibition is achieved not by down-regulation of surface MHC- II or co-stimulatory protein surface expression but rather by interference with antigen presentation. The appreciable outcome is interference with CD4+ T cell synapse formation as determined by imaging studies and lipid raft disruption. Consequently, CD4+ T cell activating stimulus shifts to uninfected antigen-presenting cells that have received antigen from infected cells. This work provides insight into the immunomodulatory strategies of orthopoxviruses by elucidating a mechanism for specific targeting of CD4+ T cell activation, reflecting the importance of this cell type in control of the virus.


Assuntos
Apresentação do Antígeno/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vírus da Ectromelia/imunologia , Ectromelia Infecciosa/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Proteínas Virais/imunologia , Animais , Ectromelia Infecciosa/metabolismo , Ectromelia Infecciosa/virologia , Feminino , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Virais/metabolismo , Virulência
12.
Nat Immunol ; 21(10): 1293-1301, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32807944

RESUMO

The SARS-CoV-2 virus emerged in December 2019 and has caused a worldwide pandemic due to the lack of any pre-existing immunity. Accurate serology testing is urgently needed to help diagnose infection, determine past exposure of populations and assess the response to a future vaccine. The landscape of antibody responses to SARS-CoV-2 is unknown. In this study, we utilized the luciferase immunoprecipitation system to assess the antibody responses to 15 different SARS-CoV-2 antigens in patients with COVID-19. We identified new targets of the immune response to SARS-CoV-2 and show that nucleocapsid, open reading frame (ORF)8 and ORF3b elicit the strongest specific antibody responses. ORF8 and ORF3b antibodies, taken together as a cluster of points, identified 96.5% of COVID-19 samples at early and late time points of disease with 99.5% specificity. Our findings could be used to develop second-generation diagnostic tests to improve serological assays for COVID-19 and are important in understanding pathogenicity.


Assuntos
Anticorpos Antivirais/sangue , Betacoronavirus/imunologia , Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus/diagnóstico , Pneumonia Viral/diagnóstico , Proteínas Virais/imunologia , Adulto , Idoso , Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Feminino , Hong Kong , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Sensibilidade e Especificidade , Fatores de Tempo
13.
Med Hypotheses ; 143: 110121, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32759006

RESUMO

SARS-CoV-2 incidence and mortality in Europe have shown wide variation. Northern Italy in particular the Lombardy region, north-eastern French regions, Switzerland and Belgium were amongst the hardest hit, while the central and southern Italian regions, all the Balkan countries from Slovenia to Greece and the Islands of Malta and Cyprus had much fewer cases and deaths per capita, and deaths per number of cases. Differences in public health measures, and health care delivery, in the author's opinion, can only partly explain the difference. The geographical distribution of Phlebotomus sand-flies and the relative distribution of arthropod borne diseases Leishmaniasis and Phlebovirus infections especially the Sicilian Sandfly fever group corresponds to most areas of low prevalence of SARS-CoV-2. A hypothesis is proposed whereby repeated arthropod or sandfly vector infection of humans by novel viruses of zoonotic origins carrying bat or mammalian RNA/DNA, such as phleboviruses may have resulted in the development of an effective evolutionary immune response to most novel zoonotic viruses such as SARS-CoV-2 by means of survival of the fittest possibly over many generations. This process probably ran in parallel and concurrent with the progressive evolution of novel coronaviruses which spread from one mammalian species to another. Other possible, but less likely mechanisms for the role of sandfly meals within a much shorter time frame may have led to, (i) previous exposure and infection of humans with the SARS-Cov-2 virus itself, or a closely related corona virus in the previous decades, or (ii) exposure of human populations to parts coronavirus protein namely either S or more likely N protein carried mechanically by arthropods, but without clinical disease causing direct immunity or (iii) by causing infection with other arthropod borne viruses which could carry bat DNA/RNA and have similar functional proteins resulting in an immediate cross-reactive immune response rather than by natural selection. The Evidence possibly supporting or disputing this hypothesis is reviewed, however the major problem with the hypothesis is that to date no coronavirus has ever been isolated from arthropods. Such a hypothesis can only be supported by research investigating the possible biological relationship of arthropods and coronaviruses where paradoxically they may be promoting immunity rather than disease.


Assuntos
Arbovirus/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Imunidade Coletiva , Insetos Vetores/virologia , Pandemias , Phlebotomus/virologia , Pneumonia Viral/imunologia , Animais , Anticorpos Antivirais/análise , Conflitos Armados , Artrópodes/virologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/veterinária , Infecções por Coronavirus/virologia , Reações Cruzadas , Reservatórios de Doenças/virologia , Europa (Continente)/epidemiologia , Especificidade de Hospedeiro , Interações Hospedeiro-Patógeno , Humanos , Incidência , Itália , Mamíferos/virologia , Pneumonia Viral/epidemiologia , Vírus da Febre do Flebótomo Napolitano/imunologia , Seleção Genética , Especificidade da Espécie , Proteínas Virais/imunologia , Zoonoses
14.
Front Immunol ; 11: 1817, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32793245

RESUMO

There is an urgent need for effective countermeasures against the current emergence and accelerating expansion of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Induction of herd immunity by mass vaccination has been a very successful strategy for preventing the spread of many infectious diseases, hence protecting the most vulnerable population groups unable to develop immunity, for example individuals with immunodeficiencies or a weakened immune system due to underlying medical or debilitating conditions. Therefore, vaccination represents one of the most promising counter-pandemic measures to COVID-19. However, to date, no licensed vaccine exists, neither for SARS-CoV-2 nor for the closely related SARS-CoV or Middle East respiratory syndrome-CoV. In addition, a few vaccine candidates have only recently entered human clinical trials, which hampers the progress in tackling COVID-19 infection. Here, we discuss potential prophylactic interventions for SARS-CoV-2 with a focus on the challenges existing for vaccine development, and we review pre-clinical progress and ongoing human clinical trials of COVID-19 vaccine candidates. Although COVID-19 vaccine development is currently accelerated via so-called fast-track programs, vaccines may not be timely available to have an impact on the first wave of the ongoing COVID-19 pandemic. Nevertheless, COVID-19 vaccines will be essential in the future for reducing morbidity and mortality and inducing herd immunity, if SARS-CoV-2 becomes established in the population like for example influenza virus.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Imunidade Coletiva/imunologia , Vacinação em Massa/métodos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas Virais/imunologia , Animais , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/transmissão , Modelos Animais de Doenças , Humanos , Pneumonia Viral/imunologia , Pneumonia Viral/transmissão , Vacinas de DNA/imunologia , Proteínas Virais/imunologia
15.
Front Immunol ; 11: 1581, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719684

RESUMO

To ultimately combat the emerging COVID-19 pandemic, it is desired to develop an effective and safe vaccine against this highly contagious disease caused by the SARS-CoV-2 coronavirus. Our literature and clinical trial survey showed that the whole virus, as well as the spike (S) protein, nucleocapsid (N) protein, and membrane (M) protein, have been tested for vaccine development against SARS and MERS. However, these vaccine candidates might lack the induction of complete protection and have safety concerns. We then applied the Vaxign and the newly developed machine learning-based Vaxign-ML reverse vaccinology tools to predict COVID-19 vaccine candidates. Our Vaxign analysis found that the SARS-CoV-2 N protein sequence is conserved with SARS-CoV and MERS-CoV but not from the other four human coronaviruses causing mild symptoms. By investigating the entire proteome of SARS-CoV-2, six proteins, including the S protein and five non-structural proteins (nsp3, 3CL-pro, and nsp8-10), were predicted to be adhesins, which are crucial to the viral adhering and host invasion. The S, nsp3, and nsp8 proteins were also predicted by Vaxign-ML to induce high protective antigenicity. Besides the commonly used S protein, the nsp3 protein has not been tested in any coronavirus vaccine studies and was selected for further investigation. The nsp3 was found to be more conserved among SARS-CoV-2, SARS-CoV, and MERS-CoV than among 15 coronaviruses infecting human and other animals. The protein was also predicted to contain promiscuous MHC-I and MHC-II T-cell epitopes, and the predicted linear B-cell epitopes were found to be localized on the surface of the protein. Our predicted vaccine targets have the potential for effective and safe COVID-19 vaccine development. We also propose that an "Sp/Nsp cocktail vaccine" containing a structural protein(s) (Sp) and a non-structural protein(s) (Nsp) would stimulate effective complementary immune responses.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Aprendizado de Máquina , Pandemias , Pneumonia Viral , Vacinas Virais , Animais , Betacoronavirus/genética , Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Epitopos de Linfócito B/genética , Epitopos de Linfócito B/imunologia , Humanos , Imunogenicidade da Vacina , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Pandemias/prevenção & controle , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Pneumonia Viral/prevenção & controle , Proteínas Virais/genética , Proteínas Virais/imunologia , Vacinas Virais/genética , Vacinas Virais/imunologia
16.
Cell Stress Chaperones ; 25(5): 731-735, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32729001

RESUMO

Severe acute respiratory syndrome-related coronavirus 2 infection has been associated with Guillain-Barré syndrome. We investigated here the potential mechanism underlying the virus-induced damage of the peripheral nervous systems by searching the viral amino acid sequence for peptides common to human autoantigens associated with immune-mediated polyneuropathies. Our results show molecular mimicry between the virus and human heat shock proteins 90 and 60, which are associated with Guillain-Barré syndrome and other autoimmune diseases. Crucially, the shared peptides are embedded in immunoreactive epitopes that have been experimentally validated in the human host.


Assuntos
Betacoronavirus/metabolismo , Chaperonina 60 , Infecções por Coronavirus/virologia , Síndrome de Guillain-Barré/metabolismo , Proteínas de Choque Térmico HSP90 , Proteínas Mitocondriais , Pneumonia Viral/virologia , Proteínas Virais , Sequência de Aminoácidos , Autoantígenos , Chaperonina 60/química , Chaperonina 60/imunologia , Bases de Dados de Proteínas , Proteínas de Choque Térmico HSP90/química , Proteínas de Choque Térmico HSP90/imunologia , Humanos , Epitopos Imunodominantes , Proteínas Mitocondriais/química , Proteínas Mitocondriais/imunologia , Mimetismo Molecular , Pandemias , Proteínas Virais/química , Proteínas Virais/imunologia
17.
Vaccine ; 38(35): 5734-5739, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32653276

RESUMO

Several protein vaccine candidates are among the COVID-19 vaccines in development. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) has prepared a standardized template to describe the key considerations for the benefit-risk assessment of protein vaccines. This will help key stakeholders to assess potential safety issues and understand the benefit-risk of such a vaccine platform. The structured and standardized assessment provided by the template would also help contribute to improved public acceptance and communication of licensed protein vaccines.


Assuntos
Vacinas Virais/efeitos adversos , Vacinas Virais/imunologia , Antígenos Virais/administração & dosagem , Antígenos Virais/efeitos adversos , Antígenos Virais/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Humanos , Segurança do Paciente , Medição de Risco , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologia , Proteínas Virais/administração & dosagem , Proteínas Virais/efeitos adversos , Proteínas Virais/imunologia , Vacinas Virais/administração & dosagem
18.
Adv Virus Res ; 107: 383-416, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32711735

RESUMO

Since the end of 2019, the global COVID-19 outbreak has once again made coronaviruses a hot topic. Vaccines are hoped to be an effective way to stop the spread of the virus. However, there are no clinically approved vaccines available for coronavirus infections. Reverse genetics technology can realize the operation of RNA virus genomes at the DNA level and provide new ideas and strategies for the development of new vaccines. In this review, we systematically describe the role of reverse genetics technology in studying the effects of coronavirus proteins on viral virulence and innate immunity, cell and tissue tropism and antiviral drug screening. An efficient reverse genetics platform is useful for obtaining the ideal attenuated strain to prepare an attenuated live vaccine.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas Sintéticas/imunologia , Proteínas Virais/genética , Proteínas Virais/imunologia , Vacinas Virais/imunologia , Infecções por Coronavirus/imunologia , Genoma Viral/genética , Humanos , Pneumonia Viral/imunologia , RNA Viral/genética , Genética Reversa/métodos
19.
Immunobiology ; 225(3): 151955, 2020 05.
Artigo em Inglês | MEDLINE | ID: covidwho-309013

RESUMO

SARS Coronavirus-2 (SARS-CoV-2) pandemic has become a global issue which has raised the concern of scientific community to design and discover a counter-measure against this deadly virus. So far, the pandemic has caused the death of hundreds of thousands of people upon infection and spreading. To date, no effective vaccine is available which can combat the infection caused by this virus. Therefore, this study was conducted to design possible epitope-based subunit vaccines against the SARS-CoV-2 virus using the approaches of reverse vaccinology and immunoinformatics. Upon continual computational experimentation, three possible vaccine constructs were designed and one vaccine construct was selected as the best vaccine based on molecular docking study which is supposed to effectively act against the SARS-CoV-2. Thereafter, the molecular dynamics simulation and in silico codon adaptation experiments were carried out in order to check biological stability and find effective mass production strategy of the selected vaccine. This study should contribute to uphold the present efforts of the researches to secure a definitive preventative measure against this lethal disease.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Pandemias , Pneumonia Viral/tratamento farmacológico , Proteínas Virais/química , Vacinas Virais/biossíntese , Sequência de Aminoácidos , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/patogenicidade , Biologia Computacional/métodos , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Progressão da Doença , Epitopos/química , Epitopos/imunologia , Epitopos de Linfócito B/genética , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Antígenos HLA/genética , Antígenos HLA/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunogenicidade da Vacina , Simulação de Acoplamento Molecular , Plasmídeos/química , Plasmídeos/imunologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Conformação Proteica , Genética Reversa/métodos , Alinhamento de Sequência , Vacinas de Subunidades , Proteínas Virais/genética , Proteínas Virais/imunologia
20.
Immunobiology ; 225(3): 151955, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32517882

RESUMO

SARS Coronavirus-2 (SARS-CoV-2) pandemic has become a global issue which has raised the concern of scientific community to design and discover a counter-measure against this deadly virus. So far, the pandemic has caused the death of hundreds of thousands of people upon infection and spreading. To date, no effective vaccine is available which can combat the infection caused by this virus. Therefore, this study was conducted to design possible epitope-based subunit vaccines against the SARS-CoV-2 virus using the approaches of reverse vaccinology and immunoinformatics. Upon continual computational experimentation, three possible vaccine constructs were designed and one vaccine construct was selected as the best vaccine based on molecular docking study which is supposed to effectively act against the SARS-CoV-2. Thereafter, the molecular dynamics simulation and in silico codon adaptation experiments were carried out in order to check biological stability and find effective mass production strategy of the selected vaccine. This study should contribute to uphold the present efforts of the researches to secure a definitive preventative measure against this lethal disease.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Pandemias , Pneumonia Viral/tratamento farmacológico , Proteínas Virais/química , Vacinas Virais/biossíntese , Sequência de Aminoácidos , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/patogenicidade , Biologia Computacional/métodos , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Progressão da Doença , Epitopos/química , Epitopos/imunologia , Epitopos de Linfócito B/genética , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Antígenos HLA/genética , Antígenos HLA/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunogenicidade da Vacina , Simulação de Acoplamento Molecular , Plasmídeos/química , Plasmídeos/imunologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Conformação Proteica , Genética Reversa/métodos , Alinhamento de Sequência , Vacinas de Subunidades , Proteínas Virais/genética , Proteínas Virais/imunologia
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