1. Recombinant vaccines of a CD4+ T-cell epitope promote efficient control of Paracoccidioides brasiliensis burden by restraining primary organ infection
- Author
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Rodrigo Assuncao Holanda, Tatiane A. Paixão, Leandro Buffoni Roque da Silva, Sthefany Pagliari, Carlos Pelleschi Taborda, Lucas Dos Santos Dias, Julliana Ribeiro Alves Santos, Daniel Assis Santos, Julián E. Muñoz, Érica Leandro Marciano Vieira, and Oscar Bruna-Romero
- Subjects
Protein Expression ,Ratón albino bagg ,Vacuna contra partículas similares a virus ,Colony Forming Unit ,Pathology and Laboratory Medicine ,Interleukin 1 ,Biochemistry ,Paracoccidioides ,Interleukin 4 ,Animal Cells ,Desarrollo y Envejecimiento ,Microscopio de transmisión por electrones ,Magnitude Estimation Method ,Lung ,Immune Response ,Lesión de tejido ,Célula humana ,Vaccines, Synthetic ,Recombinant Vaccines ,Drug Formulation ,Vacuna ,Immunogenicity ,Solid Phase Extraction ,Formulación de Medicamentos ,Virus Particle ,Experimento con animales ,Secretion (Process) ,Método de estimación de la magnitud ,Cellular Immunity ,Electroforesis en gel de poliacrilamida ,Fungal ,Partícula de virus ,Viral Pathogens ,Vacuna recombinante ,Hepatitis B Virus ,030106 microbiology ,Inmunología ,Factor de necrosis tumoral ,Microbiology ,Article ,Glucoproteinas ,03 medical and health sciences ,Antigen ,Expresión de proteínas ,Genetics ,Glycoproteins ,Inmunoprofilaxis ,Fungal vaccine ,Human Cell ,Synthetic ,Public Health, Environmental and Occupational Health ,Biology and Life Sciences ,Proteins ,lcsh:RA1-1270 ,Animal Experiment ,Célula Th1 ,030104 developmental biology ,Virus Like Particle Vaccine ,T-Lymphocyte ,Interferón gamma ,Tejido animal ,Proliferación de linfocitos ,Fungal Vaccines ,Paracoccidioidomycosis ,Proteína de 43 Kda ,Cd4+ T Lymphocyte ,CD4-Positive T-Lymphocytes ,Adenoviruses ,interleucina 12 ,Physiology ,Epitopes, T-Lymphocyte ,Growth ,Plasmid ,Quimera ,White Blood Cells ,Immunogenicity, Vaccine ,Plásmido ,Development And Aging ,Medicine and Health Sciences ,Fungus Antigen ,Vaccines ,Immune System Proteins ,T Cells ,lcsh:Public aspects of medicine ,Modelo animal ,Fungal Diseases ,interleucina 4 ,Inbred Balb C ,Animal Cell ,Infectious Diseases ,Th1 Cell ,Liver ,Inmunización ,Extracción de fase sólida ,Hepatitis B virus ,Western Blotting ,Infectious Disease Control ,Immunophenotyping ,Fungal Proteins ,Partícula similar a un virus ,medicine ,Animals ,Antigens ,Memoria Inmunológica ,Gamma Interferon ,Chimera ,South American Blastomycosis ,Th1 Cells ,biology.organism_classification ,Transferencia occidental ,Histopatología ,Blastomicosis sudamericana ,Transmission Electron Microscopy ,DNA viruses ,Linfocito T ,Inmunidad celular ,Vaccine ,Spleen ,Síntesis de péptidos ,Microbiología ,43 Kda Protein ,Epitope ,Hongos ,Immunoprophylaxis ,ANTÍGENOS DE FUNGOS ,Linfocito T Cd4+ ,Proteína fúngica ,Fungal protein ,Vaccine Immunogenicity ,Inmunofenotipado ,Vacuna contra hongos ,Medical Microbiology ,Interleucina 1 ,Cytokines ,Cellular Types ,Human ,Antigens, Fungal ,Balb endogámico C ,lcsh:RC955-962 ,Immune Cells ,Immunology ,Immunological Memory ,Crecimiento ,Sintético ,Epítopo ,Unidad de formación de Colonia ,Animal Tissue ,Secreción (Proceso) ,Humano ,Microbial Pathogens ,Paracoccidioides brasiliensis ,Fungus Vaccine ,Blood Cells ,Tissue Injury ,Glicoproteína ,Organisms ,Citocina ,medicine.disease ,Virology ,Recombinant Vaccine ,Yeast Infections ,Inmunogenicidad de la vacuna ,Centrifugación ,Animal Model ,Glycoprotein ,Replicación de ADN ,Tumor Necrosis Factor ,Immunologic Memory ,0301 basic medicine ,Fungal Protein ,Antígeno de hongos ,Centrifugation ,Polyacrylamide Gel Electrophoresis ,Interleukin 12 ,Immune Physiology ,Enzyme Linked Immunosorbent Assay ,Bagg Albino Mouse ,Mice, Inbred BALB C ,Micosis ,Hepatitis B ,Célula animal ,Recombinant Proteins ,Dna Replication ,Viruses ,Paracoccidioidomicosis ,Pathogens ,Research Article ,lcsh:Arctic medicine. Tropical medicine ,Histopathology ,Biology ,Lymphocyte Proliferation ,Vaccines, Virus-Like Particle ,Controlled Study ,Mortality ,Peptide Synthesis ,Cytokine ,Ensayo inmunoabsorbente ligado a enzimas ,Immunodominant Epitopes ,Cell Biology ,Estudio controlado ,Genética ,Virus-Like Particle ,Mortalidad ,Immunization - Abstract
Paracoccidioidomycosis (PCM) is an infectious disease endemic to South America, caused by the thermally dimorphic fungi Paracoccidioides. Currently, there is no effective human vaccine that can be used in prophylactic or therapeutic regimes. We tested the hypothesis that the immunogenicity of the immunodominant CD4+ T-cell epitope (P10) of Paracoccidioides brasiliensis gp43 antigen might be significantly enhanced by using a hepatitis B virus-derived particle (VLP) as an antigen carrier. This chimera was administered to mice as a (His)6-purified protein (rPbT) or a replication-deficient human type 5 adenoviral vector (rAdPbT) in an immunoprophylaxis assay. The highly virulent Pb18 yeast strain was used to challenge our vaccine candidates. Fungal challenge evoked robust P10-specific memory CD4+ T cells secreting protective Th-1 cytokines in most groups of immunized mice. Furthermore, the highest level of fungal burden control was achieved when rAdPbT was inoculated in a homologous prime-boost regimen, with 10-fold less CFU recovering than in non-vaccinated mice. Systemic Pb18 spreading was only prevented when rAdPbT was previously inoculated. In summary, we present here VLP/P10 formulations as vaccine candidates against PCM, some of which have demonstrated for the first time their ability to prevent progression of this pernicious fungal disease, which represents a significant social burden in developing countries., Author summary Human paracoccidioidomycosis (PCM) represents a serious public health issue due to its disabling sequelae in working-age people and mortality rates (8th among chronic infectious parasitic diseases in endemic countries and first among mycoses in Brazil). Although antifungal drugs have been widely used and provide clinical improvement for patients, the long duration of treatments (commonly from 6 to 12 months) has contributed to non-compliance and worsening of the disease in many cases. Induction of protective immune responses (either prophylactic or immune-therapeutic) remains the most cost-effective approach against most infectious agents. Members of our group have previously reported the protective properties of P10, a peptide contained in Paracoccidioides brasiliensis gp43 antigen, against PCM. However, the magnitude of the CD4+ T-cell responses elicited lacked the capacity of completely protecting experimental animals. We demonstrate here that immunogenic virus-like particles (VLP) carrying multiple copies of P10 peptide substantially improve P10-related cellular immunity in mice. This was particularly true when an adenoviral immunization vector expressed the chimeric VLP. Moreover, VLP/P10 formulations were capable of controlling the host fungal burden and prevented fungal systemic dissemination. The efficacy of diverse VLP/P10 formulations in murine PCM showed at least one promising candidate vaccine against human PCM.
- Published
- 2017