RESUMO
BACKGROUND: Adenovirus 36 (Ad-36) has been associated to adiposity in animal and in vitro studies. Ad-36 seropositivity has also been reported to contribute to obesity risk in children and adult populations. We investigated the relationship of Ad-36 serology with obesity and metabolic parameters in a Chilean population. SUBJECTS AND METHODS: Clinical and anthropometric data were obtained and blood samples were drawn from 99 lean (BMI: 18.5-24.9 kg/m2) and 151 obese (BMI > 30 kg/m2) subjects. Laboratory tests included lipid profile as well as glucose, insulin, leptin, and adiponectin levels. Ad-36 seropositivity was evaluated in serum samples by enzyme-linked immunosorbent assay. RESULTS: Seroprevalence of Ad-36 was higher in the obese group (58%) than in lean controls (34%) demonstrating that individuals previously infected with Ad-36 have higher risk of obesity in the study population (OR: 2.67, 95%CI: 1.58-4.51, p < 0.001). Interestingly, Ad-36 was related to lower concentrations of triglycerides and VLDL cholesterol in lean subjects (p = 0.049) and lower leptin in obese individuals (p = 0.014). Previous Ad-36 infection was also related to lower glycemia, insulinemia, and HOMA-IR (p < 0.05) in obese subjects who were not under antidiabetic drugs. CONCLUSIONS: Our results provide evidence of the contribution of previous Ad-36 infection to an increased risk of obesity in adult Chilean population. Ad-36 seropositivity was also associated to lipid profile, glycemic control, and leptin levels in adult Chilean population.
Assuntos
Infecções por Adenoviridae , Adenoviridae/imunologia , Glicemia/análise , Leptina/sangue , Obesidade , Infecções por Adenoviridae/complicações , Infecções por Adenoviridae/epidemiologia , Infecções por Adenoviridae/imunologia , Adulto , Anticorpos Antivirais/sangue , Estudos de Casos e Controles , Chile , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/epidemiologia , Estudos SoroepidemiológicosRESUMO
Fowl adenovirus (FAdV), which causes the high-impact diseases such as inclusion body hepatitis and hepatitis-hydropericardium syndrome, is of major concern to the poultry industry internationally. This study was carried out in direct response to mortality rates of up to 75% in commercial broiler flocks in Trinidad, West Indies. Symptoms in 3- to 8-week-old broilers and 13- to 18-week-old pullets pointed to infection with an immunosuppressive viral pathogen. The objectives of the study were to determine whether the infectious agent FAdV, along with other viral pathogens, was responsible for the clinical disease, and to obtain information on the serotypes of FAdV that were infecting the birds. Tissue samples from clinically affected birds from eight different farms were tested for chicken infectious anaemia virus (CIAV) and infectious bursal disease virus (IBDV) by real-time reverse transcription polymerase chain reaction (PCR) and for FAdV by conventional PCR. The birds tested positive for FAdV and CIAV, but negative for IBDV. The gene corresponding to the L1 loop of the hexon protein for FAdV was amplified and sequenced. Phylogenetic analysis of seven FAdV strains inferred that four serotypes were likely to be circulating in the chickens. Well supported genetic relatedness was observed for serotype 8a (97.8%), 8b (97.8%), 9 (95.8%) and 11 (98.8%-99.5%). This is the first published report from Trinidad and Tobago on the presence and circulation of pathogenic FAdV strains, in combination with CIAV, in poultry. The data demonstrate a possible need for the introduction of serotype-specific vaccines against FAdV, as well as vaccines against CIAV, in broilers in the region and emphasize the importance of maintaining high levels of biosecurity on farms to prevent the spread of these potentially devastating viruses between farms.
Assuntos
Infecções por Adenoviridae/veterinária , Adenoviridae/isolamento & purificação , Vírus da Anemia da Galinha/isolamento & purificação , Galinhas/virologia , Infecções por Circoviridae/veterinária , Doenças das Aves Domésticas/virologia , Adenoviridae/genética , Adenoviridae/imunologia , Infecções por Adenoviridae/epidemiologia , Infecções por Adenoviridae/virologia , Animais , Infecções por Birnaviridae/epidemiologia , Infecções por Birnaviridae/veterinária , Infecções por Birnaviridae/virologia , Vírus da Anemia da Galinha/genética , Vírus da Anemia da Galinha/imunologia , Infecções por Circoviridae/epidemiologia , Infecções por Circoviridae/virologia , Coinfecção/veterinária , Feminino , Vírus da Doença Infecciosa da Bursa/genética , Vírus da Doença Infecciosa da Bursa/imunologia , Vírus da Doença Infecciosa da Bursa/isolamento & purificação , Filogenia , Doenças das Aves Domésticas/epidemiologia , Sorogrupo , Trinidad e Tobago/epidemiologiaRESUMO
OBJECTIVE: To characterize the spectrum and salient clinical features of adenovirus-associated neurologic disease in immunocompetent children. STUDY DESIGN: Previously healthy children (aged 1 month-18 years) with central nervous system (CNS) disease associated with adenovirus infection were identified via the Encephalitis Registry (1996-2016) and Microbiology Database (2000-2016) at The Hospital for Sick Children, Toronto, and by systematic review of the literature. The data were pooled and analyzed to identify the spectrum of illness, clinical outcome, and risk factors for death or neurologic impairment. RESULTS: Neurologic complications associated with adenovirus infection in our institution included febrile seizures, encephalitis, acute disseminated encephalomyelitis, and aseptic meningitis. A total of 48 immunocompetent children with adenovirus-associated CNS disease were included in the pooled analysis-38 from the literature and 10 from our institution. In 85% of cases, the virus was detected in the respiratory or gastrointestinal tract, but not the cerebrospinal fluid. Eighteen of the 48 (38%) patients either died or suffered permanent neurologic sequelae. Predictors of adverse outcome included younger age, coagulopathy, the absence of meningismus, serotype 2 virus, and the presence of seizures. After multivariable adjustment, only seizures remained a significant risk factor. CONCLUSION: Adenovirus is a rare cause of CNS disease in immunocompetent children. Disease spectrum is variable, ranging from mild aspetic meningitis and fully reversible encephalopathy to severe, potentially fatal, acute necrotizing encephalopathy.
Assuntos
Infecções por Adenoviridae/complicações , Adenoviridae , Doenças do Sistema Nervoso Central/virologia , Adenoviridae/genética , Adenoviridae/imunologia , Adenoviridae/isolamento & purificação , Infecções por Adenoviridae/diagnóstico , Infecções por Adenoviridae/virologia , Anticorpos Antivirais/análise , Encéfalo/patologia , Doenças do Sistema Nervoso Central/diagnóstico , DNA Viral/análise , Feminino , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Estudos Retrospectivos , Fatores de RiscoRESUMO
The central dogma of gene therapy relies on the application of novel therapeutic genes to treat or prevent diseases. The main types of vectors used for gene transfer are adenovirus, retrovirus, lentivirus, liposome, and adeno-associated virus vectors. Gene therapy has emerged as a promising alternative for the treatment of inflammatory diseases. The main targets are cytokines, co-stimulatory molecules, and different types of cells from hematological and mesenchymal sources. In this review, we focus on molecules with anti-inflammatory effects used for in vivo gene therapy mediated by adenoviral gene transfer in the treatment of immune-mediated inflammatory diseases, with particular emphasis on autoinflammatory and autoimmune diseases.
Assuntos
Adenoviridae/imunologia , Anti-Inflamatórios/uso terapêutico , Doenças Autoimunes/terapia , Modelos Animais de Doenças , Terapia Genética/métodos , Vetores Genéticos , Inflamação/terapia , Animais , Doenças Autoimunes/imunologia , Produtos Biológicos/uso terapêutico , Inflamação/imunologia , Camundongos , Coelhos , RatosRESUMO
This study aimed to examine anti-prostate cancer immune response induced by dendritic cells (DCs) transduced with PSMA/4-1BBL recombinant adenoviruses in vitro. Ad-PSMA, Ad-4-1BBL, and Ad-GFP were transfected into DCs derived from peripheral blood of healthy volunteers. Ad-PSMA/4-1BBL-DC, Ad-PSMA-DC, Ad-4-1BBL-DC, Ad-GFP-DC, and normal-DC, PSMA and 4-1BBL protein levels in DCs were detected by western blot. IL-12, IFN-γ and IL-10 were measured by ELISA. Mixed lymphocyte reaction and the cytotoxicity of each group targeted to LNCap, Du145, and 22RV prostate cancer cells were determined by CCK-8 assay. PSMA and 4-1BBL protein could express on DC successfully, the IL-12 supernatant content (134.29 ± 2.22 pg) was higher than others (P < 0.05). The ability to stimulate autologous T lymphocyte proliferation in the co-transfection group was higher than others (P < 0.05). When the DCs were co-cultured with CTLs, the PSMA/4-1BBL-DC-CTL group showed the highest content of IFN-γ (1176.10 ± 14.37pg/5 x 10(6) cells), but the lowest IL-10 content (75.14 ± 2.01 pg/5 x 10(6) cells) (P < 0.05), and the strongest anti-tumor effect when the effector to target ratio was 40:1, along with a higher killing ratio of LNCap cells than others (P < 0.05). Overall, Mature DCs transfected with Ad-PSMA/4- 1BBL not only showed high secretion of IL-12, but also induced CTLs to stimulate and enhance the killing effect of PSMA specific effector cells to PSMA positively expressing prostate cancer cells. Furthermore, the DCs infected with two kinds of tumor-associated antigens would induce more effective tumor-specific CTL induction.
Assuntos
Ligante 4-1BB/imunologia , Adenoviridae/genética , Antígenos de Superfície/imunologia , Células Dendríticas/imunologia , Glutamato Carboxipeptidase II/imunologia , Próstata/imunologia , Linfócitos T Citotóxicos/imunologia , Ligante 4-1BB/genética , Adenoviridae/imunologia , Antígenos de Superfície/genética , Linhagem Celular Tumoral , Proliferação de Células , Técnicas de Cocultura , Citotoxicidade Imunológica , Células Dendríticas/citologia , Expressão Gênica , Vetores Genéticos/genética , Vetores Genéticos/imunologia , Glutamato Carboxipeptidase II/genética , Humanos , Imunoterapia/métodos , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-10/biossíntese , Interleucina-10/imunologia , Interleucina-12/biossíntese , Interleucina-12/imunologia , Teste de Cultura Mista de Linfócitos , Masculino , Próstata/patologia , Linfócitos T Citotóxicos/citologia , Transdução GenéticaRESUMO
Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is a prototypical neglected tropical disease. Specific immunity promotes acute phase survival. Nevertheless, one-third of CD patients develop chronic chagasic cardiomyopathy (CCC) associated with parasite persistence and immunological unbalance. Currently, the therapeutic management of patients only mitigates CCC symptoms. Therefore, a vaccine arises as an alternative to stimulate protective immunity and thereby prevent, delay progression and even reverse CCC. We examined this hypothesis by vaccinating mice with replication-defective human Type 5 recombinant adenoviruses (rAd) carrying sequences of amastigote surface protein-2 (rAdASP2) and trans-sialidase (rAdTS) T. cruzi antigens. For prophylactic vaccination, naïve C57BL/6 mice were immunized with rAdASP2+rAdTS (rAdVax) using a homologous prime/boost protocol before challenge with the Colombian strain. For therapeutic vaccination, rAdVax administration was initiated at 120 days post-infection (dpi), when mice were afflicted by CCC. Mice were analyzed for electrical abnormalities, immune response and cardiac parasitism and tissue damage. Prophylactic immunization with rAdVax induced antibodies and H-2Kb-restricted cytotoxic and interferon (IFN)γ-producing CD8+ T-cells, reduced acute heart parasitism and electrical abnormalities in the chronic phase. Therapeutic vaccination increased survival and reduced electrical abnormalities after the prime (analysis at 160 dpi) and the boost (analysis at 180 and 230 dpi). Post-therapy mice exhibited less heart injury and electrical abnormalities compared with pre-therapy mice. rAdVax therapeutic vaccination preserved specific IFNγ-mediated immunity but reduced the response to polyclonal stimuli (anti-CD3 plus anti-CD28), CD107a+ CD8+ T-cell frequency and plasma nitric oxide (NO) levels. Moreover, therapeutic rAdVax reshaped immunity in the heart tissue as reduced the number of perforin+ cells, preserved the number of IFNγ+ cells, increased the expression of IFNγ mRNA but reduced inducible NO synthase mRNA. Vaccine-based immunostimulation with rAd might offer a rational alternative for re-programming the immune response to preserve and, moreover, recover tissue injury in Chagas' heart disease.
Assuntos
Cardiomiopatia Chagásica/prevenção & controle , Doença de Chagas/imunologia , Doença de Chagas/terapia , Vacinas Protozoárias/uso terapêutico , Trypanosoma cruzi/imunologia , Adenoviridae/genética , Adenoviridae/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Doença Crônica , Feminino , Fenômenos do Sistema Imunitário , Camundongos , Camundongos Endogâmicos C57BL , Vacinação , Vacinas de DNA/genética , Vacinas de DNA/imunologiaRESUMO
Heterologous prime-boost vaccination using plasmid DNA followed by replication-defective adenovirus vector generates a large number of specific CD8⺠T effector memory (TEM) cells that provide long-term immunity against a variety of pathogens. In the present study, we initially characterized the frequency, phenotype, and function of these T cells in vaccinated mice that were subjected to infectious challenge with the human protozoan parasite Trypanosoma cruzi. We observed that the frequency of the specific CD8⺠T cells in the spleens of the vaccinated mice increased after challenge. Specific TEM cells differentiated into cells with a KLRG1(High) CD27(Low) CD43(Low) CD183(Low)T-bet(High) Eomes(Low) phenotype and capable to produce simultaneously the antiparasitic mediators IFNγ and TNF. Using the gzmBCreERT2/ROSA26EYFP transgenic mouse line, in which the cells that express Granzyme B after immunization, are indelibly labeled with enhanced yellow fluorescent protein, we confirmed that CD8⺠T cells present after challenge were indeed TEM cells that had been induced by vaccination. Subsequently, we observed that the in vivo increase in the frequency of the specific CD8⺠T cells was not because of an anamnestic immune response. Most importantly, after challenge, the increase in the frequency of specific cells and the protective immunity they mediate were insensitive to treatment with the cytostatic toxic agent hydroxyurea. We have previously described that the administration of the drug FTY720, which reduces lymphocyte recirculation, severely impairs protective immunity, and our evidence supports the model that when large amounts of antigen-experienced CD8⺠TEM cells are present after heterologous prime-boost vaccination, differentiation, and recirculation, rather than proliferation, are key for the resultant protective immunity.
Assuntos
Adenoviridae/genética , Linfócitos T CD8-Positivos/imunologia , Doença de Chagas/imunologia , Vetores Genéticos/genética , Memória Imunológica , Trypanosoma cruzi/imunologia , Adenoviridae/imunologia , Animais , Animais Geneticamente Modificados , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Doença de Chagas/prevenção & controle , Modelos Animais de Doenças , Feminino , Vetores Genéticos/imunologia , Humanos , Imunofenotipagem , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Camundongos , Baço/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T/imunologia , Vacinação , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologiaRESUMO
BACKGROUND: Respiratory viral infections can induce different cytokine/chemokine profiles in lung tissues and have a significant influence on patients with asthma. There is little information about the systemic cytokine status in viral respiratory-infected asthmatic patients compared with non-asthmatic patients. OBJECTIVES: The aim of this study was to determine changes in circulating cytokines (IL-1ß, TNF-α, IL-4, IL-5) and chemokines (MCP1: monocyte chemoattractant protein-1 and RANTES: regulated on activation normal T cell expressed and secreted) in patients with an asthmatic versus a non-asthmatic background with respiratory syncytial virus, parainfluenza virus or adenovirus respiratory infection. In addition, human monocyte cultures were incubated with respiratory viruses to determine the cytokine/chemokine profiles. PATIENTS/METHODS: Patients with asthmatic (n = 34) and non-asthmatic (n = 18) history and respiratory infections with respiratory syncytial virus, parainfluenza, and adenovirus were studied. Healthy individuals with similar age and sex (n = 10) were used as controls. Cytokine/chemokine content in blood and culture supernatants was determined by ELISA. Monocytes were isolated by Hystopaque gradient and cocultured with each of the above-mentioned viruses. RESULTS: Similar increased cytokine concentrations were observed in asthmatic and non-asthmatic patients. However, higher concentrations of chemokines were observed in asthmatic patients. Virus-infected monocyte cultures showed similar cytokine/chemokine profiles to those observed in the patients. CONCLUSIONS: Circulating cytokine profiles induced by acute viral lung infection were not related to asthmatic status, except for chemokines that were already increased in the asthmatic status. Monocytes could play an important role in the increased circulating concentration of cytokines found during respiratory viral infections.
Assuntos
Infecções por Adenoviridae/imunologia , Citocinas/sangue , Infecções por Paramyxoviridae/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções Respiratórias/imunologia , Adenoviridae/imunologia , Infecções por Adenoviridae/patologia , Adolescente , Adulto , Idoso , Asma/complicações , Células Cultivadas , Criança , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Infecções por Paramyxoviridae/patologia , Infecções por Vírus Respiratório Sincicial/patologia , Vírus Sinciciais Respiratórios/imunologia , Infecções Respiratórias/patologia , Respirovirus/imunologia , Soro/química , Adulto JovemRESUMO
A phase I-II study to evaluate gene-mediated cytotoxic immunotherapy in newly diagnosed prostate cancer before radical prostatectomy was conducted in Monterrey, Mexico. First, to investigate delivery of adenovirus to the prostate, fluorescently labeled vector was injected into fresh prostatectomy specimens and distribution was visually analyzed. The optimal volume and site instillation was then used for transrectal ultrasound guided intraprostatic injection in 10 patients with adenocarcinoma scheduled for radical prostatectomy. Each received two apical and two basal 0.5 ml injections of AdV-tk for a total of 1 × 10(11) vp followed by 14 days of prodrug. Nine patients continued to tumor resection: six high risk, one intermediate and two low risk. In vivo vector distribution was analyzed from the resected tissue of four patients. Patients were monitored for tumor progression and acute and long-term safety. For vector delivery, two apical and two basal injections of 0.5 ml led to optimal organ-wide distribution ex vivo and in vivo. Cytotoxicity was evidenced by transient rise in PSA and tumor histology. There were no significant adverse events deemed related to the treatment and no late toxicities after median follow-up of 11.3 years. All six high-risk patients had positive surgical margins and one had seminal vesicle involvement. Despite slow PSA rise post surgery in three of these patients, none developed metastases. The intermediate- and low-risk patients had complete resections and none have progressed. In conclusion, in vivo transrectal ultrasound guided instillation of an adenoviral vector into four sites in the prostate was practical as an outpatient procedure, well tolerated and led to distribution throughout the intraprostatic tumor mass. AdV-tk demonstrated no significant acute or late toxicities. Trends in PSA and disease progression conveyed the possibility of a sustained immune response against residual disease.
Assuntos
Adenoviridae/fisiologia , Terapia Viral Oncolítica/métodos , Neoplasias da Próstata/terapia , Adenoviridae/genética , Adenoviridae/imunologia , Idoso , Seguimentos , Técnicas de Transferência de Genes , Terapia Genética/métodos , Vetores Genéticos/genética , Vetores Genéticos/imunologia , Vetores Genéticos/farmacocinética , Humanos , Imunoterapia/métodos , Calicreínas/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/cirurgia , Neoplasias da Próstata/virologia , Simplexvirus/enzimologia , Simplexvirus/genética , Timidina Quinase/genéticaRESUMO
The aim of the present study was to assess the effect of introducing a priming step with replication-defective viral vectors encoding the capsid proteins of FMDV, followed by a boost with killed virus vaccines, using a suitable BALB/c mice model. Additionally, the immune response to other combined vector immunization regimens was studied. For this purpose, we analyzed different prime-boost immunizations with recombinant adenovirus (Ad), herpesvirus amplicons (Hs) and/or killed virus (KV) vaccines. The highest antibody titers were found in the group that received two doses of adjuvanted KV (P<0.002). Antibody titers were higher in those groups receiving a mixed regimen of vectors, compared to immunization with either vector alone (P<0.0001). Priming with any of the viral vectors induced a shift of the cytokine balance toward a Th1 type immune response regardless of the delivery system used for boosting. The highest IgG1 titer was induced by two doses of adjuvanted KV (P=0.0002) and the highest IgG2a titer corresponded to the group primed with Ad and boosted with KV (P=0.01). Re-stimulation of all groups of mice with 0.5 µg of inactivated virus five months later resulted in a fast increase of antibody titers in all the groups tested. After virus stimulation, antibody titers in the groups that received KV alone or Ad prime-KV boost, were indistinguishable (P=0.800). Protection from challenge was similar (75%) in the groups of animals that received Ad prime-Hs boost or Ad prime-KV boost, or two doses of oil-adjuvanted KV. The data presented in this study suggest that sequential immunization with viral vectors-based vaccines combined with protein-based vaccines have the potential to enhance the quality of the immune response against FMDV.