RESUMO
The discovery that a protein could mimic viral and bacterial pathogens around 1980 by Stanley Prusiner was unexpected. Evidence shows now that Creutzfeldt-Jakob disease and related disorders are caused by prions. Prions and, for example neurodegeneratives diseases, arise from the same general disease mechanism. In each, there is abnormal unfolding and then aggregation of proteins. The protein conformational changes associated with the pathogenesis of protein misfolding disorders produce ß sheet rich oligomers that are partially resistant to proteolysis and have a high tendency to form amyloid-like aggregates. It is important to distinguish between prions and amyloids: prions need not to polymerize into amyloid fibrils and can undergo self-propagation as oligomers. The prion diseases are characterized by the conformational conversion of PrP(c) to PrP(sc), the fundamental even underlying prion diseases. Despite the obvious differences between prions and conventional infectious microorganisms, prions fulfill the Koch's postulates. Meaningful treatments are likely to require cocktails of drugs that interfere with the conversion of precursor into prions and enhance the clearance of prions; such an approach may find application in the more common degenerative diseases.
Assuntos
Príons/química , Amiloide/química , Animais , Humanos , Proteínas PrPC/química , Proteínas PrPSc/química , Doenças Priônicas/epidemiologia , Doenças Priônicas/metabolismo , Doenças Priônicas/transmissão , Doenças Priônicas/veterinária , Agregação Patológica de Proteínas/metabolismo , Conformação Proteica , Dobramento de Proteína , Estrutura Secundária de Proteína , Deficiências na Proteostase/metabolismo , Relação Estrutura-AtividadeAssuntos
Cardiomiopatias/virologia , Infecções por Coxsackievirus/complicações , Imunidade Ativa , Receptores Ativados por Proteinase/fisiologia , Viroses/imunologia , Adenoviridae/fisiologia , Animais , Cardiomiopatias/patologia , Infecções por Coxsackievirus/patologia , Modelos Animais de Doenças , Enterovirus Humano B/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutAssuntos
Bacteriófagos , Pé Diabético/microbiologia , Pé Diabético/terapia , Infecções Estafilocócicas/terapia , Staphylococcus aureus/virologia , Acetamidas/administração & dosagem , Animais , Anti-Infecciosos/administração & dosagem , Terapia Combinada , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/terapia , Humanos , Linezolida , Camundongos , Camundongos Endogâmicos BALB C , Oxazolidinonas/administração & dosagem , Superinfecção/terapiaAssuntos
Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Interferons/imunologia , Infecções Sexualmente Transmissíveis/prevenção & controle , Animais , Colo do Útero/metabolismo , Feminino , Humanos , Interferons/genética , Programas de Rastreamento , Camundongos , Camundongos Knockout , Gravidez , Infecções Sexualmente Transmissíveis/imunologiaAssuntos
Doenças Transmissíveis/genética , Predisposição Genética para Doença , Antígenos de Grupos Sanguíneos/genética , Doenças Transmissíveis/sangue , Doenças Transmissíveis/imunologia , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Interações Hospedeiro-Patógeno/genética , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Esquistossomose/genética , Esquistossomose/imunologia , Tuberculose/genética , Tuberculose/imunologiaRESUMO
If the oxygen tension level is 21% in ambient air, it is only between 14% and 1% in vivo. Consequently, viral pathogens are exposed and must adapt to these fluctuating oxygen levels to colonize the host and cause diseases. The problem is that for many years, the virological studies have been performed at 21% oxygen levels and consequently this is a real handicap to have a correct view of the mechanistic aspects of human viral infections. In this brief review, we describe for some selected examples the interactions of human viruses with this relative hypoxia observed in vivo.
Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Fenômenos Fisiológicos Virais , Vírus/patogenicidade , Infecções por Vírus de DNA/genética , Infecções por Vírus de DNA/patologia , Infecções por Vírus de DNA/virologia , Vírus de DNA/patogenicidade , Vírus de DNA/fisiologia , Humanos , Infecções por Vírus de RNA/genética , Infecções por Vírus de RNA/patologia , Vírus de RNA/patogenicidade , Vírus de RNA/fisiologiaRESUMO
Since its discovery, the human parvovirus B19 (B19V) has been associated with many clinical situations in addition to the prototype clinical manifestations, i.e. erythema infectiosum and erythroblastopenia crisis. The clinical significance of the viral B19V DNA persistence in sera after acute infection remains largely unknown. Such data may constitute a new clinical entity and is discussed in this manuscript. In 2002, despite the genetic diversity among B19V viruses has been reported to be very low, the description of markedly distinct sequences showed a new organization into three genotypes. The most recent common ancestor for B19V genotypes was estimated at early 1800s. B19V replication is enhanced by hypoxia and this might to explain the high viral load detected by quantitative PCR in the sera of infected patients. The minimum infectious dose necessary to transmit B19V infection by the transfusion of labile blood products remains unclear. At the opposite, the US Food and Drug Administration proposed a limit of 10(4)IU/mL of viral DNA in plasma pools used for the production of plasma derivatives. Recently, a new human parvovirus (PARV4) has been discovered. The consequences on blood transfusion of this blood-borne agent and its pathogenicity are still unknown.
Assuntos
Infecções por Parvoviridae/virologia , Parvovirus B19 Humano/fisiologia , Viremia/virologia , Segurança do Sangue , Hipóxia Celular , DNA Viral/análise , Variação Genética , Genótipo , Humanos , Infecções por Parvoviridae/prevenção & controle , Infecções por Parvoviridae/transmissão , Parvovirus B19 Humano/classificação , Parvovirus B19 Humano/genética , Parvovirus B19 Humano/isolamento & purificação , Reação Transfusional , Viremia/prevenção & controle , Viremia/transmissão , Replicação ViralRESUMO
More than 30 years after its individualization, chronic fatigue syndrome (CFS) remains a debilitating condition for the patient and a confusing one to the physicians, both because of diagnostic difficulties and poorly codified management. Despite the numerous work carried out, its pathophysiology remains unclear, but a multifactorial origin is suggested with triggering (infections) and maintenance (psychological) factors as well as the persistence of inflammatory (low grade inflammation, microglial activation ), immunologic (decrease of NK cells, abnormal cytokine production, reactivity to a variety of allergens, role of estrogens ) and muscular (mitochondrial dysfunction and failure of bioenergetic performance) abnormalities at the origin of multiple dysfunctions (endocrine, neuromuscular, cardiovascular, digestive ). The complexity of the problem and the sometimes contradictory results of available studies performed so far are at the origin of different pathophysiological and diagnostic concepts. Based on a rigorous analysis of scientific data, the new American concept of Systemic Disease Exertion Intolerance proposed in 2015 simplifies the diagnostic approach and breaks with the past and terminologies (CFS and myalgic encephalomyelitis). It is still too early to distinguish a new disease, but this initiative is a strong signal to intensify the recognition and management of patients with CFS and stimulate research.
Assuntos
Síndrome de Fadiga Crônica/fisiopatologia , Diagnóstico Diferencial , Síndrome de Fadiga Crônica/diagnóstico , HumanosRESUMO
A permanent cell line, LEF1, has been established from the cells of an adult suffering from a Philadelphia positive acute lymphoblastic leukemia. The LEF1 cell line was obtained by maintaining peripheral blood cells from the patient in culture on a fibroblast feeder; subsequently, an autonomously growing cell population, independent of that feeder layer, developed. The karyotype of the cell line, 46, t(9;22)(q34;q11), was different from the karyotype at diagnosis which had 53 chromosomes and two Philadelphia chromosomes. Furthermore, compared with the initial leukemic blasts, the immortalized cell had three differences in surface phenotype (CD23+, CD11b-, CD10-). However, molecular studies indicated that the breakpoint in the 3' part of the first intron of the BCR gene was unchanged, confirming the leukemic origin of LEF1. The cell line was shown to be Epstein-Barr virus negative.
Assuntos
Antígenos de Diferenciação de Linfócitos B/análise , Oncogenes , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores Fc/análise , Adulto , Antígenos CD/análise , Northern Blotting , Southern Blotting , Divisão Celular , Feminino , Citometria de Fluxo , Humanos , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores de IgE , Mapeamento por Restrição , Células Tumorais Cultivadas/imunologia , Células Tumorais Cultivadas/patologiaRESUMO
Two patients presented with a large tumoral nasopharyngeal lesion with obstructive symptoms, which suggested a malignant tumor. They were black men of Caribbean origin who were infected with human immunodeficiency virus 1. In both cases, histologic examination revealed intense but benign lymphoid follicular hyperplasia, and immunohistochemical studies were consistent with its polyclonal nature. DNA studies performed on tumoral tissue failed to disclose immunoglobulin or T-cell receptor gene rearrangements. In one biopsy specimen, DNA hybridization using Epstein-Barr virus-specific probes showed no evidence of Epstein-Barr virus-DNA sequences. The nasopharynx can be involved in the diffuse extranodal lymphoid hyperplasia associated with human immunodeficiency virus infection.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Hiperplasia do Linfonodo Gigante/etiologia , Neoplasias Nasofaríngeas/etiologia , Adulto , Humanos , MasculinoAssuntos
Orthomyxoviridae , Animais , Aves/virologia , Reservatórios de Doenças , Humanos , Influenza Aviária/virologia , Influenza Humana/virologia , Orthomyxoviridae/classificação , Orthomyxoviridae/patogenicidade , Infecções por Orthomyxoviridae/veterinária , Infecções por Orthomyxoviridae/virologia , Suínos/virologia , Doenças dos Suínos/virologiaRESUMO
OBJECTIVE: To measure changes in HIV-1 virus load following zidovudine therapy, and to investigate the relationship between these changes and clinical progression. DESIGN: Prospective study of 18 symptomatic, zidovudine-naive patients, with CD4 count < 350 x 10(6)/l. METHODS: The following parameters were measured at each visit, before zidovudine therapy, after 1 month of therapy, and every 3 months thereafter. HIV-1 virus load in peripheral blood was determined by serum immune complex-dissociated HIV-1 p24 antigen (ICD-p24 Ag), quantitative plasma and cellular viraemia. A virologic response under zidovudine was defined as > 50% decrease in ICD-p24 Ag levels or > 1 log10 decrease in plasma or cellular viraemia titres from baseline values. CD4 and CD8 cell counts, and beta 2-microglobulin levels were also measured. Disease progression was defined as the time to a new AIDS-defining event or death. RESULTS: At enrolment, 13 out of 18 (72%) patients had positive ICD-p24 Ag and positive plasma viraemia, with a mean of 44 median tissue culture infective dose (TCID50) per ml; all patients had positive cellular viraemia with a mean TCID50 of 230 per 10(6)/l cells. Median CD4 cell count was 43 x 10(6)/l. Ten patients developed a new AIDS-defining event and eight died during a median follow-up of 15 months on zidovudine. Baseline prognostic markers for development of a new AIDS-defining event included ICD-p24 Ag, CD4 and CD8 cell counts, but only CD4 cell count remained predictive on multivariate analysis (P = 0.003). When each laboratory marker was analysed as a time-dependent covariate, only CD4 (P = 0.002) and CD8 (P = 0.001) cell counts predicted the occurrence of a new AIDS-defining event. Eight out of 13 (61.5%) patients had an ICD-p24 Ag response, and seven out of 13 (54%) a plasma viraemia response, but only cellular viraemia responders (five out of 18; 28%) had a 5.6-fold decrease in their risk of developing an AIDS-defining event (90% confidence interval, 1-33; P = 0.05). None of these markers correlated with survival. CONCLUSIONS: Plasma viraemia and ICD-p24 Ag, while providing useful short-term markers of zidovudine antiviral activity in vivo, do not correlate with disease progression in patients with advanced HIV infection. CD4 cell count remained the best initial and time-dependent predictor for development of new AIDS-defining events. Interestingly, a high CD8 cell count and a decrease in cellular viraemia titres also appear to be predictive of improved clinical outcome in this population.
Assuntos
Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Zidovudina/uso terapêutico , Adulto , Biomarcadores , Linfócitos T CD4-Positivos , Feminino , Proteína do Núcleo p24 do HIV/sangue , Infecções por HIV/microbiologia , Infecções por HIV/fisiopatologia , HIV-1/efeitos dos fármacos , Humanos , Contagem de Leucócitos , Masculino , Estudos Prospectivos , ViremiaRESUMO
OBJECTIVE: Seven French laboratories tested the specificity and sensitivity of the polymerase chain reaction (PCR) for the detection of HIV-1 DNA. METHODS: Following its own PCR protocols, each laboratory independently tested blind two panels of 20 coded peripheral blood mononuclear cell samples collected from HIV-1-seropositive individuals and from HIV-1-seronegative individuals at high or low risk of HIV infection. For the first panel, laboratories were free to select type and number of primers; for the second, all were required to use the two primer pairs Pol 3/4 and MMy 9/10' (Nef 1). RESULTS: False-positive and false-negative results were observed in all laboratories (concordance with serology ranged from 40 to 100%). In addition, the number of positive PCR results did not differ significantly between high- and low-risk seronegatives. The use of crude cell lysates in DNA preparation produced the same PCR results as phenol-extracted DNA. Discrepancies between laboratories indicated that factors other than primer pairs contributed strongly to laboratory variability. CONCLUSIONS: Our results emphasize the importance of both positive and negative controls in PCR and demonstrate the value of multicentre PCR quality control.
Assuntos
DNA Viral/análise , Infecções por HIV/diagnóstico , HIV-1/química , Reação em Cadeia da Polimerase/métodos , Sequência de Bases , França , Humanos , Leucócitos Mononucleares/química , Dados de Sequência Molecular , Controle de QualidadeRESUMO
PURPOSE: To determine whether Epstein-Barr virus (EBV) could be involved in the pathogenesis of Sjögren's syndrome (SS). PATIENTS AND METHODS: In situ hybridization using the BamH1-W fragment of EBV DNA was performed using labial salivary gland biopsy specimens from 14 patients with SS (eight with primary SS and six with secondary SS) and 39 control subjects. Furthermore, labial salivary gland biopsy specimens from 12 patients with SS (seven with primary SS and five with secondary SS) and 24 control subjects were submitted to the polymerase chain reaction to detect EBV DNA. RESULTS: In situ hybridization detected EBV DNA in epithelial cells of labial salivary gland biopsy specimens from four of eight (50%) patients with primary SS, zero of six patients with secondary SS, and three of 39 (8%) control subjects. The difference between patients with primary SS and control subjects was statistically significant (p less than 0.02). The polymerase chain reaction detected EBV DNA in six of seven (86%) patients with primary SS, three of five (60%) patients with secondary SS, and seven of 24 (29%) control subjects. The difference between patients with primary SS and control subjects was statistically significant (p less than 0.01). CONCLUSION: Both newly developed techniques showed that the presence of EBV DNA was significantly increased in patients with primary SS in comparison with control subjects. In all the positive SS patients who underwent in situ hybridization, epithelial cells of the labial salivary gland were the target of EBV infection. Our results suggest that this virus may play a role in the pathogenesis of SS. We cannot yet determine whether EBV is directly responsible for the destruction of the gland, or if its presence is a secondary event following gland injury.
Assuntos
DNA Viral/análise , Herpesvirus Humano 4/genética , Hibridização de Ácido Nucleico , Glândulas Salivares/microbiologia , Síndrome de Sjogren/microbiologia , Adulto , Idoso , Anticorpos Antivirais/análise , Feminino , Herpesvirus Humano 4/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Síndrome de Sjogren/imunologiaRESUMO
BACKGROUND: Secondary solid tumors are rare events occurring in patients who underwent allogeneic marrow transplantation for aplastic anemia and Fanconi's anemia. Human herpes virus 8 (HHV8), Epstein-Barr virus (EBV), and human papillomaviruses (HPV) sequences have been found in squamous cell carcinoma (SCC) occurring in organ transplant recipients. The tumor suppressor gene p53 has been strongly linked to the occurrence of SCC in the nonimmunocompromised population. PATIENTS AND METHODS: In eight patients with SCC, we searched for HHV8, EBV, varicella zoster virus, adenovirus, and HPV sequences from DNA extracted from selected areas of SCC. We also looked for p53 expression in those specimens as well as the presence of anti-p53 antibodies in the serum of these patients at the onset of SCC. RESULTS: In one patient, we found the presence of both HHV8 and EBV sequences, and in another patient we found HPV16 sequences. All five tumors that could be studied disclosed evidence of p53 accumulation, but none of the eight patients had anti-p53 antibodies in the sera. CONCLUSION: SCC developing in marrow transplant recipients seems to occur via a multistep process. Genetic predisposition may be present, as in patients with Fanconi's anemia. Transplantation-related factors, such as irradiation and chronic graft-versus-host disease, also have a role. In this article, we add two more potent risk factors: p53 alteration(s) and in some cases the presence of oncogenic viruses.
Assuntos
Anemia Aplástica/terapia , Transplante de Medula Óssea , Carcinoma de Células Escamosas/etiologia , Transplante de Medula Óssea/efeitos adversos , Carcinoma de Células Escamosas/virologia , Anemia de Fanconi/terapia , Herpesvirus Humano 4/isolamento & purificação , Herpesvirus Humano 8/isolamento & purificação , Humanos , Masculino , Papillomaviridae/isolamento & purificação , Proteína Supressora de Tumor p53/imunologia , Proteína Supressora de Tumor p53/metabolismoRESUMO
We investigated in 15 consecutive patients a possible correlation between expression of CMV or EBV in labial salivary gland (LSG) biopsies performed 100 days after allogeneic BMT and subsequent development of chronic GVHD. Three techniques were performed for the detection of each virus: immunohistochemistry, in situ hybridization and PCR. Eleven patients developed chronic GVHD. Histologic examination detected a moderate lymphoid infiltrate (grade 1 according to Sale's score) in LSG biopsy in only one patient. CMV genes or proteins could not be detected in any patients. Likewise, EBV genome or proteins were not detected by in situ hybridization and immunohistochemistry. However, in three of the 15 patients, EBV DNA was detected by PCR in LSG biopsies. Only one of these three patients developed chronic GVHD. Therefore, at the present time, the presence of a lymphoid infiltrate on lip biopsies performed at day 100 post-BMT does not appear to be sensitive enough for the diagnosis or the prediction of the subsequent development of chronic GVHD. Moreover, the absence of EBV and CMV expression in a day-100 LSG biopsy does not preclude the development of chronic GVHD.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Infecções por Citomegalovirus/diagnóstico , Citomegalovirus/isolamento & purificação , DNA Viral/isolamento & purificação , Doença Enxerto-Hospedeiro/virologia , Infecções por Herpesviridae/diagnóstico , Herpesvirus Humano 4/isolamento & purificação , Lábio/virologia , Linfonodos/virologia , Glândulas Salivares Menores/virologia , Adolescente , Adulto , Doenças Autoimunes/virologia , Criança , Doença Crônica , Citomegalovirus/genética , Citomegalovirus/crescimento & desenvolvimento , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/virologia , Feminino , Infecções por Herpesviridae/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/crescimento & desenvolvimento , Herpesvirus Humano 4/patogenicidade , Humanos , Técnicas Imunoenzimáticas , Terapia de Imunossupressão , Hibridização In Situ , Lábio/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Síndrome de Sjogren/virologia , Transplante Homólogo/efeitos adversos , Proteínas Virais/análise , Ativação ViralRESUMO
A dot-blot hybridization assay for serum B19 DNA is described using a non-radioactive (digoxigenin) M13 single-stranded DNA probe. The assay is sensitive (0.3 pg of B19 DNA) and has several advantages over similar assays which use radioactive or non-radioactive labelled plasmid probe for the routine detection of B19 DNA in sera.