RESUMO
En el año 2018 se conmemoraron 40 años desde el primer resultado exitoso producto de una fertilización in vitro (FIV), el nacimiento de Louise Brown en Inglaterra. Se estima que a la fecha han nacido más de 8 millones de seres humanos gracias a las tecnologías de reproducción asistida (TRA), técnicas que están en constante avance y desarrollo. Sin embargo, a pesar de ser cada vez más relevantes como tratamiento de la infertilidad, su acceso todavía es muy limitado y poco equitativo, alcanzando menos del 15% de la población a nivel global. En esta revisión analizamos los aspectos epidemiológicos de la infertilidad y exponemos el contraste entre la necesidad teórica de TRA y los ciclos realizados a nivel mundial, reflejando el bajo acceso a los tratamientos. Se enfatiza la realidad latinoamericana y con especial detalle la chilena, explorando tanto su dimensión histórica como actual, perfilando los desafíos que como país deberemos enfrentar en los próximos años.
The 40-year anniversary of the first in vitro fertilization (IVF) newborn, Louise Brown in England, was celebrated in 2018. To date, over 8 million children have been born with assisted reproductive technologies (ART), a group of techniques in continuous development. Despite the increasing relevance of such technologies as treatments for infertility, the access to ART has been limited to less than 15% of the world population.In this review, we analyze the epidemiological aspects of infertility and present the contrast between the theoretical demand and the actual number of ART cycles performed worldwide, reflecting the low access to infertility treatments. We put emphasis on the Latin American historic and current context, then provide more details on the Chilean reality, and finally outline the challenges Chile will face in the future regarding access to ART.
Assuntos
Humanos , Masculino , Feminino , Adulto , Técnicas de Reprodução Assistida/estatística & dados numéricos , Infertilidade/terapia , Infertilidade/epidemiologia , Fertilização in vitro , Chile , Equidade em Saúde , Fatores Sociodemográficos , Acessibilidade aos Serviços de Saúde , América LatinaRESUMO
Patients with poor ovarian response (POR) to exogenous gonadotropins stimulation for assisted reproductive technology (ART) have decreased circulating androgens during spontaneous cycles. The Patient-Oriented Strategies Encompassing Individualized Oocyte Number (POSEIDON) is a 4-tier stratification of women with POR to controlled ovarian stimulation (COH) based on age and biomarkers of ovarian reserve has been proposed to maximize the clinical management of this group for ART. The aim of the present study was to characterize the levels of androgens during COH in follicular fluid (FF) and serum in POSEIDON subgroups and compared them with women of normal ovarian response. Sixty nine consecutive patients undergoing ART were included and testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEA-S), estradiol, sex hormone-binding globulin (SHBG), and insulin-like growth factor 1 (IGF-1) were measured in serum and FF collected at the time of oocyte pick-up. The number of retrieved oocytes was registered for each patient for their allocation to the respective POSEIDON subgroup. The control group comprised 19 women and the POSEIDON group 1 (age < 35, normal ovarian reserve biomarkers) n = 14, group 2 (age ≥ 35, normal ovarian reserve biomarkers) n = 8, group 3 (age < 35, poor ovarian reserve biomarkers) n = 6 and group 4 (age ≥ 35, poor ovarian reserve biomarkers) n = 22. Serum levels of total testosterone, androstenedione and DHEA-S were not different in group 1 vs. control but significantly decreased in group 3 vs. control. DHEA-S in FF was also significantly decreased in group 3 vs. control. In addition, serum testosterone was decreased in groups 2 and 4 vs. control; and serum androstenedione and estradiol were reduced in group 4 vs. control. No differences were observed for estradiol, SHBG and IGF-1 in FF. Finally, a high correlation between serum and FF DHEA-S was observed when data from samples of all groups were pooled. Group 1 did not show hypoandrogenemia however group 3 had low levels of all measured androgens in serum and DHEA-S in FF. Such differences might help to better characterize and/or improve the clinical management of women with POR according to their respective POSEIDON stratification.
RESUMO
The Human Respiratory Syncytial Virus (hRSV) and the Human Metapneumovirus (hMPV) are two pneumoviruses that are leading agents causing acute lower respiratory tract infections (ALRTIs) affecting young infants, the elderly, and immunocompromised patients worldwide. Since these pathogens were first discovered, many approaches for the licensing of safe and effective vaccines have been explored being unsuccessful to date. We have previously described that immunization with recombinant strains of Mycobacterium bovis Bacillus Calmette-Guérin (rBCG) expressing the hRSV nucleoprotein (rBCG-N) or the hMPV phosphoprotein (rBCG-P) induced immune protection against each respective virus. These vaccines efficiently promoted viral clearance without significant lung damage, mainly through the induction of a T helper 1 cellular immunity. Here we show that upon viral challenge, rBCG-immunized mice developed a protective humoral immunity, characterized by production of antibodies specific for most hRSV and hMPV proteins. Further, isotype switching from IgG1 to IgG2a was observed in mice immunized with rBCG vaccines and correlated with an increased viral clearance, as compared to unimmunized animals. Finally, sera obtained from animals immunized with rBCG vaccines and infected with their respective viruses exhibited virus neutralizing capacity and protected naïve mice from viral replication and pulmonary disease. These results support the notion that the use of rBCG strains could be considered as an effective vaccination approach against other respiratory viruses with similar biology as hRSV and hMPV.
Assuntos
Vacina BCG/imunologia , Imunidade Humoral , Mycobacterium bovis/imunologia , Infecções Respiratórias/prevenção & controle , Animais , Vacina BCG/administração & dosagem , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Metapneumovirus/genética , Metapneumovirus/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Nucleoproteínas/administração & dosagem , Nucleoproteínas/genética , Nucleoproteínas/imunologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Vírus Sincicial Respiratório Humano/genética , Vírus Sincicial Respiratório Humano/imunologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/virologia , Células Th1/imunologia , Células Th1/metabolismo , Vacinação/métodos , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Proteínas Virais/administração & dosagem , Proteínas Virais/genética , Proteínas Virais/imunologia , Replicação Viral/imunologiaRESUMO
RESUMEN Introducción y objetivos: Aunque la criopreservación embrionaria es frecuentemente utilizada como parte de las técnicas de reproducción asistida, no existe información cuantitativa de cómo las parejas infértiles viven la experiencia de tener embriones criopreservados en Chile. El objetivo del estudio fue examinar las percepciones y creencias que tienen mujeres y hombres respecto de sus embriones criopreservados, sus perspectivas respecto de la donación reproductiva y destino de los embriones remanentes. Metodología: 153 mujeres y hombres con embriones criopreservados provenientes de un hospital público, Instituto de Investigaciones Materno Infantil y un centro privado, Clínica Las Condes, en Santiago, Chile, respondieron durante mayo 2015 a mayo 2016 un cuestionario en línea, anónimo, respecto de sus percepciones y creencias sobre criopreservación embrionaria. Resultados: Los encuestados reconocen a sus embriones criopreservados como un hijo (53.2%) o un proyecto de hijo (40.7%). Sólo 8% los considera un grupo organizado de células; sobre el 60% rechaza la opción de descartarlos o usarlos para investigación. Los participantes del hospital público tenían mayor disposición a donar sus embriones remanentes a otras parejas que aquellos del privado (61% vs 40%; P=0.016). Un 34% de las personas encuestadas estuvo de acuerdo con donar embriones a parejas de un mismo sexo. Conclusión: Este estudio muestra que las personas chilenas tienen un vínculo emocional con sus embriones criopreservados y no consideran descartarlos. Los resultados de este estudio pueden servir para dar adecuada consejería a las personas que se realizan técnicas de reproducción asistida, de tal modo de tomar decisiones informadas respecto de la criopreservación.
ABSTRACT Background and objetive: Although embryo cryopreservation is frequently used as part of assisted reproductive technology, quantitave information addressing how infertile couples live the experience of having cryopreserved embryos is lacking in Chile. The aim of this study is to examine men and women's perception and beliefs regarding their cryopreserved embryos, as well as their perspective on embryo donation and disposition. Methods: 153 women and men with frozen embryos from a public hospital, Instituto de Investigactiones Materno Infantil, and a private clinic, Clínica Las Condes, in Santiago, Chile, responded between May 2015 and May 2016 to an anonymous online survey addressing their perceptions and beliefs concerning their cryopreserved embryos. Results: Respondents considered their frozen embryos to be equivalent to a child (53.2%) or a potential child (40.7%). Only 8% regard them as an organized group of cells. Over 60% of respondents disagree with destroying surplus embryos or using them for research. Participants from the public hospital are more willing to donate their embryos to another couple than those from the private center (61% vs 40%; P=0.016); 34% of respondents agreed to donate surplus embryos to same sex couples. Conclusion: This study reveals that Chilean couples are emotionally bound to their frozen embryos, and that discarding them is not an option. The results from this survey will help strengthen counseling for couples to enable them to make informed decisions regarding their surplus embryos.
Assuntos
Humanos , Masculino , Feminino , Percepção , Criopreservação/estatística & dados numéricos , Medicina Reprodutiva/estatística & dados numéricos , Destinação do Embrião/psicologia , Inquéritos e Questionários , Tomada de Decisões , Estudo ObservacionalRESUMO
The human metapneumovirus (hMPV) is the second leading cause globally of acute infection of the respiratory tract in children, infecting the upper and lower airways. The hMPV may induce an inappropriate Th2-type immune response, which causes severe pulmonary inflammation, leading to the obstruction of airways. Despite its severe epidemiological relevance, no vaccines are currently available for the prevention of hMPV-induced illness. In this investigation, we demonstrated that immunization of mice with the recombinant hMPV nucleoprotein (hMPV-N) mixed with the AbISCO-100 adjuvant reduced viral replication in lungs following challenge with the virus. We found that immunized mice had reduced weight loss, decreased granulocytes in the lung, an increased level of specific nucleoprotein antibodies of IgG1 and IgG2a-isotypes, and a local profile of Th1/Th17-type cytokines. Our results suggest that immunization with the hMPV-N and the AbISCO-100 adjuvant induces a reduction of viral infection and could be considered for the development of an hMPV vaccine.
Assuntos
Imunização , Metapneumovirus/imunologia , Nucleoproteínas/administração & dosagem , Infecções por Paramyxoviridae/imunologia , Vacinas Virais/imunologia , Adjuvantes Imunológicos/farmacologia , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/classificação , Citocinas/análise , Células Dendríticas/classificação , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Granulócitos , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Nucleoproteínas/genética , Nucleoproteínas/isolamento & purificação , Infecções por Paramyxoviridae/prevenção & controle , Pneumonia/virologia , RNA Viral/análise , Vacinas Virais/farmacologia , Redução de PesoRESUMO
BACKGROUND AND OBJETIVE: Although embryo cryopreservation is frequently used as part of assisted reproductive technology, quantitave information addressing how infertile couples live the experience of having cryopreserved embryos is lacking in Chile. The aim of this study is to examine men and women's perception and beliefs regarding their cryopreserved embryos, as well as their perspective on embryo donation and disposition. Methods: 153 women and men with frozen embryos from a public hospital, Instituto de Investigactiones Materno Infantil, and a private clinic, Clínica Las Condes, in Santiago, Chile, responded between May 2015 and May 2016 to an anonymous online survey addressing their perceptions and beliefs concerning their cryopreserved embryos. RESULTS: Respondents considered their frozen embryos to be equivalent to a child (53.2%) or a potential child (40.7%). Only 8% regard them as an organized group of cells. Over 60% of respondents disagree with destroying surplus embryos or using them for research. Participants from the public hospital are more willing to donate their embryos to another couple than those from the private center (61% vs 40%; P=0.016); 34% of respondents agreed to donate surplus embryos to same sex couples. CONCLUSION: This study reveals that Chilean couples are emotionally bound to their frozen embryos, and that discarding them is not an option. The results from this survey will help strengthen counseling for couples to enable them to make informed decisions regarding their surplus embryos.
INTRODUCCIÓN Y OBJETIVOS: Aunque la criopreservación embrionaria es frecuentemente utilizada como parte de las técnicas de reproducción asistida, no existe información cuantitativa de cómo las parejas infértiles viven la experiencia de tener embriones criopreservados en Chile. El objetivo del estudio fue examinar las percepciones y creencias que tienen mujeres y hombres respecto de sus embriones criopreservados, sus perspectivas respecto de la donación reproductiva y destino de los embriones remanentes. METODOLOGÍA: 153 mujeres y hombres con embriones criopreservados provenientes de un hospital público, Instituto de Investigaciones Materno Infantil y un centro privado, Clínica Las Condes, en Santiago, Chile, respondieron durante mayo 2015 a mayo 2016 un cuestionario en línea, anónimo, respecto de sus percepciones y creencias sobre criopreservación embrionaria. RESULTADOS: Los encuestados reconocen a sus embriones criopreservados como un hijo (53.2%) o un proyecto de hijo (40.7%). Sólo 8% los considera un grupo organizado de células; sobre el 60% rechaza la opción de descartarlos o usarlos para investigación. Los participantes del hospital público tenían mayor disposición a donar sus embriones remanentes a otras parejas que aquellos del privado (61% vs 40%; P=0.016). Un 34% de las personas encuestadas estuvo de acuerdo con donar embriones a parejas de un mismo sexo. CONCLUSIÓN: Este estudio muestra que las personas chilenas tienen un vínculo emocional con sus embriones criopreservados y no consideran descartarlos. Los resultados de este estudio pueden servir para dar adecuada consejería a las personas que se realizan técnicas de reproducción asistida, de tal modo de tomar decisiones informadas respecto de la criopreservación.
RESUMO
Human respiratory syncytial virus (hRSV) is the leading cause of severe lower respiratory tract infections in children. The development of novel prophylactic and therapeutic antiviral drugs against hRSV is imperative to control the burden of disease in the susceptible population. In this study, we examined the effects of inducing the activity of the host enzyme heme oxygenase-1 (HO-1) on hRSV replication and pathogenesis on lung inflammation induced by this virus. Our results show that after hRSV infection, HO-1 induction with metalloporphyrin cobalt protoporphyrin IX significantly reduces the loss of body weight due to hRSV-induced disease. Further, HO-1 induction also decreased viral replication and lung inflammation, as evidenced by a reduced neutrophil infiltration into the airways, with diminished cytokine and chemokine production and reduced T cell function. Concomitantly, upon cobalt protoporphyrin IX treatment, there is a significant upregulation in the production of IFN-α/ß mRNAs in the lungs. Furthermore, similar antiviral and protective effects occur by inducing the expression of human HO-1 in MHC class II+ cells in transgenic mice. Finally, in vitro data suggest that HO-1 induction can modulate the susceptibility of cells, especially the airway epithelial cells, to hRSV infection.
Assuntos
Heme Oxigenase-1/metabolismo , Pulmão/imunologia , Infecções por Vírus Respiratório Sincicial/fisiopatologia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/fisiologia , Animais , Linhagem Celular , Citocinas/biossíntese , Citocinas/imunologia , Replicação do DNA , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Heme Oxigenase-1/genética , Humanos , Interferon-alfa/biossíntese , Interferon-alfa/imunologia , Interferon beta/imunologia , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Camundongos , Protoporfirinas/administração & dosagem , Protoporfirinas/farmacologia , Infecções por Vírus Respiratório Sincicial/imunologia , Linfócitos T/imunologia , Ligação Viral , Internalização do Vírus , Replicação ViralRESUMO
Human respiratory syncytial virus (hRSV) is a major health burden worldwide, causing the majority of hospitalizations in children under two years old due to bronchiolitis and pneumonia. HRSV causes year-to-year outbreaks of disease, which also affects the elderly and immunocompromised adults. Furthermore, both hRSV morbidity and epidemics are explained by a consistently high rate of re-infections that take place throughout the patient life. Although significant efforts have been invested worldwide, currently there are no licensed vaccines to prevent hRSV infection. Here, we describe that a recombinant Bacillus Calmette-Guerin (BCG) vaccine expressing the nucleoprotein (N) of hRSV formulated under current good manufacture practices (cGMP rBCG-N-hRSV) confers protective immunity to the virus in mice. Our results show that a single dose of the GMP rBCG-N-hRSV vaccine retains its capacity to protect mice against a challenge with a disease-causing infection of 1×107 plaque-forming units (PFUs) of the hRSV A2 clinical strain 13018-8. Compared to unimmunized infected controls, vaccinated mice displayed reduced weight loss and less infiltration of neutrophils within the airways, as well as reduced viral loads in bronchoalveolar lavages, parameters that are characteristic of hRSV infection in mice. Also, ex vivo re-stimulation of splenic T cells at 28days post-immunization activated a repertoire of T cells secreting IFN-γ and IL-17, which further suggest that the rBCG-N-hRSV vaccine induced a mixed, CD8+ and CD4+ T cell response capable of both restraining viral spread and preventing damage of the lungs. All these features support the notion that rBCG-N-hRSV is a promising candidate vaccine to be used in humans to prevent the disease caused by hRSV in the susceptible population.
Assuntos
Vacina BCG/administração & dosagem , Linfócitos T CD8-Positivos/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Vacina BCG/genética , Vacina BCG/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Humanos , Esquemas de Imunização , Imunogenicidade da Vacina , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-17/biossíntese , Interleucina-17/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/virologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Nucleoproteínas/genética , Nucleoproteínas/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/virologia , Vacinas contra Vírus Sincicial Respiratório/genética , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Vírus Sincicial Respiratório Humano/patogenicidade , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/virologia , Células Th17/imunologia , Células Th17/virologia , Vacinas Sintéticas , Proteínas Virais/genética , Proteínas Virais/imunologiaRESUMO
Osteosarcomas are the most prevalent bone tumors in pediatric patients, but can also occur later in life. Bone tumors have the potential to metastasize to lung and occasionally other vital organs. To understand how osteosarcoma cells interact with their micro-environment to support bone tumor progression and metastasis, we analyzed secreted proteins and exosomes from three human osteosarcoma cell lines. Exosome isolation was validated by transmission electron microscopy (TEM) and immuno-blotting for characteristic biomarkers (CD63, CD9, and CD81). Exosomal and soluble proteins (less than 100 kDa) were identified by mass spectrometry analysis using nanoLC-MS/MS and classified by functional gene ontology clustering. We identified a secretome set of >3,000 proteins for both fractions, and detected proteins that are either common or unique among the three osteosarcoma cell lines. Protein ontology comparison of proteomes from exosomes and exosome-free fractions revealed differences in the enrichment of functional categories associated with different biological processes, including those related to tumor progression (i.e., angiogenesis, cell adhesion, and cell migration). The secretome characteristics of osteosarcoma cells are consistent with the pathological properties of tumor cells with metastatic potential. J. Cell. Biochem. 118: 351-360, 2017. © 2016 Wiley Periodicals, Inc.
Assuntos
Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/metabolismo , Exossomos/metabolismo , Proteínas de Neoplasias/metabolismo , Osteossarcoma/metabolismo , Linhagem Celular Tumoral , HumanosRESUMO
Globally, as a leading agent of acute respiratory tract infections in children <5 years of age and the elderly, the human metapneumovirus (HMPV) has gained considerable attention. As inferred from studies comparing vaccinated and experimentally infected mice, the acquired immune response elicited by this pathogen fails to efficiently clear the virus from the airways, which leads to an exaggerated inflammatory response and lung damage. Furthermore, after disease resolution, there is a poor development of T and B cell immunological memory, which is believed to promote reinfections and viral spread in the community. In this article, we discuss the molecular mechanisms that shape the interactions of HMPV with host tissues that lead to pulmonary pathology and to the development of adaptive immunity that fails to protect against natural infections by this virus.
Assuntos
Imunidade Adaptativa , Metapneumovirus/imunologia , Metapneumovirus/fisiologia , Infecções por Paramyxoviridae/imunologia , Infecções por Paramyxoviridae/patologia , Infecções Respiratórias/patologia , Animais , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Humanos , Camundongos , Infecções Respiratórias/imunologia , Infecções Respiratórias/virologiaRESUMO
Human respiratory syncytial virus (hRSV) is the leading cause of infant hospitalization related to respiratory disease. Infection with hRSV produces abundant infiltration of immune cells into the airways, which combined with an exacerbated pro-inflammatory immune response can lead to significant damage to the lungs. Human RSV re-infection is extremely frequent, suggesting that this virus may have evolved molecular mechanisms that interfere with host adaptive immunity. Infection with hRSV can be reduced by administering a humanized neutralizing antibody against the virus fusion protein in high-risk infants. Although neutralizing antibodies against hRSV effectively block the infection of airway epithelial cells, here we show that both, bone marrow-derived dendritic cells (DCs) and lung DCs undergo infection with IgG-coated virus (hRSV-IC), albeit abortive. Yet, this is enough to negatively modulate DC function. We observed that such a process is mediated by Fcγ receptors (FcγRs) expressed on the surface of DCs. Remarkably, we also observed that in the absence of hRSV-specific antibodies FcγRIII knockout mice displayed significantly less cellular infiltration in the lungs after hRSV infection, compared with wild-type mice, suggesting a potentially harmful, IgG-independent role for this receptor in hRSV disease. Our findings support the notion that FcγRs can contribute significantly to the modulation of DC function by hRSV and hRSV-IC. Further, we provide evidence for an involvement of FcγRIII in the development of hRSV pathogenesis.
Assuntos
Células Dendríticas/metabolismo , Pulmão/metabolismo , Ativação Linfocitária , Receptores de IgG/metabolismo , Infecções por Vírus Respiratório Sincicial/metabolismo , Vírus Sincicial Respiratório Humano/patogenicidade , Linfócitos T/metabolismo , Imunidade Adaptativa , Animais , Anticorpos Neutralizantes/farmacologia , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/metabolismo , Antivirais/farmacologia , Células Cultivadas , Técnicas de Cocultura , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/virologia , Modelos Animais de Doenças , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/virologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Palivizumab/farmacologia , Receptores de IgG/deficiência , Receptores de IgG/genética , Receptores de IgG/imunologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/genética , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Vírus Sincicial Respiratório Humano/imunologia , Transdução de Sinais , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologia , Carga Viral , Replicação ViralRESUMO
Acute respiratory tract infections (ARTIs) are the major cause of child mortality worldwide. The human metapneumovirus (hMPV) is one of the leading causes of child hospitalizations due to pneumonia. The adaptive immune response generated by the host against hMPV is usually inefficient at protecting from reinfections, which is repeat throughout life, from childhood to old age. Despite considerable research efforts, to date there are no licensed vaccines to prevent respiratory disease caused by hMPV infection. In this article we review current vaccine strategies tested in animal models and the implication of such studies in understanding the different immune cell populations that contribute to hMPV clearance and the prevention and resolution of lung inflammation upon exposure to the virus.
Assuntos
Pulmão/imunologia , Metapneumovirus/fisiologia , Infecções por Paramyxoviridae/imunologia , Infecções Respiratórias/imunologia , Vacinas Virais/imunologia , Doença Aguda , Idoso , Animais , Criança , Modelos Animais de Doenças , Humanos , Pulmão/patologia , Pulmão/virologia , Carga ViralRESUMO
INTRODUCTION: Human respiratory syncytial virus (hRSV) is the leading cause of acute lower respiratory tract infections worldwide in infants, as well as an important pathogen affecting the elderly and immunocompromised individuals. Despite more than a half a century of research, no licensed vaccines are available and only palivizumab has been approved to use in humans, mostly recommended or limited to high risk infants. Therefore, novel therapeutic and preventive drugs need to be developed to fight this major human pathogen. AREAS COVERED: This review discusses current therapeutic approaches in preclinical and clinical stages, aimed at controlling or preventing hRSV infection. These methods include passive immunization, experimental drugs, vaccine candidates and maternal immunization. EXPERT OPINION: Based on the results of various immunization strategies and therapeutic approaches, it is likely that the most effective strategy against hRSV will be a prophylactic tool aimed at developing a strong antiviral T-cell response capable of both, promoting the generation of hRSV-specific high affinity antibodies and leading the protective immunity required to prevent the disease caused by this virus. Alternatively, if prophylactic strategies fail, antiviral drugs and novel passive immunity strategies could significantly contribute to reducing hospitalization rates in susceptible individuals.
Assuntos
Antivirais/administração & dosagem , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Idoso , Animais , Antivirais/uso terapêutico , Desenho de Fármacos , Humanos , Hospedeiro Imunocomprometido , Lactente , Palivizumab/administração & dosagem , Palivizumab/uso terapêutico , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vírus Sincicial Respiratório Humano/isolamento & purificação , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/prevenção & controle , Infecções Respiratórias/virologiaRESUMO
Human metapneumovirus (hMPV) is a leading cause of acute respiratory tract infections in children and the elderly. The mechanism by which this virus triggers an inflammatory response still remains unknown. Here, we evaluated whether the thymic stromal lymphopoietin (TSLP) pathway contributes to lung inflammation upon hMPV infection. We found that hMPV infection promotes TSLP expression both in human airway epithelial cells and in the mouse lung. hMPV infection induced lung infiltration of OX40L(+) CD11b(+) DCs. Mice lacking the TSLP receptor deficient mice (tslpr(-/-) ) showed reduced lung inflammation and hMPV replication. These mice displayed a decreased number of neutrophils as well a reduction in levels of thymus and activation-regulated chemokine/CCL17, IL-5, IL-13, and TNF-α in the airways upon hMPV infection. Furthermore, a higher frequency of CD4(+) and CD8(+) T cells was found in tslpr(-/-) mice compared to WT mice, which could contribute to controlling viral spread. Depletion of neutrophils in WT and tslpr(-/-) mice decreased inflammation and hMPV replication. Remarkably, blockage of TSLP or OX40L with specific Abs reduced lung inflammation and viral replication following hMPV challenge in mice. Altogether, these results suggest that activation of the TSLP pathway is pivotal in the development of pulmonary pathology and pulmonary hMPV replication.
Assuntos
Citocinas/metabolismo , Metapneumovirus/fisiologia , Infecções por Paramyxoviridae/metabolismo , Infecções por Paramyxoviridae/virologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Transdução de Sinais , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Linhagem Celular , Citocinas/genética , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Expressão Gênica , Humanos , Interleucina-33 , Interleucina-8/genética , Interleucina-8/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Metapneumovirus/efeitos dos fármacos , Camundongos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Ligante OX40/antagonistas & inibidores , Ligante OX40/genética , Ligante OX40/metabolismo , Infecções por Paramyxoviridae/tratamento farmacológico , Infecções por Paramyxoviridae/genética , Infecções por Paramyxoviridae/patologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Pneumonia Viral/patologia , Receptores de Citocinas/antagonistas & inibidores , Receptores de Citocinas/deficiência , Transdução de Sinais/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Replicação Viral , Linfopoietina do Estroma do TimoRESUMO
Globally, the human respiratory syncytial virus (hRSV) is the major cause of lower respiratory tract infections (LRTIs) in infants and children younger than 2 years old. Furthermore, the number of hospitalizations due to LRTIs has shown a sustained increase every year due to the lack of effective vaccines against hRSV. Thus, this virus remains as a major public health and economic burden worldwide. The lung pathology developed in hRSV-infected humans is characterized by an exacerbated inflammatory and Th2 immune response. In order to rationally design new vaccines and therapies against this virus, several studies have focused in elucidating the interactions between hRSV virulence factors and the host immune system. Here, we discuss the main features of hRSV biology, the processes involved in virus recognition by the immune system and the most relevant mechanisms used by this pathogen to avoid the antiviral host response.
Assuntos
Imunidade Adaptativa , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Vírus Sincicial Respiratório Humano/patogenicidade , Proteínas Virais/fisiologia , Fatores de Virulência/fisiologia , Criança , Pré-Escolar , Genoma Viral , Humanos , Evasão da Resposta Imune , Imunidade Inata , Lactente , Ativação Linfocitária , Vírus Sincicial Respiratório Humano/fisiologia , Proteínas Virais/genética , Proteínas Virais/imunologiaRESUMO
BACKGROUND: The clinical manifestations of endometriosis are infertility, dysmenorrhea, sexuality disturbances, and chronic pelvic pain. It is the cause of 30 to 50% of infertility cases. In developed countries, the prevalence of endometriosis among women undergoing surgical sterilization is approximately 6%. AIM: To determine the prevalence of endometriosis among women with proven fertility in Santiago de Chile. MATERIAL AND METHODS: Review of surgical protocols of 287 women aged 25 to 49 years, subjected to a surgical sterilization between 2007 and 2011. RESULTS: Endometriosis was found in 14 of the 287 women (4.9%). In spite of being asymptomatic, five of the 14 women with endometriosis were classified as severe, due to the presence of at least one endometrioma. In order of frequency, the most commonly affected anatomical sites were the ovary, the peritoneum, the posterior cul-de-sac and uterosacral ligaments. CONCLUSIONS: Our findings are very similar to those found elsewhere and suggest that fertile women could better tolerate endometriosis than their infertile counterparts.
Assuntos
Endometriose/epidemiologia , Esterilização Tubária/estatística & dados numéricos , Adulto , Chile/epidemiologia , Endometriose/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Prevalência , Estudos RetrospectivosRESUMO
Background: The clinical manifestations of endometriosis are infertility, dysmenorrhea, sexuality disturbances, and chronic pelvic pain. It is the cause of 30 to 50% of infertility cases. In developed countries, the prevalence of endometriosis among women undergoing surgical sterilization is approximately 6%. Aim: To determine the prevalence of endometriosis among women with proven fertility in Santiago de Chile. Material and Methods: Review of surgical protocols of 287 women aged 25 to 49 years, subjected to a surgical sterilization between 2007 and 2011. Results: Endometriosis was found in 14 of the 287 women (4.9%). In spite of being asymptomatic, five of the 14 women with endometriosis were classified as severe, due to the presence of at least one endometrioma. In order of frequency, the most commonly affected anatomical sites were the ovary, the peritoneum, the posterior cul-de-sac and uterosacral ligaments. Conclusions: Our findings are very similar to those found elsewhere and suggest that fertile women could better tolerate endometriosis than their infertile counterparts.
Assuntos
Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Endometriose/epidemiologia , Esterilização Tubária/estatística & dados numéricos , Chile/epidemiologia , Endometriose/diagnóstico , Prevalência , Estudos RetrospectivosRESUMO
BACKGROUND: Smoking may hamper female fertility, probably modifying ovarian reserve. Antimüllerian hormone (AMH) is an accurate marker for ovarian reserve. AIM: To look for an association between smoking status and plasma AMH concentration. PATIENTS AND METHODS: A cohort of 141 infertile women in a university setting in Santiago, Chile was studied. Demographic and smoking data, including the number of cigarettes smoked during the last week, were collected. A blood sample was obtained and kept frozen until determination of AMH by ELISA and follicle stimulating hormone (FSH) and estradiol at day three of the menstrual cycle, by radioimmunoanalysis. RESULTS: Thirty two participants smoked (23%). There were no significant differences in age, parity, body mass index, causes of infertility and day three FSH and estradiol between smokers and nonsmokers. According to a regression analysis, there was a significant decrease in AMH concentration with age and active cigarette smoking. A drop in AMH of -0.189 ng/mL with a unitary change in age and a decrease of -2.29 ng/mL when everything else remains constant, except the smoking status, were established (p < 0.001 and r2 = 0.134). However, no dose response was observed when the number of cigarettes smoked during the last week were introduced in the model. Furthermore, no significant association of plasma AMH with day three plasma FSH and estradiol concentrations was observed. CONCLUSIONS: Cigarette smoking is associated with decreased AMH plasma concentrations among infertile women. However there was no dose response relationship. The mechanisms underlying this association are unknown and further investigation is required.
Assuntos
Hormônio Antimülleriano/sangue , Infertilidade Feminina/sangue , Ovário/metabolismo , Fumar/sangue , Adulto , Biomarcadores/sangue , Feminino , Humanos , Modelos Lineares , Fumar/efeitos adversos , Estatísticas não ParamétricasRESUMO
Respiratory syncytial virus (RSV) is the major cause of respiratory illness in infants worldwide. Neurologic alterations, such as seizures and ataxia, have been associated with RSV infection. We demonstrate the presence of RSV proteins and RNA in zones of the brain--such as the hippocampus, ventromedial hypothalamic nucleus, and brainstem--of infected mice. One month after disease resolution, rodents showed behavioral and cognitive impairment in marble burying (MB) and Morris water maze (MWM) tests. Our data indicate that the learning impairment caused by RSV is a result of a deficient induction of long-term potentiation in the hippocampus of infected animals. In addition, immunization with recombinant bacillus Calmette-Guérin (BCG) expressing RSV nucleoprotein prevented behavioral disorders, corroborating the specific effect of RSV infection over the central nervous system. Our findings provide evidence that RSV can spread from the airways to the central nervous system and cause functional alterations to the brain, both of which can be prevented by proper immunization against RSV.
Assuntos
Encéfalo/metabolismo , Deficiências da Aprendizagem/etiologia , RNA Viral/metabolismo , Infecções por Vírus Respiratório Sincicial/complicações , Infecções por Vírus Respiratório Sincicial/imunologia , Proteínas Virais/metabolismo , Animais , Encéfalo/patologia , Deficiências da Aprendizagem/prevenção & controle , Deficiências da Aprendizagem/virologia , Potenciação de Longa Duração/fisiologia , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium bovis/imunologia , Ratos , Ratos Sprague-Dawley , Infecções por Vírus Respiratório Sincicial/metabolismo , Linfócitos T/imunologia , Vacinas Virais/imunologiaRESUMO
To circumvent pathology caused by infectious microbes and tumor growth, the host immune system must constantly clear harmful microorganisms and potentially malignant transformed cells. This task is accomplished in part by T-cells, which can directly kill infected or tumorigenic cells. A crucial event determining the recognition and elimination of detrimental cells is antigen recognition by the T cell receptor (TCR) expressed on the surface of T cells. Upon binding of the TCR to cognate peptide-MHC complexes presented on the surface of antigen presenting cells (APCs), a specialized supramolecular structure known as the immunological synapse (IS) assembles at the T cell-APC interface. Such a structure involves massive redistribution of membrane proteins, including TCR/pMHC complexes, modulatory receptor pairs, and adhesion molecules. Furthermore, assembly of the immunological synapse leads to intracellular events that modulate and define the magnitude and characteristics of the T cell response. Here, we discuss recent literature on the regulation and assembly of IS and the mechanisms evolved by tumors to modulate its function to escape T cell cytotoxicity, as well as novel strategies targeting the IS for therapy.