Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 29
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Eur J Cancer ; 143: 147-157, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33307492

RESUMO

BACKGROUND: Liquid biopsy provides real-time data about prognosis and actionable mutations in metastatic breast cancer (MBC). The aim of this study was to explore the combination of circulating tumour DNA (ctDNA) analysis and circulating tumour cells (CTCs) enumeration in estimating target organs more susceptible to MBC involvement. METHODS: This retrospective study analysed 88 MBC patients characterised for both CTCs and ctDNA at baseline. CTCs were isolated through the CellSearch kit, while ctDNA was analysed using the Guardant360 NGS-based assay. Sites of disease were collected on the basis of imaging. Associations were explored both through uni- and multivariate logistic regression and Fisher's exact test and the random forest machine learning algorithm. RESULTS: After multivariate logistic regression, ESR1 mutation was the only significant factor associated with liver metastases (OR 8.10), while PIK3CA was associated with lung localisations (OR 3.74). CTC enumeration was independently associated with bone metastases (OR 10.41) and TP53 was associated with lymph node localisations (OR 2.98). The metastatic behaviour was further investigated through a random forest machine learning algorithm. Bone involvement was described by CTC enumeration and alterations in ESR1, GATA3, KIT, CDK4 and ERBB2, while subtype, CTC enumeration, inflammatory BC diagnosis, ESR1 and KIT aberrations described liver metastases. PIK3CA, MET, AR, CTC enumeration and TP53 were associated with lung organotropism. The model, moreover, showed that AR, CCNE1, ESR1, MYC and CTC enumeration were the main drivers in HR positive MBC metastatic pattern. CONCLUSIONS: These results indicate that ctDNA and CTCs enumeration could provide useful insights regarding MBC organotropism, suggesting a possible role for future monitoring strategies that dynamically focus on high-risk organs defined by tumourbiology.


Assuntos
Neoplasias da Mama/diagnóstico , DNA Tumoral Circulante/metabolismo , Biópsia Líquida/métodos , Células Neoplásicas Circulantes/metabolismo , Medicina de Precisão/métodos , Tropismo/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Aprendizado de Máquina , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos
2.
J Virol ; 94(10)2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32102889

RESUMO

Human adenoviruses have many attractive features for gene therapy applications. However, the high prevalence of preexisting immunity against these viruses in general populations worldwide has greatly limited their clinical utility. In addition, the most commonly used human adenovirus, human adenovirus subgroup C serotype 5 (HAd5), when systemically administered, triggers systemic inflammation and toxicity, with the liver being the most severely affected organ. Here, we evaluated the utility and safety of a new low-seroprevalence gorilla adenovirus (GAd; GC46) as a gene transfer vector in mice. Biodistribution studies revealed that systemically administered GAd had a selective and robust lung endothelial cell (EC) tropism with minimal vector expression throughout many other organs and tissues. Administration of a high dose of GAd accomplished extensive transgene expression in the lung yet elicited no detectable inflammatory histopathology in this organ. Furthermore, GAd, unlike HAd5, did not exhibit hepatotropism or induce liver inflammatory toxicity in mice, demonstrating the exceptional safety profile of the vector vis-à-vis systemic utility. We further demonstrated that the GAd capsid fiber shared the flexibility of the HAd5 equivalent for permitting genetic modification; GAd with the pan-EC-targeting ligand myeloid cell-binding peptide (MBP) incorporated in the capsid displayed a reduced lung tropism and efficiently retargeted gene expression to vascular beds in other organs.IMPORTANCE In the aggregate, our mouse studies suggest that GAd is a promising gene therapy vector that utilizes lung ECs as a source of therapeutic payload production and a highly desirable toxicity profile. Further genetic engineering of the GAd capsid holds the promise of in vivo vector tropism modification and targeting.


Assuntos
Adenoviridae/genética , Capsídeo/metabolismo , Vetores Genéticos , Gorilla gorilla/virologia , Pulmão/metabolismo , Tropismo/imunologia , Infecções por Adenoviridae/patologia , Infecções por Adenoviridae/virologia , Adenovírus Humanos/genética , Animais , Proteínas do Capsídeo/genética , Células Endoteliais , Expressão Gênica , Terapia Genética , Fígado , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos C57BL , Estudos Soroepidemiológicos , Transdução Genética , Transgenes , Vírion
3.
Nat Biotechnol ; 37(10): 1163-1173, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31451733

RESUMO

A major limitation of current humanized mouse models is that they primarily enable the analysis of human-specific pathogens that infect hematopoietic cells. However, most human pathogens target other cell types, including epithelial, endothelial and mesenchymal cells. Here, we show that implantation of human lung tissue, which contains up to 40 cell types, including nonhematopoietic cells, into immunodeficient mice (lung-only mice) resulted in the development of a highly vascularized lung implant. We demonstrate that emerging and clinically relevant human pathogens such as Middle East respiratory syndrome coronavirus, Zika virus, respiratory syncytial virus and cytomegalovirus replicate in vivo in these lung implants. When incorporated into bone marrow/liver/thymus humanized mice, lung implants are repopulated with autologous human hematopoietic cells. We show robust antigen-specific humoral and T-cell responses following cytomegalovirus infection that control virus replication. Lung-only mice and bone marrow/liver/thymus-lung humanized mice substantially increase the number of human pathogens that can be studied in vivo, facilitating the in vivo testing of therapeutics.


Assuntos
Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Pulmão/fisiologia , Infecção por Zika virus/virologia , Animais , Anticorpos Antivirais , Células Apresentadoras de Antígenos , Infecções por Coronavirus/imunologia , Citocinas/genética , Citocinas/metabolismo , Citomegalovirus/fisiologia , Feminino , Regulação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos SCID , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Tropismo/imunologia , Replicação Viral , Zika virus/imunologia , Infecção por Zika virus/imunologia
4.
J Virol ; 93(6)2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30602604

RESUMO

Gammaherpesviruses are ubiquitous viruses that establish lifelong infections. Importantly, these viruses are associated with numerous cancers and lymphoproliferative diseases. While risk factors for developing gammaherpesvirus-driven cancers are poorly understood, it is clear that elevated viral reactivation from latency often precedes oncogenesis. Here, we demonstrate that the liver X receptor alpha isoform (LXRα) restricts gammaherpesvirus reactivation in an anatomic-site-specific manner. We have previously demonstrated that deficiency of both LXR isoforms (α and ß) leads to an increase in fatty acid and cholesterol synthesis in primary macrophage cultures, with a corresponding increase in gammaherpesvirus replication. Interestingly, expression of fatty acid synthesis genes was not derepressed in LXRα-deficient hosts, indicating that the antiviral effects of LXRα are independent of lipogenesis. Additionally, the critical host defenses against gammaherpesvirus reactivation, virus-specific CD8+ T cells and interferon (IFN) signaling, remained intact in the absence of LXRα. Remarkably, using a murine gammaherpesvirus 68 (MHV68) reporter virus, we discovered that LXRα expression dictates the cellular tropism of MHV68 in the peritoneal cavity. Specifically, LXRα-/- mice exhibit reduced latency within the peritoneal B cell compartment and elevated latency within F4/80+ cells. Thus, LXRα restricts gammaherpesvirus reactivation through a novel mechanism that is independent of the known CD8+ T cell-based antiviral responses or changes in lipid synthesis and likely involves changes in the tropism of MHV68 in the peritoneal cavity.IMPORTANCE Liver X receptors (LXRs) are nuclear receptors that mediate cholesterol and fatty acid homeostasis. Importantly, as ligand-activated transcription factors, LXRs represent potential targets for the treatment of hypercholesterolemia and atherosclerosis. Here, we demonstrate that LXRα, one of the two LXR isoforms, restricts reactivation of latent gammaherpesvirus from peritoneal cells. As gammaherpesviruses are ubiquitous oncogenic agents, LXRs may represent a targetable host factor for the treatment of poorly controlled gammaherpesvirus infection and associated lymphomagenesis.


Assuntos
Linfócitos B/virologia , Gammaherpesvirinae/imunologia , Gammaherpesvirinae/fisiologia , Infecções por Herpesviridae/imunologia , Receptores X do Fígado/imunologia , Cavidade Peritoneal/virologia , Latência Viral/imunologia , Animais , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Feminino , Infecções por Herpesviridae/virologia , Interações Hospedeiro-Patógeno/imunologia , Interferons/imunologia , Lipogênese/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peritônio/imunologia , Peritônio/virologia , Transdução de Sinais/imunologia , Tropismo/imunologia , Ativação Viral/imunologia , Replicação Viral/imunologia
5.
J Immunol ; 200(12): 3970-3980, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29720424

RESUMO

Recent evidence suggests early environmental factors are important for gut immune tolerance. Although the role of regulatory T (Treg) cells for gut immune homeostasis is well established, the development and tissue homing characteristics of Treg cells in children have not been studied in detail. In this article, we studied the development and homing characteristics of human peripheral blood Treg cell subsets and potential mechanisms inducing homing molecule expression in healthy children. We found contrasting patterns of circulating Treg cell gut and skin tropism, with abundant ß7 integrin+ Treg cells at birth and increasing cutaneous lymphocyte Ag (CLA+) Treg cells later in life. ß7 integrin+ Treg cells were predominantly naive, suggesting acquisition of Treg cell gut tropism early in development. In vitro, IL-7 enhanced gut homing but reduced skin homing molecule expression in conventional T cells, whereas IL-2 induced a similar effect only in Treg cells. This effect was more pronounced in cord compared with adult blood. Our results suggest that early in life, naive Treg cells may be driven for gut tropism by their increased sensitivity to IL-2-induced ß7 integrin upregulation, implicating a potential role of IL-2 in gut immune tolerance during this critical period of development.


Assuntos
Trato Gastrointestinal/imunologia , Interleucina-2/imunologia , Receptores de Retorno de Linfócitos/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Antígenos/imunologia , Células Cultivadas , Criança , Pré-Escolar , Feminino , Humanos , Tolerância Imunológica/imunologia , Lactente , Recém-Nascido , Cadeias beta de Integrinas/imunologia , Interleucina-7/imunologia , Masculino , Pele/imunologia , Tropismo/imunologia , Regulação para Cima/imunologia
6.
Microb Pathog ; 117: 206-218, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29476787

RESUMO

Here, we studied the in vivo expression of Th1 (IL2 and IFN gamma) and Th2 (IL4 and IL10) - cytokines and antiviral molecules - IRF3 and ISG15 in peripheral blood mononuclear cells in relation to antigen and antibody dynamics under Peste des petits ruminants virus (PPRV) vaccination, infection and challenge in both sheep and goats. Vaccinated goats were seropositive by 9 days post vaccination (dpv) while in sheep idiosyncratic response was observed between 9 and 14 dpv for different animals. Expression of PPRV N gene was not detected in PBMCs of vaccinated and vaccinated challenged groups of both species, but was detected in unvaccinated infected PBMCs at 9 and 14 days post infection. The higher viral load at 9 dpi coincided with the peak clinical signs of the disease. The peak in viral replication at 9 dpi correlated with significant expression of antiviral molecules IRF3, ISG15 and IFN gamma in both the species. With the progression of disease, the decrease in N gene expression also correlated with the decrease in expression of IRF3, ISG15 and IFN gamma. In the unvaccinated infected animals ISG15, IRF3, IFN gamma and IL10 expression was higher than vaccinated animals. The IFN gamma expression predominated over IL4 in both vaccinated and infected animals with the infected exhibiting a stronger Th1 response. The persistent upregulation of this antiviral molecular signature - ISG15 and IRF3 even after 2 weeks post vaccination, presumably reflects the ongoing stimulation of innate immune cells.


Assuntos
Citocinas/biossíntese , Regulação da Expressão Gênica/imunologia , Peste dos Pequenos Ruminantes/imunologia , Vírus da Peste dos Pequenos Ruminantes/imunologia , Tropismo/imunologia , Vacinação/veterinária , Vacinas Virais/imunologia , Eliminação de Partículas Virais/imunologia , Animais , Anticorpos Antivirais/sangue , Antígenos Virais/sangue , Antivirais/farmacologia , Citocinas/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Genes Virais/genética , Doenças das Cabras/imunologia , Doenças das Cabras/prevenção & controle , Doenças das Cabras/virologia , Cabras , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Fator Regulador 3 de Interferon/biossíntese , Fator Regulador 3 de Interferon/genética , Interferon gama/biossíntese , Interferon gama/genética , Interleucina-10/biossíntese , Interleucina-10/genética , Interleucina-2/biossíntese , Interleucina-2/genética , Interleucina-4/biossíntese , Interleucina-4/genética , Cinética , Leucócitos Mononucleares/imunologia , Peste dos Pequenos Ruminantes/patologia , Peste dos Pequenos Ruminantes/prevenção & controle , Peste dos Pequenos Ruminantes/virologia , Vírus da Peste dos Pequenos Ruminantes/genética , Vírus da Peste dos Pequenos Ruminantes/patogenicidade , Ruminantes/imunologia , Ovinos , Doenças dos Ovinos/imunologia , Doenças dos Ovinos/prevenção & controle , Doenças dos Ovinos/virologia , Fatores de Tempo , Vacinas Atenuadas/imunologia , Carga Viral , Replicação Viral
7.
Geroscience ; 39(3): 251-259, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28681110

RESUMO

Human cytomegalovirus (CMV) is one of the largest viruses known to cause human diseases. Chronic CMV infection, as defined by anti-CMV IgG serology, increases with age and is highly prevalent in older adults. It has complex biology with significant immunologic and health consequences. This article aims to summarize research findings presented at the 6th International Workshop on CMV and Immunosenescence that relate to advances in the areas of CMV tropism, latency, CMV manipulation of cell metabolism, and T cell memory inflation, as well as novel diagnostic evaluation and translational research of chronic CMV infection in older adults. Information summarized here represents the current state of knowledge in these important fields. Investigators have also identified a number of areas that deserve further and more in-depth investigation, including building more precise parallels between mouse CMV (mCMV) and human CMV (HCMV) research. It is hoped that this article will also stimulate engaging discussion on strategies and direction to advance the science to the next level.


Assuntos
Envelhecimento/imunologia , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Imunossenescência , Idoso , Animais , Anticorpos Antivirais/sangue , Biomarcadores/sangue , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/epidemiologia , Humanos , Imunoglobulina G/sangue , Memória Imunológica/imunologia , Linfócitos T/imunologia , Tropismo/imunologia , Estados Unidos/epidemiologia , Latência Viral/imunologia
8.
Proc Natl Acad Sci U S A ; 114(23): 6104-6109, 2017 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-28533400

RESUMO

Human cytomegalovirus (HCMV) strains that have been passaged in vitro rapidly acquire mutations that impact viral growth. These laboratory-adapted strains of HCMV generally exhibit restricted tropism, produce high levels of cell-free virus, and develop susceptibility to natural killer cells. To permit experimentation with a virus that retained a clinically relevant phenotype, we reconstructed a wild-type (WT) HCMV genome using bacterial artificial chromosome technology. Like clinical virus, this genome proved to be unstable in cell culture; however, propagation of intact virus was achieved by placing the RL13 and UL128 genes under conditional expression. In this study, we show that WT-HCMV produces extremely low titers of cell-free virus but can efficiently infect fibroblasts, epithelial, monocyte-derived dendritic, and Langerhans cells via direct cell-cell transmission. This process of cell-cell transfer required the UL128 locus, but not the RL13 gene, and was significantly less vulnerable to the disruptive effects of IFN, cellular restriction factors, and neutralizing antibodies compared with cell-free entry. Resistance to neutralizing antibodies was dependent on high-level expression of the pentameric gH/gL/gpUL128-131A complex, a feature of WT but not passaged strains of HCMV.


Assuntos
Técnicas de Cultura de Células/métodos , Citomegalovirus/genética , Citomegalovirus/metabolismo , Anticorpos Neutralizantes , Linhagem Celular , Células Cultivadas , Cromossomos Artificiais Bacterianos/metabolismo , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/metabolismo , Fibroblastos/metabolismo , Humanos , Glicoproteínas de Membrana/metabolismo , Mutação , Fenótipo , Tropismo/imunologia , Proteínas do Envelope Viral/metabolismo , Internalização do Vírus , Replicação Viral/imunologia
9.
Med Sci (Paris) ; 30(6-7): 644-50, 2014.
Artigo em Francês | MEDLINE | ID: mdl-25014455

RESUMO

Endometrial receptivity to embryo implantation is one of the fundamental features of reproduction. Success of natural or assisted embryo implantation is low (20-25%). Implantation remains the result of a successful collaboration, tightly regulated and closely coordinated, between maternal and embryonic tissues located at the crossroads of endocrinology and immunology. In scientific terms, this collaboration is a mystery of human reproduction. The implanted blastocyst within the endometrium is dependent on a fine-tuned synchronization. Therefore, an accurate dialogue between the mother and the embryo is timely required to orchestrate mutual and well-synchronized changes in the developing embryo and maternal responsiveness in order to achieve a successful implantation. Maternal-derived mediators, such as steroid hormones, matrix-degrading enzymes, integrins, cytokines, chemokines, and many embryonic growth factors could be involved in the feto-maternal dialogue. Therefore, what is the maternal molecular signature compatible with embryo implantation?


Assuntos
Implantação do Embrião/genética , Interleucina-1/fisiologia , Animais , Citocinas/fisiologia , Embrião de Mamíferos/imunologia , Embrião de Mamíferos/metabolismo , Endométrio/imunologia , Endométrio/metabolismo , Feminino , Humanos , Imunidade , Gravidez , Tropismo/imunologia
10.
J Virol ; 88(16): 9010-6, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24899187

RESUMO

UNLABELLED: The migration of pathogen-specific T cells into nonlymphoid tissues, such as the lung, is critical to control peripheral infections. Use of in vivo intravascular labeling of leukocytes has allowed for improved discrimination between cells located in the blood from cells present within peripheral tissues, such as the lung. This is particularly important in the lung, which is comprised of an intricate network of blood vessels that harbors a large proportion of the total blood volume at any given time. Recent work has demonstrated that >80% of antigen-specific effector CD8 T cells remain in the pulmonary vasculature following an intratracheal infection with a systemic viral pathogen. However, it remains unclear what proportion of effector CD8 T cells are located within lung tissue following a localized respiratory viral infection. We confirm that most effector and memory CD8 T cells are found in the vasculature after an intranasal infection with the systemic pathogens lymphocytic choriomeningitis virus (LCMV) or vaccinia virus (VACV). In contrast, following pulmonary viral infections with either respiratory syncytial virus (RSV) or influenza A virus (IAV), 80 to 90% of the antigen-specific effector CD8 T cells were located within lung tissue. Similarly, the majority of antigen-specific CD4 T cells were present within lung tissue during a pulmonary viral infection. Furthermore, a greater proportion of gamma interferon-positive (IFN-γ(+)) effector CD8 and CD4 T cells were located within lung tissue following a localized respiratory viral infection. Our results indicate that T cells exhibit significantly altered distribution patterns dependent upon the tissue tropism of the infection. IMPORTANCE: The migration of T cells to nonlymphoid sites, such as the lung, is critical to mediate clearance of viral infections. The highly vascularized lung holds up to 40% of blood, and thus, the T cell response may be a reflection of lymphocytes localized to the pulmonary vasculature instead of lung tissue. We examined the localization of T cell responses within the lung following either a localized or systemic viral infection. We demonstrate that following intranasal infection with a systemic pathogen, most T cells are localized to the pulmonary vasculature. In contrast, T cells are primarily localized to lung tissue following a respiratory viral infection. Our results demonstrate vast differences in the localization of T cell responses within the lung parenchyma between pathogens that can replicate locally versus systemically and that intravascular antibody labeling can be utilized to assess the localization patterns of T cell responses in nonlymphoid organs.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Pulmão/imunologia , Tropismo/imunologia , Animais , Vírus da Influenza A/imunologia , Interferon gama/imunologia , Pulmão/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/imunologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/virologia
11.
Biol Blood Marrow Transplant ; 20(7): 920-8, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24691220

RESUMO

We reported previously that anti-CD3 mAb treatment before hematopoietic cell transplantation (HCT) prevented graft-versus-host disease (GVHD) and preserved graft-versus-leukemia (GVL) effects in mice. These effects were associated with downregulated donor T cell expression of tissue-specific homing and chemokine receptors, marked reduction of donor T cell migration into GVHD target tissues, and deletion of CD103(+) dendritic cells (DCs) in mesenteric lymph nodes (MLN). MLN CD103(+) DCs and peripheral lymph node (PLN) DCs include CCR7(+) and CCR7(-) subsets, but the role of these DC subsets in regulating donor T cell expression of homing and chemokine receptors remain unclear. Here, we show that recipient CCR7(+), but not CCR7(-), DCs in MLN induced donor T cell expression of gut-specific homing and chemokine receptors in a retinoid acid-dependent manner. CCR7 regulated activated DC migration from tissue to draining lymph node, but it was not required for the ability of DCs to induce donor T cell expression of tissue-specific homing and chemokine receptors. Finally, anti-CD3 treatment depleted CCR7(+) but not CCR7(-) DCs by inducing sequential expansion and apoptosis of CCR7(+) DCs in MLN and PLN. Apoptosis of CCR7(+) DCs was associated with DC upregulation of Fas expression and natural killer cell but not T, B, or dendritic cell upregulation of FasL expression in the lymph nodes. These results suggest that depletion of CCR7(+) host-type DCs, with subsequent inhibition of donor T cell migration into GVHD target tissues, can be an effective approach in prevention of acute GVHD and preservation of GVL effects.


Assuntos
Células Dendríticas/imunologia , Receptores CCR7/imunologia , Linfócitos T/imunologia , Linfócitos T/transplante , Condicionamento Pré-Transplante/métodos , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Complexo CD3/imunologia , Movimento Celular/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Quimiocinas/imunologia , Doadores de Tecidos , Transplante Homólogo , Tropismo/imunologia
12.
Lancet Respir Med ; 1(7): 534-42, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24461614

RESUMO

BACKGROUND: Since March, 2013, an avian-origin influenza A H7N9 virus has caused severe pneumonia in China. The aim of this study was to investigate the pathogenesis of this new virus in human beings. METHODS: We obtained ex-vivo cultures of the human bronchus, lung, nasopharynx, and tonsil and in-vitro cultures of primary human alveolar epithelial cells and peripheral blood monocyte-derived macrophages. We compared virus tropism and induction of proinflammatory cytokine responses of two human influenza A H7N9 virus isolates, A/Shanghai/1/2013 and A/Shanghai/2/2013; a highly pathogenic avian influenza H5N1 virus; the highly pathogenic avian influenza H7N7 virus that infected human beings in the Netherlands in 2003; the 2009 pandemic influenza H1N1 virus, and a low pathogenic duck H7N9 virus that was genetically different to the human disease causing A H7N9 viruses. FINDINGS: Both human H7N9 viruses replicated efficiently in human bronchus and lung ex-vivo cultures, whereas duck/H7N9 virus failed to replicate in either. Both human A H7N9 viruses infected both ciliated and non-ciliated human bronchial epithelial cells and replicated to higher titres than did H5N1 (p<0.0001 to 0.0046) and A/Shanghai/1/2013 replicated to higher titres than did H7N7 (p=0.0002-0.01). Both human A H7N9 viruses predominantly infected type II alveolar epithelial cells and alveolar macrophages in the human lung and replicated to higher titres than did H5N1 (p<0.0001 to 0.0078); A/Shanghai/1/2013 replicated to higher titres than did H1N1 (p=0.0052-0.05) and H7N7 (p=0.0031-0.0151). Human H7N9 viruses were less potent inducers of proinflammatory cytokines compared with H5N1 virus. INTERPRETATION: Collectively, the results suggest that the novel H7N9 viruses are better adapted to infect and replicate in the human conducting and lower airways than are other avian influenza viruses, including H5N1, and pose an important pandemic threat. FUNDING: Area of Excellence Scheme of the University Grants Committee (AoE/M-12/96), Hong Kong Special Administrative Region.


Assuntos
Imunidade Inata/imunologia , Vírus da Influenza A Subtipo H7N7/imunologia , Influenza Humana/imunologia , Sistema Respiratório/imunologia , Células Cultivadas , Citocinas/metabolismo , Genes Virais/imunologia , Humanos , Imuno-Histoquímica , Macrófagos/imunologia , Macrófagos/virologia , Sistema Respiratório/virologia , Tropismo/imunologia , Regulação para Cima/imunologia
13.
Immunol Cell Biol ; 90(8): 763-73, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22546735

RESUMO

Hepatitis C virus (HCV) infection is a global pandemic associated with a growing disease burden due to cirrhosis and the consequent morbidity and mortality. Transmission is largely via blood-to-blood contact. Following primary infection, a minority of individuals clear the infection predominantly via cellular immune mechanisms, whereas the majority become chronically infected. Recent data suggest that a third outcome may also be possible, termed 'occult' infection in which subjects who are known, or suspected to have previously been infected with HCV, no longer have viral RNA in their serum at levels detectable by sensitive commercial assays, but do have virus detected by ultra-sensitive techniques. Occult infection has also been detected in peripheral blood mononuclear cells, which may indicate an extra-hepatic reservoir of the virus. Although the clinical significance of occult infection remains unknown, most authors have raised concerns of recrudescent infection. Here we critically review the published literature, suggest further avenues of investigation and propose that occult infection may be beneficial to the host by maintaining immunological memory to protect against reinfection.


Assuntos
Hepacivirus/fisiologia , Hepatite C/diagnóstico , Hepatite C/virologia , Animais , Antivirais/uso terapêutico , Técnicas e Procedimentos Diagnósticos , Hepacivirus/imunologia , Hepacivirus/isolamento & purificação , Hepatite C/tratamento farmacológico , Hepatite C/imunologia , Humanos , RNA Viral/sangue , RNA Viral/genética , Tropismo/imunologia
14.
AIDS Res Hum Retroviruses ; 28(10): 1344-8, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22264071

RESUMO

In Vietnam, where an estimated 280,000 people will be HIV-positive by 2012, recommended antiretroviral regimens do not include more recently developed therapeutics, such as Integrase inhibitors (INI) and coreceptor antagonists. This study examined HIV-1 coreceptor tropism and INI drug resistance profiles, in parallel with CCR5 genotypes, in a cohort of 60 HIV-positive individuals from different regions of Vietnam. No evidence of INI resistance was detected. Some 40% of individuals had X4-tropic HIV-1, making them unsuitable for treatment with CCR5 antagonists. We identified a novel CCR5 variant-S272P-along with other, previously reported variants: G106R, C178R, W153C, R223Q, and S336I. Interestingly, CCR5 variants known to affect HIV-1 infectivity were observed only in individuals harboring X4-tropic virus. Together, this study presents valuable baseline information on HIV-1 INI resistance, coreceptor tropism, and CCR5 variants in HIV-positive individuals in Vietnam. This should help inform policy on the future use of novel antiretrovirals in Vietnam.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Pirrolidinonas/farmacologia , Receptores CCR5/genética , Tropismo/efeitos dos fármacos , Tropismo/genética , Antagonistas dos Receptores CCR5 , Farmacorresistência Viral , Feminino , Predisposição Genética para Doença , Genoma Viral , Genótipo , Proteína gp120 do Envelope de HIV/efeitos dos fármacos , Proteína gp120 do Envelope de HIV/genética , Infecções por HIV/epidemiologia , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/imunologia , Humanos , Masculino , Dados de Sequência Molecular , Pirrolidinonas/uso terapêutico , Raltegravir Potássico , Tropismo/imunologia , Vietnã/epidemiologia
15.
PLoS One ; 6(10): e25294, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22022385

RESUMO

gp350, the major envelope protein of Epstein-Barr-Virus, confers B-cell tropism to the virus by interacting with the B lineage marker CD21. Here we utilize gp350 to generate tailored exosomes with an identical tropism. These exosomes can be used for the targeted co-transfer of functional proteins to normal and malignant human B cells. We demonstrate here the co-transfer of functional CD154 protein on tailored gp350+ exosomes to malignant B blasts from patients with B chronic lymphocytic leukemia (B-CLL), rendering B blasts immunogenic to tumor-reactive autologous T cells. Intriguingly, engulfment of gp350+ exosomes by B-CLL cells and presentation of gp350-derived peptides also re-stimulated EBV-specific T cells and redirected the strong antiviral cellular immune response in patients to leukemic B cells. In essence, we show that gp350 alone confers B-cell tropism to exosomes and that these exosomes can be further engineered to simultaneously trigger virus- and tumor-specific immune responses. The simultaneous exploitation of gp350 as a tropism molecule for tailored exosomes and as a neo-antigen in malignant B cells provides a novel attractive strategy for immunotherapy of B-CLL and other B-cell malignancies.


Assuntos
Antígenos Virais/imunologia , Linfócitos B/imunologia , Exossomos/metabolismo , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/terapia , Tropismo/imunologia , Proteínas da Matriz Viral/metabolismo , Linfócitos B/patologia , Linfócitos B/virologia , Linfócitos T CD4-Positivos/imunologia , Ligante de CD40/metabolismo , Células HEK293 , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Ativação Linfocitária/imunologia , Linfócitos T Citotóxicos/imunologia , Montagem de Vírus
16.
Nat Rev Immunol ; 9(9): 645-55, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19696766

RESUMO

The specificity of a given virus for a cell type, tissue or species - collectively known as viral tropism - is an important factor in determining the outcome of viral infection in any particular host. Owing to the increased prevalence of zoonotic infections and the threat of emerging and re-emerging pathogens, gaining a better understanding of the factors that determine viral tropism has become particularly important. In this Review, we summarize our current understanding of the central role of antiviral and pro-inflammatory cytokines, particularly the interferons and tumour necrosis factor, in dictating viral tropism and how these cytokine pathways can be exploited therapeutically for cancer treatment and to better counter future threats from emerging zoonotic pathogens.


Assuntos
Citocinas/imunologia , Interferons/imunologia , Tropismo/imunologia , Fator de Necrose Tumoral alfa/imunologia , Vírus/imunologia , Animais , Citocinas/metabolismo , Humanos , Interferons/metabolismo , Terapia Viral Oncolítica , Fator de Necrose Tumoral alfa/metabolismo , Vírus/metabolismo
17.
J Neuroimmune Pharmacol ; 2(1): 32-41, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18040824

RESUMO

Human immunodeficiency virus (HIV)-positive individuals frequently suffer from progressive encephelopathy, which is characterized by sensory neuropathy, sensory myelopathy, and dementia. Our group and others have reported the presence of highly macrophage-tropic R5 variants of HIV-1 in brain tissue of patients with neurological complications. These variants are able to exploit low amounts of CD4 and/or CCR5 for infection and potentially confer an expanded tropism for any cell types that express low CD4 and/or CCR5. In contrast to the brain-derived envelopes, we found that envelopes from lymph node tissue, blood, or semen were predominantly non-macrophage-tropic and required high amounts of CD4 for infection. Nevertheless, where tested, the non-macrophage-tropic envelopes conferred efficient replication in primary CD4(+) T-cell cultures. Determinants of R5 macrophage tropism appear to involve changes in the CD4 binding site, although further unknown determinants are also involved. The variation of R5 envelopes also affects their sensitivity to inhibition by ligands and entry inhibitors that target CD4 and CCR5. In summary, HIV-1 R5 viruses vary extensively in macrophage tropism. In the brain, highly macrophage-tropic variants may represent neurotropic or neurovirulent viruses. In addition, variation in R5 macrophage tropism may also have implications (1) for transmission, depending on what role macrophages or cells that express low CD4 and/or CCR5 play in the establishment of infection in a new host, and (2) for pathogenesis and depletion of CD4(+) T cells (i.e., do highly macrophage-tropic variants confer a broader tropism among CD4(+) T-cell populations late in disease and contribute to their depletion?).


Assuntos
Complexo AIDS Demência/virologia , Encéfalo/imunologia , Encéfalo/virologia , Variação Genética/imunologia , Macrófagos/imunologia , Macrófagos/virologia , Receptores CCR5/genética , Tropismo/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Complexo AIDS Demência/imunologia , Complexo AIDS Demência/patologia , Animais , Encéfalo/patologia , Antígenos CD4/biossíntese , Antígenos CD4/genética , Humanos , Macrófagos/patologia , Especificidade de Órgãos/imunologia , Tropismo/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/biossíntese
18.
Vet Immunol Immunopathol ; 117(1-2): 106-15, 2007 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-17353055

RESUMO

We serially passaged classical infectious bursal disease virus (cIBDV) and antigenic variant IBDV (vIBDV) in an avian macrophage cell line, NCSU cells, referred as mcIBDV and mvIBDV respectively and examined the in vitro and in vivo characteristics of the macrophage-adapted viruses. NCSU adapted viruses caused earlier destruction of NCSU cells than the unadapted viruses. Nitric oxide (NO) was detected earlier in cultures infected with mcIBDV and mvIBDV than in cultures infected with cIBDV and vIBDV. cIBDV and vIBDV were able to infect DF-1 cells, a chicken embryo fibroblast cell line, only after one replication cycle in NCSU cells. The genetic basis of altered tropism of progeny virus from NCSU cells infected cultures was not identified. No aa substitutions were observed in hypervariable region of VP2 of cIBDV and vIBDV passaged 1 time in NCSU cells whereas both mcIBDV and mvIBDV had multiple aa substitutions. To assess protective efficacy of mcIBDV and mvIBDV, embryonated chicken eggs were inoculated with mcIBDV and mvIBDV at embryonation day 18 (ED 18) and challenged with a virulent cIBDV at 3 weeks of age. mcIBDV and mvIBDV were immunogenic and generated antibody responses and provided 100% protection against cIBDV.


Assuntos
Infecções por Birnaviridae/veterinária , Vírus da Doença Infecciosa da Bursa/fisiologia , Macrófagos/imunologia , Macrófagos/virologia , Tropismo/imunologia , Replicação Viral/imunologia , Animais , Anticorpos Antivirais/sangue , Variação Antigênica/genética , Variação Antigênica/imunologia , Apoptose/imunologia , Infecções por Birnaviridae/imunologia , Infecções por Birnaviridae/virologia , Embrião de Galinha , Ensaio de Imunoadsorção Enzimática/veterinária , Imunofluorescência/veterinária , Vírus da Doença Infecciosa da Bursa/genética , Vírus da Doença Infecciosa da Bursa/imunologia , RNA Viral/química , RNA Viral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/veterinária , Organismos Livres de Patógenos Específicos , Proteínas Virais/genética , Proteínas Virais/imunologia , Replicação Viral/genética
19.
J Intern Med ; 260(4): 285-304, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16961667

RESUMO

Parvovirus B19 is a significant human pathogen that causes a wide spectrum of clinical complications ranging from mild, self-limiting erythema infectiosum in immunocompetent children to lethal cytopenias in immunocompromised patients and intrauterine foetal death in primary infected pregnant women. The infection may also be persistent and can mimic or trigger autoimmune inflammatory disorders. Another important clinical aspect to consider is the risk of infection through B19-contaminated blood products. Recent advances in diagnosis and pathogenesis, new insights in the cellular immune response and newly discovered genotypes of human parvoviruses form a platform for the development of modern therapeutic and prophylactic alternatives.


Assuntos
Infecções por Parvoviridae/imunologia , Parvovirus B19 Humano/imunologia , Doenças Autoimunes/imunologia , Eritema Infeccioso/imunologia , Eritrócitos/fisiologia , Feminino , Morte Fetal/virologia , Humanos , Hidropisia Fetal/virologia , Artropatias/imunologia , Artropatias/virologia , Infecções por Parvoviridae/diagnóstico , Infecções por Parvoviridae/tratamento farmacológico , Parvovirus B19 Humano/fisiologia , Gravidez , Complicações Infecciosas na Gravidez/virologia , Tropismo/imunologia , Vacinas Virais/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...