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1.
Nat Immunol ; 20(8): 1004-1011, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31263280

RESUMO

Innate lymphoid cells (ILCs) are tissue-resident sentinels that are essential for early host protection from pathogens at initial sites of infection. However, whether pathogen-derived antigens directly modulate the responses of tissue-resident ILCs has remained unclear. In the present study, it was found that liver-resident type 1 ILCs (ILC1s) expanded locally and persisted after the resolution of infection with mouse cytomegalovirus (MCMV). ILC1s acquired stable transcriptional, epigenetic and phenotypic changes a month after the resolution of MCMV infection, and showed an enhanced protective effector response to secondary challenge with MCMV consistent with a memory lymphocyte response. Memory ILC1 responses were dependent on the MCMV-encoded glycoprotein m12, and were independent of bystander activation by proinflammatory cytokines after heterologous infection. Thus, liver ILC1s acquire adaptive features in an MCMV-specific manner.


Assuntos
Memória Imunológica/imunologia , Fígado/imunologia , Linfócitos/imunologia , Glicoproteínas de Membrana/imunologia , Muromegalovirus/imunologia , Proteínas do Envelope Viral/imunologia , Animais , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/virologia , Imunidade Inata/imunologia , Subunidade alfa de Receptor de Interleucina-18/metabolismo , Fígado/citologia , Camundongos
2.
PLoS Pathog ; 15(6): e1007890, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31220189

RESUMO

Cytomegalovirus (CMV) is a ubiquitous herpesvirus infecting most of the world's population. CMV has been rigorously investigated for its impact on lifelong immunity and potential complications arising from lifelong infection. A rigorous adaptive immune response mounts during progression of CMV infection from acute to latent states. CD8 T cells, in large part, drive this response and have very clearly been demonstrated to take up residence in the salivary gland and lungs of infected mice during latency. However, the role of tissue resident CD8 T cells as an ongoing defense mechanism against CMV has not been studied in other anatomical locations. Therefore, we sought to identify additional locations of anti-CMV T cell residency and the physiological consequences of such a response. Through RT-qPCR we found that mouse CMV (mCMV) infected the visceral adipose tissue and that this resulted in an expansion of leukocytes in situ. We further found, through flow cytometry, that adipose tissue became enriched in cytotoxic CD8 T cells that are specific for mCMV antigens from day 7 post infection through the lifespan of an infected animal (> 450 days post infection) and that carry markers of tissue residence. Furthermore, we found that inflammatory cytokines are elevated alongside the expansion of CD8 T cells. Finally, we show a correlation between the inflammatory state of adipose tissue in response to mCMV infection and the development of hyperglycemia in mice. Overall, this study identifies adipose tissue as a location of viral infection leading to a sustained and lifelong adaptive immune response mediated by CD8 T cells that correlates with hyperglycemia. These data potentially provide a mechanistic link between metabolic syndrome and chronic infection.


Assuntos
Tecido Adiposo , Linfócitos T CD8-Positivos , Infecções por Herpesviridae , Hiperglicemia , Muromegalovirus/imunologia , Paniculite , Tecido Adiposo/imunologia , Tecido Adiposo/patologia , Tecido Adiposo/virologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/patologia , Infecções por Herpesviridae/virologia , Hiperglicemia/genética , Hiperglicemia/imunologia , Hiperglicemia/patologia , Hiperglicemia/virologia , Memória Imunológica , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Inflamação/virologia , Camundongos , Camundongos Knockout , Paniculite/genética , Paniculite/imunologia , Paniculite/patologia , Paniculite/virologia
3.
Immunity ; 50(6): 1381-1390.e5, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31103381

RESUMO

The process of affinity maturation, whereby T and B cells bearing antigen receptors with optimal affinity to the relevant antigen undergo preferential expansion, is a key feature of adaptive immunity. Natural killer (NK) cells are innate lymphocytes capable of "adaptive" responses after cytomegalovirus (CMV) infection. However, whether NK cells are similarly selected on the basis of their avidity for cognate ligand is unknown. Here, we showed that NK cells with the highest avidity for the mouse CMV glycoprotein m157 were preferentially selected to expand and comprise the memory NK cell pool, whereas low-avidity NK cells possessed greater capacity for interferon-γ (IFN-γ) production. Moreover, we provide evidence for avidity selection occurring in human NK cells during human CMV infection. These results delineate how heterogeneity in NK cell avidity diversifies NK cell effector function during antiviral immunity, and how avidity selection might serve to produce the most potent memory NK cells.


Assuntos
Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Citomegalovirus/imunologia , Interações Hospedeiro-Patógeno/imunologia , Células Matadoras Naturais/imunologia , Animais , Infecções por Citomegalovirus/metabolismo , Citotoxicidade Imunológica , Regulação da Expressão Gênica , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/metabolismo , Infecções por Herpesviridae/virologia , Interações Hospedeiro-Patógeno/genética , Humanos , Memória Imunológica , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Muromegalovirus/imunologia , Subfamília A de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília A de Receptores Semelhantes a Lectina de Células NK/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T
4.
Fish Shellfish Immunol ; 91: 78-86, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31039439

RESUMO

Type I interferons, as a class of multipotent cytokines, play a key role in host antiviral immune responses. In this study, a type I IFN coding gene of gibel carp, Carassius auratus gibelio, CagIFNa was cloned and sequenced. The full-length cDNA sequence of CagIFNa consists of 724 nucleotides that encode a predicted protein of 183 amino acids. CagIFNa has two highly conserved cysteine residues in the deduced protein, which is mostly conserved in the fish group I type I IFNs. CagIFNa was identified as a member of the IFNa subgroup of group I type I IFNs by phylogenetic analysis. CagIFNa transcripts were detected in all investigated tissues with higher levels in the liver, intestine, spleen and head kidney of gibel carp. Following injection with Cyprinid herpesvirus 2 (CyHV-2), CagIFNa gene expression was significantly inhibited in the spleen but delayed and then increased in head kidneys. Similarly, while CagIFNa expression was rapidly induced in gibel carp brain (GiCB) cells by poly I:C stimulation and its high induction level was delayed following CyHV-2 infection. CagIFNa overexpression in GiCB cells drastically reduced virus CPE and titer. Furthermore, several genes associated with type I IFN signaling pathway including IRF3, IRF7, IRF9, STAT1, Mx1 and PKR were induced in GiCB cells overexpressing CagIFNa upon CyHV-2 infection. These results show that CagIFNa plays a role in antiviral immune system in gibel carp.


Assuntos
Doenças dos Peixes/imunologia , Regulação da Expressão Gênica/imunologia , Carpa Dourada/genética , Carpa Dourada/imunologia , Imunidade Inata/genética , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , Herpesviridae , Infecções por Herpesviridae/imunologia , Interferon Tipo I/química , Filogenia , Poli I-C/farmacologia , Distribuição Aleatória , Alinhamento de Sequência/veterinária
5.
Mol Immunol ; 111: 136-144, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31054407

RESUMO

Production of antimicrobial peptides cathelicidins, interferons and cytokines is an important feature in airway epithelial host defense. The innate immune response to alpha-herpesvirus infection at the sites of primary replication has not been fully studied. Thus, the aim of this study was to determine the expression of innate immune components, cathelicidins, IFNß, TNFα and TNF receptors (TNFRI and TNFRII) during acute infection and reactivation of bovine herpesvirus type 1 (BoHV-1) and 5 (BoHV-5) in the respiratory tract and lymphoid tissue of their natural host. We found that BoHV infection modulates mainly the expression of BMAP28, a key cathelicidin in cattle. It was downregulated by both viruses in retropharyngeal lymph nodes of acutely infected-calves, and it was accompanied by a lower expression of IFNß, TNFα and TNFRI. BoHV-5 showed a pronounced role in the downregulation of BMAP28, even in nasal mucosa and lung. However, during reactivation, BoHV-5 upregulated both BMAP28 and IFNß in retropharyngeal lymph nodes. Acute replication induced also TNFα mRNA and protein synthesis, and expression of TNFRI and II was positively regulated during both acute infection and reactivation, particularly in the trachea. Moreover, BMAP27 was detected during BoHV-1 reactivation suggesting a potential role at this stage. Thus, cathelicidins are implicated in alpha-herpesvirus infections of the bovine respiratory system and the response is distinct during BoHV-1 and BoHV-5 acute infection and reactivation. This demonstrates that these viruses modulate differentially the components of innate immune response, possibly influencing their pathogenesis. This study provides an initial pilot analysis of factors that might be implicated in alpha-herpesvirus infection of the bovine respiratory system.


Assuntos
Catelicidinas/imunologia , Doenças dos Bovinos/imunologia , Infecções por Herpesviridae/imunologia , Herpesvirus Bovino 1/imunologia , Interferon beta/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Bovinos , Citocinas/imunologia , Infecções por Herpesviridae/veterinária , Imunidade Inata/imunologia , Projetos Piloto , RNA Mensageiro/imunologia , Receptores do Fator de Necrose Tumoral/imunologia , Sistema Respiratório/imunologia , Sistema Respiratório/virologia , Regulação para Cima/imunologia
6.
BMC Genomics ; 20(1): 432, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138127

RESUMO

BACKGROUND: Accompanied with rapid growth and high density aquaculture, gibel carp has been seriously threatened by Carassius auratus herpesvirus (CaHV) since 2012. In previous study, distinct CaHV resistances and immune responses were revealed in the diseased individuals of three gibel carp gynogenetic clones (A+, F and H). However, little is known about the gene expression changes in the survivors after CaHV challenge, particularly their differences of innate and adaptive immune system between susceptible clone and resistant clone. RESULTS: We firstly confirmed the CaHV carrier state in the survivors of three gibel carp clones after CaHV challenge by evaluating the abundances of five CaHV genes. The assay of viral loads indicated the resistant clone H possessed not only stronger resistance but also higher tolerance to CaHV. Then, 2818, 4047 and 3323 differentially expressed unigenes (DEUs) were screened from the head-kidney transcriptome profiles of survivors compared with controls from clone A+, F and H. GO and KEGG analysis suggested that a persistent immune response might sustain in resistant clone H and F, while susceptible clone A+ had a long-term impact on the circulatory system which was consistent with the major symptoms of bleeding caused by CaHV. Among the top 30 enriched pathways of specifically up-regulated DEUs in respective clones, 26, 7 and 15 pathways in clone H, F and A+ were associated with infections, diseases, or immune-related pathways respectively. In addition, 20 pathways in clone F belonged to "metabolism" or "biogenesis", and 7 pathways involved in "circulatory system" were enriched in clone A+. Significantly, we revealed the differential expression changes of IFN system genes and immunoglobulin (Ig) genes among the survivors of three clones. Finally, myosins and Igs were identified as co-expression modules which were positively or negatively correlated to CaHV viral loads respectively. CONCLUSIONS: Our results revealed the common and distinct gene expression changes in immune and circulatory system in the survivors of three gibel carp gynogenetic clones with different CaHV resistances. The current study represents a paradigm of differential innate and adaptive immune reactions in teleost, and will be beneficial to the disease-resistance breeding of gibel carp.


Assuntos
Carpas/genética , Carpas/imunologia , Doenças dos Peixes/imunologia , Doenças dos Peixes/virologia , Infecções por Herpesviridae/veterinária , Imunidade Adaptativa/genética , Animais , Carpas/metabolismo , Carpas/virologia , Doenças dos Peixes/genética , Doenças dos Peixes/metabolismo , Genes de Imunoglobulinas , Herpesviridae , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/metabolismo , Imunidade Inata/genética , Interferons/metabolismo , Miosinas/genética , Transdução de Sinais
7.
Prev Vet Med ; 167: 32-38, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31027718

RESUMO

The aim of the study was to determine the seroprevalence of feline panleukopenia virus (FPV), feline herpesvirus type 1 (FHV-1) and feline calicivirus (FCV) in stray colony cats from Milan, Italy. Cats were divided in groups based on age, gender, reproductive status, health status and colony of origin. Blood samples were tested with an in-clinic ELISA test. The possible presence of a link between the antibody titre or the presence of seropositive results and the independent variables (age, gender, reproductive status, health status and colony location) was assessed by means of multinomial and univariate logistic regression models, respectively. Seroprevalence of 85.4% was reported for FCV. The diffusion of the other two pathogens in the cat population was much lower compared to FCV, with 45.7% and 37.1% seroprevalence observed for FPV and FHV-1, respectively. An increase of antibody titres from kitten to senior was generally observed for the three pathogens. Age was a statistically significant variable for FHV-1, with senior cats significantly associated with higher antibody titres and higher percentages of seropositive animals compared to younger age groups. Neutered cats had significantly higher antibody titres and showed significantly higher FHV-1 seroprevalences compared to sexually intact cats. Colonies from two of the nine administrative districts of Milan showed significantly higher FPV seroprevalences compared to the others. No other significant differences were observed. Our results, based on cats belonging to 70 different colonies located in urban areas far from each other, suggest that the three viruses circulate in the feline population of stray cats in Milan. The feline calicivirus represents the most common circulating pathogen, as observed also in other studies worldwide. Finally, our results suggest that stray cats may be not adequately protected against FPV, FHV-1 and FCV and vaccination could be a possible strategic solution, especially for FPV.


Assuntos
Anticorpos Antivirais/sangue , Infecções por Caliciviridae/veterinária , Panleucopenia Felina/sangue , Infecções por Herpesviridae/veterinária , Animais , Infecções por Caliciviridae/sangue , Infecções por Caliciviridae/epidemiologia , Infecções por Caliciviridae/imunologia , Calicivirus Felino/imunologia , Gatos , Panleucopenia Felina/epidemiologia , Panleucopenia Felina/imunologia , Vírus da Panleucopenia Felina/imunologia , Feminino , Herpesviridae/imunologia , Infecções por Herpesviridae/sangue , Infecções por Herpesviridae/epidemiologia , Infecções por Herpesviridae/imunologia , Itália , Masculino , Prevalência
8.
Virology ; 531: 219-232, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30928700

RESUMO

Equid herpesvirus-1 (EHV-1) outbreaks continue despite widely used vaccination. We demonstrated previously that an ORF1/ORF71 gene deletion mutant of the EHV-1 strain Ab4 (Ab4ΔORF1/71) is less virulent than its parent Ab4 virus. Here, we describe the Ab4 challenge infection evaluating protection induced by the Ab4ΔORF1/71 vaccine candidate. Susceptible control horses developed respiratory disease, fever, nasal shedding, and viremia. Full protection after challenge infection was observed in 5/5 previously Ab4 infected horses and 3/5 Ab4ΔORF1/71 horses. Two Ab4ΔORF1/71 horses developed short-lasting viremia and/or virus shedding. Protective immunity in the respiratory tract was characterized by pre-existing EHV-1-specific IgG4/7 antibodies, the absence of IFN-α secretion and rapidly increasing IgG4/7 upon challenge infection. Pre-existing systemic EHV-1-specific IgG4/7 highly correlated with protection. T-cell immunity was overall low. In conclusion, protective immunity against EHV-1 infection including prevention of viremia was associated with robust systemic and intranasal IgG4/7 antibodies suggesting immediate virus neutralization at the local site.


Assuntos
Anticorpos Antivirais/imunologia , Infecções por Herpesviridae/veterinária , Herpesvirus Equídeo 1/imunologia , Vacinas contra Herpesvirus/administração & dosagem , Doenças dos Cavalos/prevenção & controle , Imunoglobulina G/imunologia , Viremia/veterinária , Administração Intranasal , Animais , Feminino , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/prevenção & controle , Infecções por Herpesviridae/virologia , Herpesvirus Equídeo 1/efeitos dos fármacos , Herpesvirus Equídeo 1/genética , Herpesvirus Equídeo 1/fisiologia , Vacinas contra Herpesvirus/imunologia , Doenças dos Cavalos/imunologia , Doenças dos Cavalos/virologia , Cavalos , Masculino , Mucosa Nasal/imunologia , Mucosa Nasal/virologia , Vacinação , Viremia/imunologia , Viremia/prevenção & controle , Viremia/virologia , Eliminação de Partículas Virais
9.
J Vet Intern Med ; 33(2): 831-837, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30847973

RESUMO

BACKGROUND: Feline herpesvirus-1 (FHV-1) infection can result in serious morbidity and mortality, especially in kittens. Immunotherapy using liposome-toll-like receptor (TLR) ligand complexes (LTC) has been shown to activate innate immune responses. OBJECTIVES: To determine in kittens whether mucosal administration of LTC before FHV-1 inoculation would decrease severity of clinical signs and decrease quantities of FHV-1 DNA in materials collected on oropharyngeal swabs. ANIMALS: Nineteen, 14-week-old, purpose-bred kittens. METHODS: Pilot clinical trial with 2 groups of kittens allocated to either an LTC or control group. The LTC were administered into both nares and the oropharynx of the 12 LTC group kittens, and all 19 kittens were inoculated with FHV-1 24 hours later. Clinical scores were determined daily for 28 days, and oropharyngeal mucosal materials were collected every 7 days to assess FHV-1 DNA quantities for comparison between groups. RESULTS: Conjunctivitis was more common in kittens in the control group on Days 15-28 (P = .01) and Days 1-28 (P = .02). Total respiratory scores were higher in the LTC group on days 15-28 (P = .03). The LTC group had significantly decreased FHV-1 DNA on swabs when compared to the control group on some postinoculation days, using 2 methods of calculation. CONCLUSIONS AND CLINICAL IMPORTANCE: Administration of LTC to kittens was shown to decrease FHV-1 DNA and some manifestations of illness in kittens when administrated 24 hours before inoculation, suggesting clinical benefit.


Assuntos
Doenças do Gato/virologia , Infecções por Herpesviridae/veterinária , Lipossomos/administração & dosagem , Receptores Toll-Like/agonistas , Varicellovirus/imunologia , Animais , Doenças do Gato/imunologia , Doenças do Gato/prevenção & controle , Gatos , DNA Viral/isolamento & purificação , Feminino , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/prevenção & controle , Imunidade Inata , Masculino , Membrana Mucosa/imunologia , Membrana Mucosa/virologia , Projetos Piloto , Varicellovirus/isolamento & purificação
10.
PLoS Pathog ; 15(3): e1007667, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30901352

RESUMO

Host innate immune defences play a critical role in restricting the intracellular propagation and pathogenesis of invading viral pathogens. Here we show that the histone H3.3 chaperone HIRA (histone cell cycle regulator) associates with promyelocytic leukaemia nuclear bodies (PML-NBs) to stimulate the induction of innate immune defences against herpes simplex virus 1 (HSV-1) infection. Following the activation of innate immune signalling, HIRA localized at PML-NBs in a Janus-Associated Kinase (JAK), Cyclin Dependent Kinase (CDK), and Sp100-dependent manner. RNA-seq analysis revealed that HIRA promoted the transcriptional upregulation of a broad repertoire of host genes that regulate innate immunity to HSV-1 infection, including those involved in MHC-I antigen presentation, cytokine signalling, and interferon stimulated gene (ISG) expression. ChIP-seq analysis revealed that PML, the principle scaffolding protein of PML-NBs, was required for the enrichment of HIRA onto ISGs, identifying a role for PML in the HIRA-dependent regulation of innate immunity to virus infection. Our data identifies independent roles for HIRA in the intrinsic silencing of viral gene expression and the induction of innate immune defences to restrict the initiation and propagation of HSV-1 infection, respectively. These intracellular host defences are antagonized by the HSV-1 ubiquitin ligase ICP0, which disrupts the stable recruitment of HIRA to infecting viral genomes and PML-NBs at spatiotemporally distinct phases of infection. Our study highlights the importance of histone chaperones to regulate multiple phases of intracellular immunity to virus infection, findings that are likely to be highly pertinent in the cellular restriction of many clinically important viral pathogens.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Fibroblastos/imunologia , Infecções por Herpesviridae/imunologia , Herpesvirus Humano 1/patogenicidade , Chaperonas de Histonas/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata/imunologia , Fatores de Transcrição/metabolismo , Proteínas de Ciclo Celular/genética , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/virologia , Regulação Viral da Expressão Gênica , Infecções por Herpesviridae/metabolismo , Infecções por Herpesviridae/virologia , Chaperonas de Histonas/genética , Humanos , Fatores de Transcrição/genética , Replicação Viral
11.
Virol J ; 16(1): 33, 2019 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-30866975

RESUMO

BACKGROUND: Elephant endotheliotropic herpesviruses (EEHV) can cause an acute highly fatal hemorrhagic disease in young Asian elephants (Elephas maximus), both ex situ and in situ. Amongst eight EEHV types described so far, type 1 (subtype 1A and 1B) is the predominant disease-associated type. Little is known about routes of infection and pathogenesis of EEHV, and knowledge of disease prevalence, especially in range countries, is limited. METHODS: A large cross-sectional serological survey was conducted in captive elephants (n = 994) throughout Thailand using an EEHV-1A glycoprotein B protein antigen specific antibody ELISA. RESULTS: Antibody seroprevalence was 42.3%, with 420 of 994 elephants testing positive. Associations between seropositivity and potential risk factors for EEHV infection were assessed and included: elephant age, sex, camp cluster size, management type (extensive versus intensive), sampling period (wet vs. dry season) and location of camp (region). Univariable regression analysis identified management system and region as risk factors for the presence of EEHV antibodies in elephants, with region being significant in the final multivariable regression model. Prevalence was highest in the North region of the country (49.4%). CONCLUSIONS: This study produced baseline serological data for captive elephants throughout Thailand, and showed a significant EEHV burden likely to be maintained in the captive population.


Assuntos
Anticorpos Antivirais/sangue , Elefantes/virologia , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/veterinária , Proteínas Virais/imunologia , Animais , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Herpesviridae , Infecções por Herpesviridae/epidemiologia , Masculino , Prevalência , Análise de Regressão , Estudos Retrospectivos , Fatores de Risco , Estudos Soroepidemiológicos , Tailândia/epidemiologia
12.
Arch Virol ; 164(5): 1371-1382, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30888564

RESUMO

Equine herpesvirus 1 (EHV-1) induces serious respiratory infections, viral abortion, neurological signs, and neonatal mortality in horses. Despite the use of vaccines, EHV-1 infection also causes a high annual economic burden to the equine industry. The poor immunogenicity of and protection conferred by EHV-1 vaccines are the major factors responsible for the spread of EHV-1 infection. The present study examined the immunogenicity of a novel DNA vaccine co-expressing FliC, a flagellin protein, in Salmonella abortus equi and the gD protein of EHV-1. Mice and horses were immunized intramuscularly with the vaccine, and mice were challenged with EHV-1. Immunofluorescence and western blotting revealed that FliC and gD can be efficiently expressed in cells. This novel vaccine significantly increased gD-specific antibody and interferon gamma (IFN-γ) levels in immunized mice and horses. Compared with controls, the viral load and morbidity were markedly reduced in FliC-gD-immunized mice after they were challenged with EHV-1. Furthermore, the immunogenicity of FliC-gD in a natural host was tested. Our results indicate that vaccinated mice and horses exhibit increased humoral and improved cellular immune responses.


Assuntos
Anticorpos Antivirais/sangue , Flagelina/imunologia , Infecções por Herpesviridae/prevenção & controle , Infecções por Herpesviridae/veterinária , Herpesvirus Equídeo 1/imunologia , Vacinas de DNA/imunologia , Proteínas do Envelope Viral/imunologia , Vacinas Virais/imunologia , Animais , Linhagem Celular , Feminino , Flagelina/genética , Células HEK293 , Infecções por Herpesviridae/imunologia , Cavalos , Humanos , Imunoglobulina G/sangue , Interferon gama/sangue , Camundongos , Camundongos Endogâmicos C57BL , Testes de Neutralização , Salmonella/imunologia , Receptor 5 Toll-Like/metabolismo , Proteínas do Envelope Viral/genética , Carga Viral
13.
Fish Shellfish Immunol ; 87: 809-819, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30776543

RESUMO

Carp from breeding strains with different genetic background present diverse levels of resistance to viral pathogens. Carp strains of Asian origin, currently being treated as Cyprinus rubrofuscus L., especially Amur wild carp (AS), were proven to be more resistant to koi herpesvirus disease (KHVD; caused by cyprinid herpesvirus 3, CyHV-3) than strains originating from Europe and belonging to Cyprinus carpio L., like the Prerov scale carp (PS) or koi carp from a breed in the Czech Republic. We hypothesised that it can be associated with a higher magnitude of type I interferon (IFN) response as a first line of innate defence mechanisms against viral infections. To evaluate this hypothesis, four strains of common carp (AS, Rop, PS and koi) were challenged using two viral infection models: Rhabdovirus SVCV (spring viremia of carp virus) and alloherpesvirus CyHV-3. The infection with SVCV induced a low mortality rates and the most resistant was the Rop strain (no mortalities), whereas the PS strain was the most susceptible (survival rate of 78%). During CyHV-3 infection, Rop and AS strains performed better (survival rates of 78% and 53%, respectively) than PS and koi strains (survival rates of 35% and 10%, respectively). The evaluation of virus loads and virus replication showed significant differences between the carp strains, which correlated with the mortality rate. The evaluation of type I IFN responses showed that there were fundamental differences between the virus infection models. While responses to the SVCV were high, the CyHV-3 generally induced low responses. Furthermore, the results demonstrated that the magnitude of type I IFN responses did not correlate with a higher resistance in infected carp. In the case of a CyHV-3 infection, reduced type I IFN responses could be related to the potential ability of the virus to interfere with cellular sensing of foreign nucleic acids. Taken together, the results broaden our understanding of how common carp from different genetic strains interact with various viral pathogens.


Assuntos
Carpas/genética , Carpas/imunologia , Resistência à Doença/genética , Doenças dos Peixes/imunologia , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Animais , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Herpesviridae/fisiologia , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/veterinária , Rhabdoviridae/fisiologia , Infecções por Rhabdoviridae/imunologia , Infecções por Rhabdoviridae/veterinária
15.
BMC Infect Dis ; 19(1): 91, 2019 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683065

RESUMO

BACKGROUND: Making a definite diagnosis of infectious uveitis is a challenging task because many other infectious, and non-infectious uveitis, may have similar non-specific symptoms and overlapping clinical appearances. Co-infections in immunocompetent patients are not frequently proved with traditional serologic-diagnostic tools. METHODS: Descriptive transversal study, in a Uveitis Service of an Ophthalmology Reference Center, in Bogotá, Colombia, from July 2014 to February 2016. Aqueous humor (AH) and/or vitreous fluid, blood and serum samples were collected from consecutive patients suspected of having infectious uveitis. The diagnosis of ocular toxoplasmosis (OT) was confirmed by the Goldmann-Witmer coefficient (GWC) and by polymerase chain reaction (PCR). Differential diagnosis by PCR in AH was done for viral origin such as Cytomegalovirus (CMV), Herpes simplex virus type 1 (HSV1), Herpes simplex virus type 2 (HSV2), Varicella zoster virus (VZV), Epstein-Barr virus (EBV) and Mycobacterium tuberculosis. RESULTS: In 66 Colombian patients with uveitis of presumed infectious origin: 22 (33.3%) were confirmed as OT, 16 (24.2%) as undetermined OT, five (7.5%) as co-infections and 23 (34.8%) as other uveitis. Toxoplasma coinfection with M. tuberculosis was identified in one case by PCR and in four cases with HSV by GWC. The initial clinical diagnosis changed, after laboratory examination, in 21 cases (31.8%). CONCLUSIONS: Clinical diagnosis can be changed by laboratory examination in a significant proportion of cases of uveitis. Diagnosis of OT should combine the use of PCR and GWC to reach the maximum of confirmation of cases. The use of multiple laboratory methods is necessary to identify co-infections and viral infections that can mimic OT in immunocompetent patients.


Assuntos
Coinfecção/diagnóstico , Infecções Oculares Parasitárias/diagnóstico , Infecções Oculares Virais/diagnóstico , Infecções por Herpesviridae/diagnóstico , Imunocompetência , Toxoplasmose/diagnóstico , Adolescente , Adulto , Idoso , Coinfecção/epidemiologia , Coinfecção/imunologia , Colômbia/epidemiologia , Citomegalovirus/genética , DNA Viral/análise , Diagnóstico Diferencial , Infecções Oculares Parasitárias/complicações , Infecções Oculares Virais/complicações , Infecções Oculares Virais/imunologia , Infecções Oculares Virais/virologia , Feminino , Infecções por Herpesviridae/complicações , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Toxoplasmose/complicações , Toxoplasmose/imunologia , Adulto Jovem
16.
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
17.
J Virol ; 93(7)2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30651370

RESUMO

Equine herpesvirus 1 (EHV1) replicates in the respiratory epithelium and disseminates through the body via a cell-associated viremia in leukocytes, despite the presence of neutralizing antibodies. "Hijacked" leukocytes, previously identified as monocytic cells and T lymphocytes, transmit EHV1 to endothelial cells of the endometrium or central nervous system, causing reproductive (abortigenic variants) or neurological (neurological variants) disorders. In the present study, we questioned the potential route of EHV1 infection of T lymphocytes and how EHV1 misuses T lymphocytes as a vehicle to reach the endothelium of the target organs in the absence or presence of immune surveillance. Viral replication was evaluated in activated and quiescent primary T lymphocytes, and the results demonstrated increased infection of activated versus quiescent, CD4+ versus CD8+, and blood- versus lymph node-derived T cells. Moreover, primarily infected respiratory epithelial cells and circulating monocytic cells efficiently transferred virions to T lymphocytes in the presence of neutralizing antibodies. Albeit T-lymphocytes express all classes of viral proteins early in infection, the expression of viral glycoproteins on their cell surface was restricted. In addition, the release of viral progeny was hampered, resulting in the accumulation of viral nucleocapsids in the T cell nucleus. During contact of infected T lymphocytes with endothelial cells, a late viral protein(s) orchestrates T cell polarization and synapse formation, followed by anterograde dynein-mediated transport and transfer of viral progeny to the engaged cell. This represents a sophisticated but efficient immune evasion strategy to allow transfer of progeny virus from T lymphocytes to adjacent target cells. These results demonstrate that T lymphocytes are susceptible to EHV1 infection and that cell-cell contact transmits infectious virus to and from T lymphocytes.IMPORTANCE Equine herpesvirus 1 (EHV1) is an ancestral alphaherpesvirus that is related to herpes simplex virus 1 and causes respiratory, reproductive, and neurological disorders in Equidae. EHV1 is indisputably a master at exploiting leukocytes to reach its target organs, accordingly evading the host immunity. However, the role of T lymphocytes in cell-associated viremia remains poorly understood. Here we show that activated T lymphocytes efficiently become infected and support viral replication despite the presence of protective immunity. We demonstrate a restricted expression of viral proteins on the surfaces of infected T cells, which prevents immune recognition. In addition, we indicate a hampered release of progeny, which results in the accumulation of nucleocapsids in the T cell nucleus. Upon engagement with the target endothelium, late viral proteins orchestrate viral synapse formation and viral transfer to the contact cell. Our findings have significant implications for the understanding of EHV1 pathogenesis, which is essential for developing innovative therapies to prevent the devastating clinical symptoms of infection.


Assuntos
Infecções por Herpesviridae/imunologia , Herpesvirus Equídeo 1/imunologia , Doenças dos Cavalos/imunologia , Cavalos/imunologia , Linfócitos T/imunologia , Animais , Células Cultivadas , Células Endoteliais/imunologia , Células Endoteliais/virologia , Células Epiteliais/imunologia , Células Epiteliais/virologia , Infecções por Herpesviridae/virologia , Doenças dos Cavalos/virologia , Cavalos/virologia , Evasão da Resposta Imune/imunologia , Monócitos/imunologia , Monócitos/virologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/virologia , Linfócitos T/virologia , Proteínas Virais/imunologia , Viremia/imunologia , Viremia/virologia , Replicação Viral/imunologia
18.
BMC Immunol ; 20(1): 1, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30606111

RESUMO

BACKGROUND: Mannose-binding lectin (MBL) plays an important role in the innate immune response by activating the complement system via the lectin pathway, and it has been studied in several viral infections; however, the influence of MBL in PLWHA infected with HHV-8 is unknown. The objective of this study was to verify the association of MBL deficient plasma concentrations in HIV/HHV-8 coinfected and HIV monoinfected patients and to correlate these concentrations with HIV viral load and CD4 counts in both groups. RESULTS: This was an analytical study of case-controls consisting of PLWHA monitored at the medical outpatient of Infectious and Parasitic Diseases of the clinical hospital in the Federal University of Pernambuco. Plasma concentrations of MBL were obtained by an enzyme-linked immunosorbent assay (ELISA) using a commercial Human Mannose Binding Lectin kit (MyBioSource, Inc.) that was performed according to the manufacturer's guidelines, with values < 100 ng/ml considered deficient. A total of 245 PLWHA samples were analysed; 118 were HIV/HHV-8 coinfected and 127 were HIV monoinfected; 5.1% (6/118) of the coinfected patients and 3.2% (4/127) of the monoinfected patients (p = 0.445) were considered plasma concentration deficient. The median of the plasma concentrations of MBL in the coinfected patients was 2803 log10 ng/ml and was 2.959 log10 ng/ml in the monoinfected patients (p = 0.001). There was an inverse correlation between the plasma concentrations of MBL and the HIV viral load in both groups, but no correlation with the CD4 count. CONCLUSIONS: Although the plasma concentrations considered deficient in MBL were not associated with HHV-8 infection in PLWHA, the coinfected patients showed lower MBL concentrations and an inverse correlation with HIV viral load, suggesting that there may be consumption and reduction of MBL due to opsonization of HIV and HHV-8, leading to the reduction of plasma MBL and non-accumulation in the circulation.


Assuntos
Coinfecção , Infecções por HIV/sangue , Infecções por HIV/virologia , HIV-1 , Infecções por Herpesviridae/virologia , Herpesvirus Humano 8 , Lectina de Ligação a Manose/sangue , Adulto , Contagem de Linfócito CD4 , Estudos de Casos e Controles , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , HIV-1/imunologia , Infecções por Herpesviridae/epidemiologia , Infecções por Herpesviridae/imunologia , Herpesvirus Humano 8/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Masculino , Pessoa de Meia-Idade , Vigilância em Saúde Pública , Carga Viral
19.
Infect Dis (Lond) ; 51(3): 189-196, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30676829

RESUMO

METHODS: A computer-based search of the English literature for articles relative to Human Herpesviruses (HHVs) infection and pleural effusions (PEs) in the immunocompetent host was performed in PubMed and Scopus. The reference lists of the retrieved articles were also reviewed for relevant articles. RESULTS: A total of 20 articles satisfied the selection criteria and were included in the study. In the majority of the articles, PEs were reported as clinical complications of systemic HHV-induced infection. The frequency of HHVs within the reported cases was five for HHV-1/2, one for HHV-3, six for HHV-4, six for HHV-5 and one for HHV-6. One case involved HHV-4 and HHV-5 co-infection. No case of HHV-7 or HHV-8 related PE in the immunocompetent host was retrieved. CONCLUSIONS: Pleural effusions in the immunocompetent host occur in severe viral infections and can be due to comorbidities (or septic complications) or due to the direct HHV pathogenicity although research relative to the susceptibility of pleural mesothelial cells to HHV infection is lacking. HHV pathogenicity needs to be studied further as it could explain undiagnosed PEs.


Assuntos
Infecções por Herpesviridae/patologia , Derrame Pleural/virologia , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/virologia , Humanos , Imunocompetência , Derrame Pleural/imunologia
20.
Cancer Treat Res ; 177: 23-62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30523620

RESUMO

Discovered in 1994, Kaposi's sarcoma-associated herpesvirus (KSHV) has been associated with four human malignancies including Kaposi's sarcoma, primary effusion lymphoma, a subset of multicentric Castleman's disease, and KSHV inflammatory cytokine syndrome. These malignancies mostly occur in immunocompromised patients including patients with acquired immunodeficiency syndrome and often cause significant mortality because of the lack of effective therapies. Significant progresses have been made to understand the molecular basis of KSHV infection and KSHV-induced oncogenesis in the last two decades. This chapter provides an update on the recent advancements focusing on the molecular events of KSHV primary infection, the mechanisms regulating KSHV life cycle, innate and adaptive immunity, mechanism of KSHV-induced tumorigenesis and inflammation, and metabolic reprogramming in KSHV infection and KSHV-transformed cells.


Assuntos
Síndrome de Imunodeficiência Adquirida/virologia , Infecções por Herpesviridae/genética , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/imunologia , Neoplasias/virologia , Síndrome de Imunodeficiência Adquirida/complicações , Carcinogênese/genética , Carcinogênese/imunologia , Hiperplasia do Linfonodo Gigante/fisiopatologia , Hiperplasia do Linfonodo Gigante/virologia , Coinfecção/virologia , Citocinas/imunologia , Infecções por HIV/complicações , Infecções por HIV/virologia , Infecções por Herpesviridae/complicações , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/virologia , Herpesvirus Humano 8/fisiologia , Humanos , Hospedeiro Imunocomprometido , Inflamação/imunologia , Inflamação/fisiopatologia , Inflamação/virologia , Linfoma de Efusão Primária/fisiopatologia , Linfoma de Efusão Primária/virologia , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/fisiopatologia , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/virologia , Síndrome , Viremia/imunologia , Viremia/fisiopatologia , Viremia/virologia
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