Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.045
Filtrar
1.
Arch Virol ; 166(2): 571-579, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33410993

RESUMO

This study compared concurrent and separate primary vaccination against equid alphaherpesviruses 1 and 4, genus Varicellovirus, subfamily Alphaherpesvirinae, family Herpesviridae, and equine influenza A virus, genus Alphainfluenzavirus, family Orthomyxoviridae. Their vernacular names are equine herpesvirus 1 and 4 (EHV1/4) and equine influenza virus (EIV). Infection with these respiratory pathogens is associated with loss of performance, interruption of training schedules, and on occasion, cancellation of equestrian events. Vaccination is highly recommended, and for some activities it is a mandatory requirement of the relevant authority. As there is a dearth of information relating to the impact of concurrent vaccination on the antibody response to EHV and EIV vaccines, they are usually administered separately, often 2 weeks apart. In a previous study of booster vaccination in Thoroughbred racehorses, concurrent vaccination with whole-virus inactivated carbopol-adjuvanted EHV and EIV vaccines did not impact negatively on the antibody response. In this study, investigations were extended to concurrent versus separate primary vaccination of warmblood foals. A field study was conducted to compare the immune response to a carbopol-adjuvanted EHV vaccine and an immune stimulating complex (ISCOM)-adjuvanted EI vaccine administered concurrently and 2 weeks apart. No adverse clinical reactions were observed, the pattern of EI and EHV antibody response was similar for both groups, and there was no evidence that concurrent primary vaccination compromised the humoral response. The results are of relevance to horse owners who wish to decrease veterinary costs, limit handling of young animals, and simplify record keeping by vaccinating concurrently.


Assuntos
Infecções por Herpesviridae/imunologia , Vacinas contra Herpesvirus/imunologia , Doenças dos Cavalos/imunologia , Cavalos/imunologia , Vírus da Influenza A/imunologia , Vacinas contra Influenza/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Feminino , Doenças dos Cavalos/virologia , Cavalos/virologia , Imunidade Humoral/imunologia , Imunização Secundária/métodos , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Vacinação/métodos , Vacinas de Produtos Inativados/imunologia
2.
BMJ Case Rep ; 14(1)2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33408110

RESUMO

A 10-year-old boy underwent stem cell transplant for Hodgkin's lymphoma and developed vomiting and seizure in the postoperative period. An ophthalmic referral was made from intensive care unit, to rule out papilledema. On examination, there was no papilledema in both eyes, instead there were areas of retinal necrosis with no haemorrhages or vitritis in right eye. Cerebrospinal fluid serology was negative for herpes but MRI showed hyperintensity in temporal lobe. A clinical diagnosis of progressive outer retinal necrosis (PORN) was made and fundus picture was documented with help of a smartphone and 20D lens. High-dose intravenous injection acyclovir was started and PORN lesion improved on treatment.


Assuntos
Antivirais/administração & dosagem , Transplante de Medula Óssea/efeitos adversos , Infecções por Herpesviridae/diagnóstico , Doença de Hodgkin/terapia , Retina/patologia , Retinite/diagnóstico , Aciclovir/administração & dosagem , Criança , Diagnóstico Diferencial , Relação Dose-Resposta a Droga , Infecções por Herpesviridae/tratamento farmacológico , Infecções por Herpesviridae/imunologia , Doença de Hodgkin/imunologia , Humanos , Imunossupressores/efeitos adversos , Achados Incidentais , Imagem por Ressonância Magnética , Masculino , Necrose/diagnóstico , Necrose/tratamento farmacológico , Necrose/imunologia , Retina/diagnóstico por imagem , Retina/virologia , Síndrome de Necrose Retiniana Aguda/diagnóstico , Retinite/tratamento farmacológico , Retinite/imunologia , Resultado do Tratamento , Ativação Viral/imunologia
3.
PLoS Pathog ; 16(7): e1008701, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32735617

RESUMO

Gammaherpesviruses have evolved various strategies to take advantage of host cellular factors or signaling pathways to establish a lifelong latent infection. Like the human gammaherpesvirus Epstein-Barr virus, murine gammaherpesvirus 68 (MHV68) establishes and maintains latency in the memory B cells during infection of laboratory mice. We have previously shown that MHV68 can immortalize fetal liver-derived B cells that induce lymphomas when injected into immunodeficient mice. Here we identify interleukin 16 (IL16) as a most abundantly expressed cytokine in MHV68-immortalized B cells and show that MHV68 infection elevates IL16 expression. IL16 is not important for MHV68 lytic infection but plays a critical role in MHV68 reactivation from latency. IL16 deficiency increases MHV68 lytic gene expression in MHV68-immortalized B cells and enhances reactivation from splenic latency. Correlatively, IL16 deficiency increases the frequency of MHV68-infected plasma cells that can be attributed to enhanced MHV68 reactivation. Furthermore, similar to TPA-mediated lytic replication of Kaposi's sarcoma-associated herpesvirus, IL16 deficiency markedly induces Tyr705 STAT3 de-phosphorylation and elevates p21 expression, which can be counteracted by the tyrosine phosphatase inhibitor orthovanadate. Importantly, orthovanadate strongly blocks MHV68 lytic gene expression mediated by IL16 deficiency. These data demonstrate that virus-induced IL16 does not directly participate in MHV68 lytic replication, but rather inhibits virus reactivation to facilitate latent infection, in part through the STAT3-p21 axis.


Assuntos
Infecções por Herpesviridae/metabolismo , Interleucina-16/metabolismo , Infecções Tumorais por Vírus/metabolismo , Ativação Viral/fisiologia , Latência Viral/fisiologia , Animais , Linfócitos B/virologia , Infecções por Herpesviridae/imunologia , Interleucina-16/imunologia , Linfoma/virologia , Camundongos , Rhadinovirus/imunologia , Rhadinovirus/metabolismo
4.
J Vis Exp ; (160)2020 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-32597850

RESUMO

This protocol describes a footpad inoculation model used to study the initiation and development of neuroinflammatory responses during alphaherpesvirus infection in mice. As alphaherpesviruses are main invaders of the peripheral nervous system (PNS), this model is suitable to characterize the kinetics of viral replication, its spread from the PNS to CNS, and associated neuroinflammatory responses. The footpad inoculation model allows virus particles to spread from a primary infection site in the footpad epidermis to sensory and sympathetic nerve fibers that innervate the epidermis, sweat glands, and dermis. The infection spreads via the sciatic nerve to the dorsal root ganglia (DRG) and ultimately through the spinal cord to the brain. Here, a mouse footpad is inoculated with pseudorabies virus (PRV), an alphaherpesvirus closely related to herpes simplex virus (HSV) and varicella-zoster virus (VZV). This model demonstrates that PRV infection induces severe inflammation, characterized by neutrophil infiltration in the footpad and DRG. High concentrations of inflammatory cytokines are subsequently detected in homogenized tissues by ELISA. In addition, a strong correlation is observed between PRV gene and protein expression (via qPCR and IF staining) in DRG and the production of pro-inflammatory cytokines. Therefore, the footpad inoculation model provides a better understanding of the processes underlying alphaherpesvirus-induced neuropathies and may lead to the development of innovative therapeutic strategies. In addition, the model can guide research on peripheral neuropathies, such as multiple sclerosis and associated viral-induced damage to the PNS. Ultimately, it can serve as a cost-effective in vivo tool for drug development.


Assuntos
Alphaherpesvirinae/imunologia , Gânglios Espinais/imunologia , Infecções por Herpesviridae/imunologia , Membro Posterior/virologia , Inflamação/etiologia , Doenças do Sistema Nervoso Periférico/etiologia , Nervo Isquiático/imunologia , Animais , Modelos Animais de Doenças , Gânglios Espinais/virologia , Infecções por Herpesviridae/complicações , Infecções por Herpesviridae/virologia , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Doenças do Sistema Nervoso Periférico/patologia , Nervo Isquiático/virologia , Replicação Viral
5.
PLoS Pathog ; 16(4): e1008438, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32353066

RESUMO

One of the defining characteristics of the B cell receptor (BCR) is the extensive diversity in the repertoire of immunoglobulin genes that make up the BCR, resulting in broad range of specificity. Gammaherpesviruses are B lymphotropic viruses that establish life-long infection in B cells, and although the B cell receptor plays a central role in B cell biology, very little is known about the immunoglobulin repertoire of gammaherpesvirus infected cells. To begin to characterize the Ig genes expressed by murine gammaherpesvirus 68 (MHV68) infected cells, we utilized single cell sorting to sequence and clone the Ig variable regions of infected germinal center (GC) B cells and plasma cells. We show that MHV68 infection is biased towards cells that express the Igλ light chain along with a single heavy chain variable gene, IGHV10-1*01. This population arises through clonal expansion but is not viral antigen specific. Furthermore, we show that class-switching in MHV68 infected cells differs from that of uninfected cells. Fewer infected GC B cells are class-switched compared to uninfected GC B cells, while more infected plasma cells are class-switched compared to uninfected plasma cells. Additionally, although they are germinal center derived, the majority of class switched plasma cells display no somatic hypermutation regardless of infection status. Taken together, these data indicate that selection of infected B cells with a specific BCR, as well as virus mediated manipulation of class switching and somatic hypermutation, are critical aspects in establishing life-long gammaherpesvirus infection.


Assuntos
Linfócitos B/imunologia , Gammaherpesvirinae/fisiologia , Infecções por Herpesviridae/veterinária , Cadeias Pesadas de Imunoglobulinas/imunologia , Região Variável de Imunoglobulina/imunologia , Cadeias lambda de Imunoglobulina/imunologia , Doenças dos Roedores/imunologia , Animais , Linfócitos B/virologia , Feminino , Gammaherpesvirinae/genética , Centro Germinativo/imunologia , Centro Germinativo/virologia , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/virologia , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Cadeias lambda de Imunoglobulina/genética , Camundongos , Camundongos Endogâmicos C57BL , Plasmócitos/imunologia , Plasmócitos/virologia , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Doenças dos Roedores/genética , Doenças dos Roedores/virologia
6.
Biochim Biophys Acta Proteins Proteom ; 1868(9): 140457, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32473350

RESUMO

We investigated the molecular basis for the remarkably different survival outcomes of mice expressing different alloforms of the pro-apoptotic serine protease granzyme B to mouse cytomegalovirus infection. Whereas C57BL/6 mice homozygous for granzyme BP (GzmBP/P) raise cytotoxic T lymphocytes that efficiently kill infected cells, those of C57BL/6 mice congenic for the outbred allele (GzmBW/W) fail to kill MCMV-infected cells and died from uncontrolled hepatocyte infection and acute liver failure. We identified subtle differences in how GzmBP and GzmBW activate cell death signalling - both alloforms predominantly activated pro-caspases directly, and cleaved pro-apoptotic Bid poorly. Consequently, neither alloform initiated mitochondrial outer membrane permeabilization, or was blocked by Bcl-2, Bcl-XL or co-expression of MCMV proteins M38.5/M41.1, which together stabilize mitochondria by sequestering Bak/Bax. Remarkably, mass spectrometric analysis of proteins from MCMV-infected primary mouse embryonic fibroblasts identified 13 cleavage sites in nine viral proteins (M18, M25, M28, M45, M80, M98, M102, M155, M164) that were cleaved >20-fold more efficiently by either GzmBP or GzmBW. Notably, M18, M28, M45, M80, M98, M102 and M164 were cleaved 20- >100-fold more efficiently by GzmBW, and so, would persist in infected cells targeted by CTLs from GzmBP/P mice. Conversely, M155 was cleaved >100-fold more efficiently by GzmBP, and would persist in cells targeted by CTLs of GzmBW/W mice. M25 was cleaved efficiently by both proteases, but at different sites. We conclude that different susceptibility to MCMV does not result from skewed endogenous cell death pathways, but rather, to as yet uncharacterised MCMV-intrinsic pathways that ultimately inhibit granzyme B-induced cell death.


Assuntos
Granzimas/química , Granzimas/metabolismo , Muromegalovirus/imunologia , Peptídeos/metabolismo , Animais , Apoptose , Caspases/metabolismo , Morte Celular , Linhagem Celular , Modelos Animais de Doenças , Feminino , Granzimas/genética , Infecções por Herpesviridae/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Peptídeos/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Especificidade por Substrato , Linfócitos T Citotóxicos/imunologia , Proteínas Virais/imunologia , Proteínas Virais/metabolismo , Proteína bcl-X/metabolismo
7.
Med Sci (Paris) ; 36(5): 479-486, 2020 May.
Artigo em Francês | MEDLINE | ID: mdl-32452370

RESUMO

Infection of the brain with various types of pathogens, and the resulting inflammatory response, is becoming increasingly important in our understanding of the etiology of Alzheimer's disease (AD). The fact that several genes identified as risk factors are actually involved in the modulation of the immune response, as well as the very diversity of the infectious agents identified as possible actors in the evolution of this disease, argue in favor of the neuro-inflammatory hypothesis, as does the demonstration that the protein Aß, one of the most important markers of AD, is an antimicrobial peptide. Among others, herpes viruses (mainly, but not only, HSV-1), which can establish latent infections in brain neurons, especially in the elder population, punctuated by episodes of reactivation following stress or immunosuppression, appear as very strong candidates to play an etiological role, if only as cofactors, of AD. Recent results show that, in human and rat neurons, infection with HSV-1 increases the formation of Aß along the amyloidogenic pathway, as well as the phosphorylation of Tau proteins, another essential marker of AD. The growing evidence that chronic infections and defense mechanisms, including inflammatory processes, are at the heart of AD, warrants reviewing antiviral drugs such as acyclovir, and possibly vaccination, as potential avenues for AD control.


Assuntos
Doença de Alzheimer/etiologia , Herpesviridae/fisiologia , Inflamação/complicações , Neurônios/imunologia , Neurônios/virologia , Doença de Alzheimer/imunologia , Doença de Alzheimer/terapia , Doença de Alzheimer/virologia , Animais , Antivirais/uso terapêutico , Infecções por Herpesviridae/complicações , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/patologia , Humanos , Inflamação/patologia , Inflamação/virologia , Neuroimunomodulação/fisiologia , Neurônios/patologia , Ratos , Fatores de Risco , Transdução de Sinais/fisiologia
8.
Nat Commun ; 11(1): 2295, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385253

RESUMO

Cytomegalovirus-based vaccine vectors offer interesting opportunities for T cell-based vaccination purposes as CMV infection induces large numbers of functional effector-like cells that accumulate in peripheral tissues, a process termed memory inflation. Maintenance of high numbers of peripheral CD8 T cells requires continuous replenishment of the inflationary T cell pool. Here, we show that the inflationary T cell population contains a small subset of cells expressing the transcription factor Tcf1. These Tcf1+ cells resemble central memory T cells and are proliferation competent. Upon sensing viral reactivation events, Tcf1+ cells feed into the pool of peripheral Tcf1- cells and depletion of Tcf1+ cells hampers memory inflation. TCR repertoires of Tcf1+ and Tcf1- populations largely overlap, with the Tcf1+ population showing higher clonal diversity. These data show that Tcf1+ cells are necessary for sustaining the inflationary T cell response, and upholding this subset is likely critical for the success of CMV-based vaccination approaches.


Assuntos
Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/virologia , Muromegalovirus/fisiologia , Fator 1 de Transcrição de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/virologia , Animais , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Células Clonais , Memória Imunológica , Interferon Tipo I/metabolismo , Interleucina-12/metabolismo , Camundongos Endogâmicos C57BL , Fenótipo
9.
Res Vet Sci ; 130: 184-192, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32199177

RESUMO

Cyprinid herpesvirus 3 (CyHV-3) is the etiological agent of koi herpersvirus disease (KHVD), which causes serious economic losses in global common carp and ornamental koi carp production of larvae as well as adult type fish. To control KHVD, vaccines against CyHV-3 utilizing different immunization routes have been developed, among them, oral vaccination is the most desirable method to prevent fish diseases occurring at the early larval stage. Here, we developed an oral subunit vaccine through the Saccharomyces cerevisiae cell surface display of CyHV-3 envelope protein pORF65, then, the recombinant yeast fed to Artemia which served as bio-encapsulation vector by subsequently feeding the common carp (Cyprinus carpio var. Jian) larvae. The fluorescent observation showed that the Artemia and S. cerevisiae could deliver intact antigen to the hindgut of carp larvae suggesting the possibility of the vector for oral immunization. On this basis, after three immunizations at a week interval, the oral vaccine induced high level of specific anti-pORF65 antibody. Meanwhile, a significant difference of immune-related genes expression occurred including cxca, IL-1ß, IFN-a1, lysozyme, IgM and CD8α between vaccined group and blank control group. In addition, 30% of relative percent survival of carp larvae after immunization was obtained post the animal infection assay, offered an certain immune protection. Our results indicated that the oral pORF65 subunit vaccine bioencapsulated in Artemia induced the activation of immune response and high level of antibodies, which could be served as an oral vaccine candidate for the prevention of CyHV-3 infection.


Assuntos
Antígenos Virais/imunologia , Doenças dos Peixes/imunologia , Infecções por Herpesviridae/veterinária , Herpesviridae/imunologia , Vacinas contra Herpesvirus/administração & dosagem , Vacinação/veterinária , Adjuvantes Imunológicos/administração & dosagem , Administração Oral , Animais , Artemia/química , Infecções por Herpesviridae/imunologia , Imunidade Inata/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Saccharomyces cerevisiae/química , Vacinas Sintéticas/administração & dosagem , Proteínas do Envelope Viral/imunologia
10.
Proc Natl Acad Sci U S A ; 117(15): 8563-8572, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32220963

RESUMO

The small GTPase RABL3 is an oncogene of unknown physiological function. Homozygous knockout alleles of mouse Rabl3 were embryonic lethal, but a viable hypomorphic allele (xiamen [xm]) causing in-frame deletion of four amino acids from the interswitch region resulted in profound defects in lymphopoiesis. Impaired lymphoid progenitor development led to deficiencies of B cells, T cells, and natural killer (NK) cells in Rabl3 xm/xm mice. T cells and NK cells exhibited impaired cytolytic activity, and mice infected with mouse cytomegalovirus (MCMV) displayed elevated titers in the spleen. Myeloid cells were normal in number and function. Biophysical and crystallographic studies demonstrated that RABL3 formed a homodimer in solution via interactions between the effector binding surfaces on each subunit; monomers adopted a typical small G protein fold. RABL3xm displayed a large compensatory alteration in switch I, which adopted a ß-strand configuration normally provided by the deleted interswitch residues, thereby permitting homodimer formation. Dysregulated effector binding due to conformational changes in the switch I-interswitch-switch II module likely underlies the xm phenotype. One such effector may be GPR89, putatively an ion channel or G protein-coupled receptor (GPCR). RABL3, but not RABL3xm, strongly associated with and stabilized GPR89, and an N-ethyl-N-nitrosourea (ENU)-induced mutation (explorer) in Gpr89 phenocopied Rabl3 xm.


Assuntos
Linfócitos B/imunologia , Linfopoese , Proteínas Mutantes/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Linfócitos T/imunologia , Proteínas rab de Ligação ao GTP/química , Proteínas rab de Ligação ao GTP/fisiologia , Animais , Linfócitos B/metabolismo , Linfócitos B/patologia , Cristalografia por Raios X , Feminino , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/virologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Muromegalovirus/imunologia , Proteínas Mutantes/química , Proteínas Mutantes/genética , Mutação , Conformação Proteica , Linfócitos T/metabolismo , Linfócitos T/patologia
11.
J Immunol ; 204(6): 1582-1591, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32015010

RESUMO

NK cells play an important role in antiviral resistance. The integrin α2, which dimerizes with integrin ß1, distinguishes NK cells from innate lymphoid cells 1 and other leukocytes. Despite its use as an NK cell marker, little is known about the role of α2ß1 in NK cell biology. In this study, we show that in mice α2ß1 deficiency does not alter the balance of NK cell/ innate lymphoid cell 1 generation and slightly decreases the number of NK cells in the bone marrow and spleen without affecting NK cell maturation. NK cells deficient in α2ß1 had no impairment at entering or distributing within the draining lymph node of ectromelia virus (ECTV)-infected mice or at becoming effectors but proliferated poorly in response to ECTV and did not increase in numbers following infection with mouse CMV (MCMV). Still, α2ß1-deficient NK cells efficiently protected from lethal mousepox and controlled MCMV titers in the spleen. Thus, α2ß1 is required for optimal NK cell proliferation but is dispensable for protection against ECTV and MCMV, two well-established models of viral infection in which NK cells are known to be important.


Assuntos
Ectromelia Infecciosa/imunologia , Infecções por Herpesviridae/imunologia , Integrina alfa2beta1/metabolismo , Células Matadoras Naturais/imunologia , Animais , Contagem de Células , Proliferação de Células , Modelos Animais de Doenças , Vírus da Ectromelia/imunologia , Ectromelia Infecciosa/sangue , Ectromelia Infecciosa/virologia , Feminino , Infecções por Herpesviridae/sangue , Infecções por Herpesviridae/virologia , Humanos , Imunidade Inata , Integrina alfa2beta1/imunologia , Células Matadoras Naturais/metabolismo , Masculino , Camundongos , Muromegalovirus/imunologia , Replicação Viral/imunologia
12.
Sci Rep ; 10(1): 2371, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32047224

RESUMO

Immunopathogenesis in systemic viral infections can induce a septic state with leaky capillary syndrome, disseminated coagulopathy, and high mortality with limited treatment options. Murine gammaherpesvirus-68 (MHV-68) intraperitoneal infection is a gammaherpesvirus model for producing severe vasculitis, colitis and lethal hemorrhagic pneumonia in interferon gamma receptor-deficient (IFNγR-/-) mice. In prior work, treatment with myxomavirus-derived Serp-1 or a derivative peptide S-7 (G305TTASSDTAITLIPR319) induced immune protection, reduced disease severity and improved survival after MHV-68 infection. Here, we investigate the gut bacterial microbiome in MHV-68 infection. Antibiotic suppression markedly accelerated MHV-68 pathology causing pulmonary consolidation and hemorrhage, increased mortality and specific modification of gut microbiota. Serp-1 and S-7 reduced pulmonary pathology and detectable MHV-68 with increased CD3 and CD8 cells. Treatment efficacy was lost after antibiotic treatments with associated specific changes in the gut bacterial microbiota. In summary, transkingdom host-virus-microbiome interactions in gammaherpesvirus infection influences gammaherpesviral infection severity and reduces immune modulating therapeutic efficacy.


Assuntos
Microbioma Gastrointestinal , Infecções por Herpesviridae/microbiologia , Animais , Antibacterianos/farmacologia , Infecções por Herpesviridae/tratamento farmacológico , Infecções por Herpesviridae/imunologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Linfócitos/imunologia , Camundongos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/uso terapêutico , Proteínas Recombinantes/química , Proteínas Recombinantes/uso terapêutico , Serpinas/química
13.
J Gen Virol ; 101(4): 420-425, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31985394

RESUMO

The γ-herpesviruses have proved hard to vaccination against, with no convincing protection against long-term latent infection by recombinant viral subunits. In experimental settings, whole-virus vaccines have proved more effective, even when the vaccine virus itself establishes latent infection poorly. The main alternative is replication-deficient virus particles. Here high-dose, replication-deficient murid herpesvirus-4 only protected mice partially against wild-type infection. By contrast, latency-deficient but replication-competent vaccine protected mice strongly, even when delivered non-invasively to the olfactory epithelium. Thus, this approach seems to provide the best chance of a safe and effective γ-herpesvirus vaccine.


Assuntos
Infecções por Herpesviridae/prevenção & controle , Rhadinovirus/imunologia , Vacinas Virais , Animais , Anticorpos Antivirais/sangue , Gammaherpesvirinae/imunologia , Infecções por Herpesviridae/imunologia , Proteínas Imediatamente Precoces/genética , Camundongos , Camundongos Endogâmicos C57BL , Testes de Neutralização , Transativadores/genética , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologia , Vírion/imunologia , Latência Viral/imunologia , Replicação Viral/genética
14.
Immunol Cell Biol ; 98(4): 332-343, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31997396

RESUMO

Vaccination against γ-herpesviruses has proved difficult. CD4+ T cells are essential to contain infection, but how best to prime them and whether this can reduce viral loads remain unclear. To address these questions, we used ovalbumin (OVA) as a model antigen, delivering it with murine cytomegalovirus (MCMV) to protect mice against OVA-expressing murine herpesvirus-4 (MuHV-4). Membrane-associated OVA (mOVA) was more effective than soluble OVA, both to prime CD4+ T cells and as an effector target. It was also a better target than an OVA epitope limited to infected cells, suggesting that protective CD4+ T cells recognize infected cell debris rather than infected cells themselves. While MCMV-mOVA protected acutely against MuHV-4-mOVA, long-term protection was incomplete, even when OVA-specific CD8+ T cells and B cells were also primed. Thus, even optimized single-target vaccines may poorly reduce long-term γ-herpesvirus infections.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por Herpesviridae/imunologia , Vacinas contra Herpesvirus/imunologia , Imunogenicidade da Vacina/imunologia , Ovalbumina/imunologia , Rhadinovirus/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Infecções por Herpesviridae/prevenção & controle , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Rhadinovirus/genética , Fatores de Tempo , Vacinação
15.
J Vet Sci ; 21(1): e5, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31940684

RESUMO

The major glycoproteins of bovine gammaherpesvirus 4 (BoHV-4) are gB, gH, gM, gL, and gp180 with gB, gH, and gp180 being the most glycosylated. These glycoproteins participate in cell binding while some act as neutralization targets. Glycosylation of these envelope proteins may be involved in virion protection against neutralization by antibodies. In infected cattle, BoHV-4 induces an immune response characterized by low neutralizing antibody levels or an absence of such antibodies. Therefore, virus seroneutralization in vitro cannot always be easily demonstrated. The aim of this study was to evaluate the neutralizing capacity of 2 Argentine BoHV-4 strains and to associate those findings with the gene expression profiles of the major envelope glycoproteins. Expression of genes coding for the envelope glycoproteins occurred earlier in cells infected with isolate 10/154 than in cells infected with strain 07/435, demonstrating a distinct difference between the strains. Differences in serological response can be attributed to differences in the expression of antigenic proteins or to post-translational modifications that mask neutralizing epitopes. Strain 07/435 induced significantly high titers of neutralizing antibodies in several animal species in addition to bovines. The most relevant serological differences were observed in adult animals. This is the first comprehensive analysis of the expression kinetics of genes coding for BoHV-4 glycoproteins in 2 Argentine strains (genotypes 1 and 2). The results further elucidate the BoHV-4 life cycle and may also help determine the genetic variability of the strains circulating in Argentina.


Assuntos
Antígenos Virais/análise , Infecções por Herpesviridae/veterinária , Herpesvirus Bovino 4/genética , Infecções Tumorais por Vírus/veterinária , Proteínas Virais/análise , Animais , Argentina , Bovinos , Doenças dos Bovinos/imunologia , Cervos , Feminino , Doenças das Cabras/imunologia , Doenças das Cabras/virologia , Cabras , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/virologia , Herpesvirus Bovino 4/imunologia , Masculino , Ovinos , Doenças dos Ovinos/imunologia , Doenças dos Ovinos/virologia , Transcrição Genética , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/virologia
16.
Int Immunol ; 32(1): 27-38, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31504561

RESUMO

Immune responses against certain viruses are accompanied by auto-antibody production although the origin of these infection-associated auto-antibodies is unclear. Here, we report that murine γ-herpesvirus 68 (MHV68)-induced auto-antibodies are derived from polyreactive B cells in the germinal center (GC) through the activity of short-lived plasmablasts. The analysis of recombinant antibodies from MHV68-infected mice revealed that about 40% of IgG+ GC B cells were self-reactive, with about half of them being polyreactive. On the other hand, virion-reactive clones accounted for only a minor proportion of IgG+ GC B cells, half of which also reacted with self-antigens. The self-reactivity of most polyreactive clones was dependent on somatic hypermutation (SHM), but this was dispensable for the reactivity of virus mono-specific clones. Furthermore, both virus-mono-specific and polyreactive clones were selected to differentiate to B220lo CD138+ plasma cells (PCs). However, the representation of GC-derived polyreactive clones was reduced and that of virus-mono-specific clones was markedly increased in terminally differentiated PCs as compared to transient plasmablasts. Collectively, our findings demonstrate that, during acute MHV68 infection, self-reactive B cells are generated through SHM and selected for further differentiation to short-lived plasmablasts but not terminally differentiated PCs.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Infecções por Herpesviridae/imunologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
17.
Immunol Cell Biol ; 98(1): 67-78, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31630452

RESUMO

γ-Herpesviruses establish latent infections of lymphocytes and drive their proliferation, causing cancers and motivating a search for vaccines. Effective vaccination against murid herpesvirus-4 (MuHV-4)-driven lymphoproliferation by latency-impaired mutant viruses suggests that lytic access to the latency reservoir is a viable target for control. However, the vaccines retained the immunogenic MuHV-4 M2 latency gene. Here, a strong reduction in challenge virus load was maintained when the challenge virus lacked the main latency-associated CD8+ T-cell epitope of M2, or when the vaccine virus lacked M2 entirely. This protection was maintained also when the vaccine virus lacked both episome maintenance and the genomic region encompassing M1, M2, M3, M4 and ORF4. Therefore, protection did not require immunity to known MuHV-4 latency genes. As the remaining vaccine virus genes have clear homologs in human γ-herpesviruses, this approach of deleting viral latency genes could also be applied to them, to generate safe and effective vaccines against human disease.


Assuntos
Infecções por Herpesviridae , Rhadinovirus/fisiologia , Vacinas Virais , Latência Viral/genética , Animais , Linhagem Celular , Cricetinae , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Vacinas Virais/genética , Vacinas Virais/imunologia , Vacinas Virais/farmacologia , Latência Viral/imunologia
18.
Virology ; 539: 18-25, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31629226

RESUMO

KSHV-associated inflammatory cytokine syndrome (KICS) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV). KICS is associated with high-level, systemic replication of KSHV. This study characterized the clinical and virologic features of a KICS patient over time. Additionally, it compared the cytokine profiles of the KICS case to Kaposi's sarcoma (KS) (n = 11) and non-KS (n = 6) cases. This KICS case presented with elevated levels of KSHV and IL-10, as expected. Surprisingly, this case did not have elevated levels of IL-6 or human immunodeficiency virus 1 (HIV-1). Nevertheless, treatment with anti-IL6 receptor antibody (tocilizumab) reduced KSHV viral load and IL-10. The KSHV genome sequence showed no significant changes over time, except in ORF24. Phylogenetic analysis established this isolate as belonging to KSHV clade A and closely related to other US isolates. These findings suggest IL-10 as potential biomarker and therapy target for KICS.


Assuntos
Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/virologia , Herpesvirus Humano 8/fisiologia , Interleucina-10/sangue , Replicação Viral/imunologia , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/imunologia , Infecções Oportunistas Relacionadas com a AIDS/virologia , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores/sangue , Síndrome da Liberação de Citocina , DNA Viral/sangue , DNA Viral/genética , Genoma Viral/genética , Infecções por Herpesviridae/diagnóstico , Infecções por Herpesviridae/tratamento farmacológico , Herpesvirus Humano 8/classificação , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/isolamento & purificação , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Filogenia , Sarcoma de Kaposi/imunologia , Sarcoma de Kaposi/virologia , Carga Viral
19.
Med Microbiol Immunol ; 209(1): 41-49, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31586222

RESUMO

Human gammaherpesvirus 8 (HHV-8) replication is influenced by a complex interaction between viral and host elements. Here, we evaluated the expression of NFκB and TNF-α in B (CD19 +) and T (CD3 +) lymphocytes, and the serum concentration of IL-1ß and IL-12 cytokines in people living with HIV/AIDS (PLHA), negative for HHV-8-related diseases, and who presented antibodies to latent or lytic antigens from HHV-8. In addition, we also evaluated the correlation of HHV-8 viral load with NFκB, TNF-α, IL-1ß and IL-12 levels. The expression of NFκB (p < 0.0001) or TNF-α (p < 0.0001) in B lymphocytes (CD19 +) and the IL-1ß (p < 0.0266) and IL-12 (p < 0.0001) concentrations were associated with the presence of antibodies to HHV-8 lytic antigens. The CD19 + NFκB + TNF-α + and CD3 + NFκB + TNF-α + cells were also associated with the presence of antibodies to lytic infection (p < 0.0001). Among all PLHA evaluated, only individuals with the highest titers of lytic antibodies, i.e., 1:320, had detectable HHV-8 viral load. In these, HHV-8 viral load was correlated to NFκB (r = 0.6, p = 0.003) and TNF-α (r = 0.5, p = 0.01) (both in CD19 + lymphocytes) and with IL-1ß (r = 0.5, p = 0.01) and IL-12 (r = 0.6, p = 0.006) levels. We believe that viral replication and/or reactivation, in addition to being associated with the development of lytic antibodies against HHV-8, may be associated with inflammatory response via NFκB. Finally, although immune response imbalance has been previously related to HHV-8-associated diseases, our results indicate that important changes in immunity, mainly in the inflammatory response, may be clearly observed in individuals with HHV-8, but who have not yet presented clinical manifestations.


Assuntos
Anticorpos Antivirais/imunologia , Citocinas/metabolismo , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/metabolismo , Herpesvirus Humano 8/imunologia , NF-kappa B/metabolismo , Carga Viral , Biomarcadores , Brasil , Coinfecção , Infecções por HIV , Infecções por Herpesviridae/virologia , Humanos , Imunofenotipagem , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo
20.
J Virol ; 94(2)2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31645449

RESUMO

A replication-competent, recombinant strain of rhesus monkey rhadinovirus (RRV) expressing the Gag protein of SIVmac239 was constructed in the context of a glycoprotein L (gL) deletion mutation. Deletion of gL detargets the virus from Eph family receptors. The ability of this gL-minus Gag recombinant RRV to infect, persist, and elicit immune responses was evaluated after intravenous inoculation of two Mamu-A*01 + RRV-naive rhesus monkeys. Both monkeys responded with an anti-RRV antibody response, and quantitation of RRV DNA in peripheral blood mononuclear cells (PBMC) by real-time PCR revealed levels similar to those in monkeys infected with recombinant gL+ RRV. Comparison of RRV DNA levels in sorted CD3+ versus CD20+ versus CD14+ PBMC subpopulations indicated infection of the CD20+ subpopulation by the gL-minus RRV. This contrasts with results obtained with transformed B cell lines in vitro, in which deletion of gL resulted in markedly reduced infectivity. Over a period of 20 weeks, Gag-specific CD8+ T cell responses were documented by major histocompatibility complex class I (MHC-I) tetramer staining. Vaccine-induced CD8+ T cell responses, which were predominantly directed against the Mamu-A*01-restricted Gag181-189CM9 epitope, could be inhibited by blockade of MHC-I presentation. Our results indicate that gL and the interaction with Eph family receptors are dispensable for the colonization of the B cell compartment following high-dose infection by the intravenous route, which suggests the existence of alternative receptors. Further, gL-minus RRV elicits cellular immune responses that are predominantly canonical in nature.IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with a substantial disease burden in sub-Saharan Africa, often in the context of human immunodeficiency virus (HIV) infection. The related rhesus monkey rhadinovirus (RRV) has shown potential as a vector to immunize monkeys with antigens from simian immunodeficiency virus (SIV), the macaque model for HIV. KSHV and RRV engage cellular receptors from the Eph family via the viral gH/gL glycoprotein complex. We have now generated a recombinant RRV that expresses the SIV Gag antigen and does not express gL. This recombinant RRV was infectious by the intravenous route, established persistent infection in the B cell compartment, and elicited strong immune responses to the SIV Gag antigen. These results argue against a role for gL and Eph family receptors in B cell infection by RRV in vivo and have implications for the development of a live-attenuated KSHV vaccine or vaccine vector.


Assuntos
Deleção de Genes , Produtos do Gene gag , Vetores Genéticos , Infecções por Herpesviridae , Rhadinovirus , Vacinas contra a SAIDS , Vírus da Imunodeficiência Símia , Animais , Antígenos CD/imunologia , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Produtos do Gene gag/genética , Produtos do Gene gag/imunologia , Vetores Genéticos/genética , Vetores Genéticos/imunologia , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/imunologia , Humanos , Macaca mulatta , Rhadinovirus/genética , Rhadinovirus/imunologia , Vacinas contra a SAIDS/genética , Vacinas contra a SAIDS/imunologia , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/imunologia , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA