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1.
Curr Top Microbiol Immunol ; 422: 1-30, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31278515

RESUMO

Melanins are a class of pigments that are ubiquitous throughout biology. They play incredibly diverse and important roles ranging from radiation protection to immune defense, camouflage, and virulence. Fungi have evolved to use melanin to be able to persist in the environment and within organisms. Fungal melanins are often located within the cell well and are able to neutralize reactive oxygen species and other radicals, defend against UV radiation, bind and sequester non-specific peptides and compounds, and produce a physical barrier that defends the cell. For this reason, melanized fungi are often well-suited to be human pathogens-melanin allows fungi to neutralize the microbicidal oxidative bursts of our innate immune system, bind and inactivate to antimicrobial peptides and enzymes, sequester antifungal pharmaceuticals, and create a shield to block immune recognition of the fungus. Due to the importance and pervasiveness of melanin in fungal virulence, mammalian immune systems have evolved antifungal strategies that involve directly detecting and binding to fungal melanins. Such strategies include the use of melanin-specific antibody responses and C-type lectins like the newly discovered melanin-specific MelLec receptor.


Assuntos
Fungos/metabolismo , Fungos/patogenicidade , Melaninas/metabolismo , Animais , Fungos/imunologia , Interações Hospedeiro-Patógeno/imunologia , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Lectinas Tipo C/metabolismo , Melaninas/imunologia , Virulência
2.
Nat Immunol ; 20(7): 890-901, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209400

RESUMO

Progenitor-like CD8+ T cells mediate long-term immunity to chronic infection and cancer and respond potently to immune checkpoint blockade. These cells share transcriptional regulators with memory precursor cells, including T cell-specific transcription factor 1 (TCF1), but it is unclear whether they adopt distinct programs to adapt to the immunosuppressive environment. By comparing the single-cell transcriptomes and epigenetic profiles of CD8+ T cells responding to acute and chronic viral infections, we found that progenitor-like CD8+ T cells became distinct from memory precursor cells before the peak of the T cell response. We discovered a coexpression gene module containing Tox that exhibited higher transcriptional activity associated with more abundant active histone marks in progenitor-like cells than memory precursor cells. Moreover, thymocyte selection-associated high mobility group box protein TOX (TOX) promoted the persistence of antiviral CD8+ T cells and was required for the programming of progenitor-like CD8+ T cells. Thus, long-term CD8+ T cell immunity to chronic viral infection requires unique transcriptional and epigenetic programs associated with the transcription factor TOX.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Regulação da Expressão Gênica , Proteínas de Homeodomínio/genética , Infecção/etiologia , Análise de Célula Única , Animais , Biomarcadores , Imunoprecipitação da Cromatina , Epigênese Genética , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Homeodomínio/metabolismo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Memória Imunológica , Infecção/metabolismo , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Fatores de Tempo , Transcriptoma
3.
Nat Commun ; 10(1): 2727, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227708

RESUMO

A fundamental challenge in medical microbiology is to characterize the dynamic protein-protein interaction networks formed at the host-pathogen interface. Here, we generate a quantitative interaction map between the significant human pathogen, Streptococcus pyogenes, and proteins from human saliva and plasma obtained via complementary affinity-purification and bacterial-surface centered enrichment strategies and quantitative mass spectrometry. Perturbation of the network using immunoglobulin protease cleavage, mixtures of different concentrations of saliva and plasma, and different S. pyogenes serotypes and their isogenic mutants, reveals how changing microenvironments alter the interconnectivity of the interaction map. The importance of host immunoglobulins for the interaction with human complement proteins is demonstrated and potential protective epitopes of importance for phagocytosis of S. pyogenes cells are localized. The interaction map confirms several previously described protein-protein interactions; however, it also reveals a multitude of additional interactions, with possible implications for host-pathogen interactions involving other bacterial species.


Assuntos
Anticorpos Antibacterianos/metabolismo , Proteínas de Bactérias/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Infecções Estreptocócicas/imunologia , Streptococcus pyogenes/imunologia , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/imunologia , Cromatografia de Afinidade , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Mapeamento de Epitopos , Voluntários Saudáveis , Humanos , Espectrometria de Massas , Proteínas Opsonizantes/imunologia , Proteínas Opsonizantes/metabolismo , Ligação Proteica , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/imunologia , Infecções Estreptocócicas/sangue , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/metabolismo
4.
Nat Immunol ; 20(7): 879-889, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31182807

RESUMO

CD8+ T cells and natural killer (NK) cells are central cellular components of immune responses against pathogens and cancer, which rely on interleukin (IL)-15 for homeostasis. Here we show that IL-15 also mediates homeostatic priming of CD8+ T cells for antigen-stimulated activation, which is controlled by a deubiquitinase, Otub1. IL-15 mediates membrane recruitment of Otub1, which inhibits ubiquitin-dependent activation of AKT, a kinase that is pivotal for T cell activation and metabolism. Otub1 deficiency in mice causes aberrant responses of CD8+ T cells to IL-15, rendering naive CD8+ T cells hypersensitive to antigen stimulation characterized by enhanced metabolic reprograming and effector functions. Otub1 also controls the maturation and activation of NK cells. Deletion of Otub1 profoundly enhances anticancer immunity by unleashing the activity of CD8+ T cells and NK cells. These findings suggest that Otub1 controls the activation of CD8+ T cells and NK cells by functioning as a checkpoint of IL-15-mediated priming.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Cisteína Endopeptidases/metabolismo , Interleucina-15/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Cisteína Endopeptidases/deficiência , Enzimas Desubiquitinantes/metabolismo , Modelos Animais de Doenças , Metabolismo Energético , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interleucina-15/genética , Melanoma Experimental , Camundongos , Camundongos Transgênicos , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Interleucina-15/metabolismo , Tolerância a Antígenos Próprios/genética , Tolerância a Antígenos Próprios/imunologia , Transdução de Sinais , Especificidade do Receptor de Antígeno de Linfócitos T , Ubiquitinação
5.
Future Microbiol ; 14: 705-716, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31161794

RESUMO

Aim: Aspergillus fumigatus is one of the most common opportunistic fungi that can cause invasive infection. To profile the kinetic variation of immune cells and cytokines after exposure to A. fumigatus thoroughly, we established a pulmonary A. fumigatus infection model in temporarily immunosuppressed mice. Materials & methods: Systematic and kinetic studies of different immune cells and cytokines were performed. Results: We observed that the granulocytes and macrophages recruited to the site of infection played an important role in the infectious phase. There was a significant increase in the cytokines IFN-γ, IL-6, TNF-α as well as the chemokines CXCL1, MIP-1α, MIP-2 and CCL5 after infection. IL-10 was found to participate in balancing the anti-inflammatory response in the recovery phases. The immune response mediated by T cells was mainly presented by the Th1-type on day 7 after exposure with a high proportion of IFN-γ+ CD4+ T cells and CD4+CD44highCD62Llow effector T cells. Conclusion: These kinetic parameters of the immune response might provide diagnostic clues for A. fumigatus infection.


Assuntos
Aspergilose/imunologia , Aspergillus fumigatus/patogenicidade , Quimiocinas/metabolismo , Citocinas/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Animais , Linfócitos T CD4-Positivos , Quimiocina CCL3/metabolismo , Quimiocina CCL5/metabolismo , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/metabolismo , Quimiocinas/sangue , Citocinas/sangue , Modelos Animais de Doenças , Hospedeiro Imunocomprometido , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Cinética , Pulmão/microbiologia , Pulmão/patologia , Linfonodos/microbiologia , Linfonodos/patologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Linfócitos T/imunologia , Células Th1/imunologia , Fator de Necrose Tumoral alfa/metabolismo
6.
Nat Immunol ; 20(7): 793-801, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31213715

RESUMO

Unlike other cells in the body, immune cells have to be able to enter and adapt to life within diverse tissues. Immune cells develop within dedicated immune system organs, such as the bone marrow, thymus and lymphoid tissues, but also inhabit other tissues, wherein they not only provide defense against infection and malignancies but also contribute to homeostatic tissue function. Because different tissues have widely divergent metabolic rates and fuel requirements, this raises interesting questions about the adaptation of immune cells in specific tissues. When immune cells take up residence in different tissues, they develop a transcriptional signature that reflects adaptation to life and function within that tissue. Genes encoding metabolic-pathway proteins are strongly represented within these signatures, reflective of the importance of metabolic adaptation to tissue residence. In this Review, we discuss the available data on the metabolic adaptation of immune cells to life in different tissue sites, within the broader framework of how functional adaptation versus maladaptation in the niche can affect tissue homeostasis.


Assuntos
Adaptação Biológica , Metabolismo Energético , Sistema Imunitário/citologia , Sistema Imunitário/fisiologia , Especificidade de Órgãos/imunologia , Animais , Biomarcadores , Homeostase , Interações Hospedeiro-Patógeno/imunologia , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Transdução de Sinais
8.
Nat Commun ; 10(1): 2699, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221976

RESUMO

Human cytomegalovirus (CMV) causes a wide array of disease to diverse populations of immune-compromised individuals. Thus, a more comprehensive understanding of how CMV enters numerous host cell types is necessary to further delineate the complex nature of CMV pathogenesis and to develop targeted therapeutics. To that end, we establish a vaccination strategy utilizing membrane vesicles derived from epithelial cells to generate a library of monoclonal antibodies (mAbs) targeting cell surface proteins in their native conformation. A high-throughput inhibition assay is employed to screen these antibodies for their ability to limit infection, and mAbs targeting CD46 are identified. In addition, a significant reduction of viral proliferation in CD46-KO epithelial cells confirms a role for CD46 function in viral dissemination. Further, we demonstrate a CD46-dependent entry pathway of virus infection in trophoblasts, but not in fibroblasts, highlighting the complexity of CMV entry and identifying CD46 as an entry factor in congenital infection.


Assuntos
Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Interações Hospedeiro-Patógeno/imunologia , Proteína Cofatora de Membrana/imunologia , Internalização do Vírus , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/imunologia , Linhagem Celular , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/virologia , Células Epiteliais/imunologia , Células Epiteliais/virologia , Fibroblastos/imunologia , Fibroblastos/virologia , Técnicas de Inativação de Genes , Humanos , Proteína Cofatora de Membrana/genética , RNA Interferente Pequeno/metabolismo , Trofoblastos/imunologia , Trofoblastos/virologia , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologia
10.
Nat Commun ; 10(1): 2297, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31127085

RESUMO

Candida albicans is a fungal pathobiont, able to cause epithelial cell damage and immune activation. These functions have been attributed to its secreted toxin, candidalysin, though the molecular mechanisms are poorly understood. Here, we identify epidermal growth factor receptor (EGFR) as a critical component of candidalysin-triggered immune responses. We find that both C. albicans and candidalysin activate human epithelial EGFR receptors and candidalysin-deficient fungal mutants poorly induce EGFR phosphorylation during murine oropharyngeal candidiasis. Furthermore, inhibition of EGFR impairs candidalysin-triggered MAPK signalling and release of neutrophil activating chemokines in vitro, and diminishes neutrophil recruitment, causing significant mortality in an EGFR-inhibited zebrafish swimbladder model of infection. Investigation into the mechanism of EGFR activation revealed the requirement of matrix metalloproteinases (MMPs), EGFR ligands and calcium. We thus identify a PAMP-independent mechanism of immune stimulation and highlight candidalysin and EGFR signalling components as potential targets for prophylactic and therapeutic intervention of mucosal candidiasis.


Assuntos
Candida albicans/imunologia , Proteínas Fúngicas/imunologia , Interações Hospedeiro-Patógeno/imunologia , Sacos Aéreos/microbiologia , Animais , Candida albicans/genética , Candida albicans/metabolismo , Candidíase/imunologia , Candidíase/microbiologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Receptores ErbB/genética , Receptores ErbB/imunologia , Receptores ErbB/metabolismo , Feminino , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/imunologia , Metaloproteinases da Matriz/imunologia , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Membrana Mucosa/imunologia , Membrana Mucosa/microbiologia , Faringite/imunologia , Faringite/microbiologia , Fosforilação , Peixe-Zebra
11.
BMC Bioinformatics ; 20(Suppl 7): 192, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31074372

RESUMO

BACKGROUND: The Iridoviridae family is categorized into five genera and clustered into two subfamilies: Alphairidovirinae includes Lymphocystivirus, Ranavirus (GIV), and Megalocystivirus (TGIV), which infect vertebrate hosts and Betairidovirinae includes Iridovirus and Chloriridovirus, which infect invertebrate hosts. Clustered Iridoviridae subfamilies possess host-specific characteristics, which can be considered as exclusive features for in-silico prediction of effective epitopes for vaccine development. A voting mechanism-based linear epitope (LE) prediction system was applied to identify and endorse LE candidates with a minimum length requirement for each clustered subfamily RESULTS: The experimental results showed that four conserved epitopes among the Iridovirideae family, one exclusive epitope for invertebrate subfamily and two exclusive epitopes for vertebrate family were predicted. These predicted LE candidates were further validated by ELISA assays for evaluating the strength of antigenicity and cross antigenicity. The conserved LEs for Iridoviridae family reflected high antigenicity responses for the two subfamilies, while exclusive LEs reflected high antigenicity responses only for the host-specific subfamily CONCLUSIONS: Host-specific characteristics are important features and constraints for effective epitope prediction. Our proposed voting mechanism based system provides a novel approach for in silico LE prediction prior to vaccine development, and it is especially powerful for analyzing antigen sequences with exclusive features between two clustered groups.


Assuntos
Infecções por Vírus de DNA/imunologia , Epitopos/imunologia , Interações Hospedeiro-Patógeno/imunologia , Invertebrados/imunologia , Iridoviridae/imunologia , Vertebrados/imunologia , Proteínas Virais/imunologia , Animais , Infecções por Vírus de DNA/virologia , Invertebrados/virologia , Iridoviridae/classificação , Iridoviridae/genética , Vertebrados/virologia
12.
Int J Mol Sci ; 20(9)2019 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-31083555

RESUMO

Candida albicans and Candida glabrata are the two most prevalent etiologic agents of candidiasis worldwide. Although both are recognized as pathogenic, their choice of virulence traits is highly divergent. Indeed, it appears that these different approaches to fungal virulence may be equally successful in causing human candidiasis. In this review, the virulence mechanisms employed by C. albicans and C. glabrata are analyzed, with emphasis on the differences between the two systems. Pathogenesis features considered in this paper include dimorphic growth, secreted enzymes and signaling molecules, and stress resistance mechanisms. The consequences of these traits in tissue invasion, biofilm formation, immune system evasion, and macrophage escape, in a species dependent manner, are discussed. This review highlights the observation that C. albicans and C. glabrata follow different paths leading to a similar outcome. It also highlights the lack of knowledge on some of the specific mechanisms underlying C. glabrata pathogenesis, which deserve future scrutiny.


Assuntos
Candida albicans/patogenicidade , Candida glabrata/patogenicidade , Animais , Biofilmes/crescimento & desenvolvimento , Candida albicans/imunologia , Candida albicans/fisiologia , Candida glabrata/imunologia , Candida glabrata/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Evasão da Resposta Imune , Virulência/imunologia
13.
Int J Mol Sci ; 20(9)2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035661

RESUMO

Inflammasome activation is essential for host immune responses during pathogenic infection and sterile signals insult, whereas excessive activation is injurious. Thus, inflammasome activation is tightly regulated at multiple layers. Ubiquitination is an important post-translational modification for orchestrating inflammatory immune responses during pathogenic infection, and a major target hijacked by pathogenic bacteria for promoting their survival and proliferation. This review summarizes recent insights into distinct mechanisms of the inflammasome activation and ubiquitination process triggered by bacterial infection. We discuss the complex regulatory of inflammasome activation mediated by ubiquitination machinery during bacterial infection, and provide therapeutic approaches for specifically targeting aberrant inflammasome activation.


Assuntos
Infecções Bacterianas/metabolismo , Inflamassomos/metabolismo , Animais , Bactérias/imunologia , Bactérias/metabolismo , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Biomarcadores , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Ubiquitinação
14.
BMC Res Notes ; 12(1): 243, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036050

RESUMO

OBJECTIVE: Conifer genomes show high genetic diversity in intergenic regions that contain diverse sets of transposable elements with dominating long terminal repeat (LTR) retrotransposons (RE). Transcription of RE in response to environmental stimuli could produce various types of regulatory non-coding RNAs, but global genomic methylation changes could result in a coincidental expression of normally silent genomic regions. Expression of several RE families was evaluated in Scots pine seedlings after controlled inoculations with two fungal species that exhibit different modes of pathogenicity (necrotrophic and likely biotrophic); data compared to the overall RE distribution in genome. Recognition of regulatory non-coding RNA involved in host-pathogen interplay could be valuable in understanding defence mechanisms of perennial plants. RESULTS: In the case of necrotrophic fungi Heterobasidion annosum (HA), short activation followed by restriction of RE expression was revealed after inoculation and during the spread of the pathogen. After inoculation with Lophodermium seditiosum (LS), an early increase in RE expression was revealed with the spread of the pathogen and subsequent transcription rise in all seedlings. Our observations indicate that in the complex plant genome multiple RE families constitutively express in response to pathogen invasion and these sequences could undergo regulation related to host response or pathogen influence.


Assuntos
Regulação da Expressão Gênica de Plantas/imunologia , Genoma de Planta , Pinus sylvestris/genética , Doenças das Plantas/genética , Retroelementos/imunologia , Plântula/genética , Ascomicetos/genética , Ascomicetos/crescimento & desenvolvimento , Ascomicetos/patogenicidade , Basidiomycota/genética , Basidiomycota/crescimento & desenvolvimento , Basidiomycota/patogenicidade , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Pinus sylvestris/imunologia , Pinus sylvestris/microbiologia , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Raízes de Plantas/genética , Raízes de Plantas/imunologia , Raízes de Plantas/microbiologia , Brotos de Planta/genética , Brotos de Planta/imunologia , Brotos de Planta/microbiologia , Plântula/imunologia , Plântula/microbiologia , Sequências Repetidas Terminais , Transcrição Genética
15.
BMC Res Notes ; 12(1): 242, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036079

RESUMO

OBJECTIVE: Resting CD4+ T cells are major reservoirs of latent HIV-1 infection, and may be formed during the early phase of the infection. Although CCR5-tropic (R5) HIV-1 is highly transmissible during the early phase, newly infected individuals have usually been exposed to a mixture of R5 and CXCR4-tropic (X4) viruses, and X4 viral DNA is also detectable in the host. Our aim was to identify which subsets of resting CD4+ T cells contribute to forming the latent reservoir in the presence of both X4 and R5 viruses. RESULTS: Primary resting CD4+ naïve T (TN) cells, CCR5- memory T (TM) cells, and CCR5+ TM cells isolated by flow cytometry were infected simultaneously with X4 and R5 HIV-1, which harbored different reporter genes, and were cultured in the resting condition. Flow cytometry at 3 days post-infection demonstrated that X4 HIV-1+ cells were present in all three subsets of cells, whereas R5 HIV-1+ cells were present preferentially in CCR5+ TM cells, but not in TN cells. Following CD3/CD28-mediated activation at 3 days post-infection, numbers of R5 HIV-1+ cells and X4 HIV-1+ cells increased significantly only in the CCR5+ TM subset, suggesting that it provides a major reservoir of replication-competent, latently infected viruses.


Assuntos
Linfócitos T CD4-Positivos/virologia , DNA Viral/genética , HIV-1/fisiologia , Receptores CCR5/genética , Receptores CXCR4/genética , Latência Viral , Adulto , Linfócitos T CD4-Positivos/imunologia , DNA Viral/metabolismo , Expressão Gênica , HIV-1/patogenicidade , Voluntários Saudáveis , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Memória Imunológica , Cultura Primária de Células , Receptores CCR5/imunologia , Receptores CXCR4/imunologia , Tropismo Viral , Replicação Viral
16.
J Immunol Res ; 2019: 8685312, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31089479

RESUMO

Type I Interferons were first described for their profound antiviral abilities in cell culture and animal models, and later, they were translated into potent antiviral therapeutics. However, as additional studies into the function of Type I Interferons progressed, it was also seen that pathogenic viruses have coevolved to encode potent mechanisms allowing them to evade or suppress the impact of Type I Interferons on their replication. For chronic viral infections, such as HIV and many of the AIDS-associated viruses, including HTLV, HCV, KSHV, and EBV, the clinical efficacy of Type I Interferons is limited by these mechanisms. Here, we review some of the ways that HIV and AIDS-associated viruses thrive in Type I Interferon-rich environments via mechanisms that block the function of this important antiviral cytokine. Overall, a better understanding of these mechanisms creates avenues to better understand the innate immune response to these viruses as well as plan the development of antivirals that would allow the natural antiviral effect of Type I Interferons to manifest during these infections.


Assuntos
Síndrome de Imunodeficiência Adquirida/imunologia , Infecções por HIV/imunologia , Interações Hospedeiro-Patógeno/imunologia , Interferon Tipo I/imunologia , Transdução de Sinais , Síndrome de Imunodeficiência Adquirida/virologia , Animais , Ensaios Clínicos como Assunto , HIV/imunologia , Humanos , Imunidade Inata , Camundongos
17.
Microb Pathog ; 133: 103556, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31128172

RESUMO

To investigate cytokine expression in chicken embryo fibroblast (CEF) cells, a virulent avian avulavirus 1 (AAvV-1) strain called SG10 that rapidly causes 100% mortality in its host, and a vaccine strain (La Sota) were characterized. Real-time quantitative PCR was performed on RNA samples from CEF cells, which were collected at 0, 24, 48 and 72 h post-infection. The dynamic expression patterns of ten cytokines (TNF-α, IFN-α, IFN-ß, IL-1ß, IL-2, IL-6, IL-10, IL-13, IL-15 and IL-18) were investigated. The results showed that infection with lentogenic La Sota induced significantly higher levels of the antiviral cytokines IFN-α and IFN-ß, proinflammatory cytokines IL-2, IL-15 and IL-18, and the anti-inflammatory cytokine IL-10, than did infection with virulent SG10. Furthermore, the SG10 strain induced dramatically higher levels of the inflammatory cytokine IL-6 than those observed in cells infected with La Sota. However, the expression patterns of the other cytokines that were tested did not show any obvious trends or statistically significant differences between cells infected with the virulent and avirulent strains. These data show that infection with lentogenic La Sota induced more effective immune responses and anti-viral effects than did infection with virulent SG10 in CEFs. Our data provide distinct expression patterns of IFNs and proinflammatory and anti-inflammatory cytokines to AAvV-1 by virulence in CEF cells.


Assuntos
Embrião de Galinha/imunologia , Citocinas/metabolismo , Fibroblastos/imunologia , Doença de Newcastle/imunologia , Vírus da Doença de Newcastle/imunologia , Animais , Galinhas/imunologia , Galinhas/metabolismo , Citocinas/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Doença de Newcastle/virologia , Vacinas Virais/imunologia
18.
Immunogenetics ; 71(5-6): 421-432, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31089760

RESUMO

Cathepsins are key mammalian proteases that play an important role in the immune response. Several studies have revealed the versatile and critical functions of cathepsins. Here, we obtained ten kinds of cathepsin homologs and identified seven homologs with complete coding sequences. Phylogenetic analysis verified their identities and supported the classification of cathepsins into seven families, which is similar to other vertebrates. Tissue-specific expression analysis showed that all lamprey cathepsins (L-cathepsins) are present in the supraneural body (SB), kidney, gill, intestine, brain, heart, and liver, but their relative abundance varied among tissues. Additionally, we focused on the lamprey cathepsin L (L-cathepsin L) and used recombinant L-cathepsin L protein (rL-cathepsin L) to prepare anti rL-cathepsin L polyclonal antibodies, which were used to detect its distribution in lamprey tissues. The L-cathepsin L protein was primarily detected in the SB, kidney, gill, intestine, brain, and liver via western blot and immunohistochemistry assays. Importantly, quantitative real-time PCR (RT-PCR) revealed that the expression level of L-cathepsins mRNA significantly increased after exposure to three different stimuli (poly I:C, Staphylococcus aureus (S.a) and Vibro anguilarum (V.an)). This suggested that L-cathepsins may participate in defense processes. These results revealed that L-cathepsins may play key roles in the immune response to exogenous stimuli. The findings provide important information for future studies aiming to understand the molecular mechanisms underlying the immune response to pathogen invasion in lamprey.


Assuntos
Catepsinas/genética , Lampreias/genética , Sequência de Aminoácidos , Animais , Catepsinas/química , Catepsinas/metabolismo , Clonagem Molecular , Evolução Molecular , Expressão Gênica , Genômica/métodos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Imunomodulação , Lampreias/classificação , Lampreias/imunologia , Família Multigênica , Filogenia , Análise de Sequência de DNA
19.
Int J Mol Sci ; 20(9)2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-31060328

RESUMO

The small GTase Arf6 has several important functions in intracellular vesicular trafficking and regulates the recycling of different types of cargo internalized via clathrin-dependent or -independent endocytosis. It activates the lipid modifying enzymes PIP 5-kinase and phospholipase D, promotes actin polymerization, and affects several functionally distinct processes in the cell. Arf6 is used for the phagocytosis of pathogens and can be directly or indirectly targeted by various pathogens to block phagocytosis or induce the uptake of intracellular pathogens. Arf6 is also used in the signaling of Toll-like receptors and in the activation of NADPH oxidases. In this review, we first give an overview of the different roles and mechanisms of action of Arf6 and then focus on its role in innate immunity and host-pathogen interactions.


Assuntos
Fatores de Ribosilação do ADP/genética , Fatores de Ribosilação do ADP/metabolismo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Animais , Biomarcadores , Ativação Enzimática , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia , Humanos , Fagocitose/genética , Fagocitose/imunologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Receptores Toll-Like/metabolismo , Virulência
20.
Vet Immunol Immunopathol ; 211: 49-57, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31084894

RESUMO

Histophilus somni is a Gram negative coccobacillus that causes respiratory, reproductive and central nervous system disease in cattle. The hallmark of H. somni infection is diffuse vasculitis and intravascular thrombosis that can lead to an acute central nervous system disease known as thrombotic meningoencephalitis (TME). Because neutrophils are major players in the pathophysiology of septic meningitis, we sought to determine their role in H. somni-induced fibrin clot formation in vitro. Bovine brain endothelial cells (TBBE cells) were exposed to H. somni cells at a 1:25 ratio, respectively. Conditioned media (CM) were collected after a 6 h incubation at 37 °C with 5% CO2, and then incubated with bovine peripheral blood polymorphonuclear neutrophils (PMNs). Following incubation, fibrin clot formation and tissue factor activity were assessed by a re-calcified plasma clotting assay. We found greater tissue factor activity in cell lysates and CM from H. somni-stimulated TBBE cells than unstimulated control TBBE cells. In addition, PMNs exposed to CM or extracellular vesicles from H. somni-stimulated TBBE cells expressed von Willenbrand factor, exhibited increased fibrin clot formation, and displayed greater tissue factor activity than PMNs exposed to CM or extracellular vesicles from unstimulated control TBBE cells. These results suggest that bovine PMNs might acquire extracellular vesicles from endothelial cells that leads to thrombus formation in bovine brain microvasculature and contribute to the process that characterizes TME.


Assuntos
Encéfalo/microbiologia , Doenças dos Bovinos/microbiologia , Células Endoteliais/microbiologia , Vesículas Extracelulares/microbiologia , Neutrófilos/imunologia , Infecções por Pasteurellaceae/veterinária , Pasteurellaceae , Animais , Encéfalo/imunologia , Bovinos , Doenças dos Bovinos/imunologia , Meios de Cultivo Condicionados , Células Endoteliais/imunologia , Vesículas Extracelulares/imunologia , Interações Hospedeiro-Patógeno/imunologia , Neutrófilos/fisiologia , Pasteurellaceae/imunologia , Infecções por Pasteurellaceae/imunologia , Trombose/imunologia , Trombose/microbiologia , Trombose/veterinária
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