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1.
PLoS Pathog ; 17(10): e1009928, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34695164

RESUMO

Non-specific protective effects of certain vaccines have been reported, and long-term boosting of innate immunity, termed trained immunity, has been proposed as one of the mechanisms mediating these effects. Several epidemiological studies suggested cross-protection between influenza vaccination and COVID-19. In a large academic Dutch hospital, we found that SARS-CoV-2 infection was less common among employees who had received a previous influenza vaccination: relative risk reductions of 37% and 49% were observed following influenza vaccination during the first and second COVID-19 waves, respectively. The quadrivalent inactivated influenza vaccine induced a trained immunity program that boosted innate immune responses against various viral stimuli and fine-tuned the anti-SARS-CoV-2 response, which may result in better protection against COVID-19. Influenza vaccination led to transcriptional reprogramming of monocytes and reduced systemic inflammation. These epidemiological and immunological data argue for potential benefits of influenza vaccination against COVID-19, and future randomized trials are warranted to test this possibility.


Assuntos
COVID-19/imunologia , Proteção Cruzada/fisiologia , Imunidade Inata/fisiologia , Vacinas contra Influenza/administração & dosagem , COVID-19/epidemiologia , COVID-19/prevenção & controle , Citocinas/imunologia , Citocinas/metabolismo , Regulação para Baixo , Imidazóis/imunologia , Incidência , Vacinas contra Influenza/imunologia , Países Baixos/epidemiologia , Recursos Humanos em Hospital , Poli I-C/imunologia , Proteômica , Fatores de Risco , Análise de Sequência de RNA
2.
J Immunol ; 207(2): 408-420, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34193600

RESUMO

Type I IFNs (IFN-I) are important for tumor immune surveillance and contribute to the therapeutic responses for numerous treatment regimens. Nevertheless, certain protumoral activities by IFN-I have been increasingly recognized. Indeed, our recent work showed that systemic poly(I:C)/IFN treatment can undesirably trigger high arginase (ARG1) expression within the tumor-associated monocyte/macrophage compartment. Using a line of CRISPR-generated Arg1-YFP reporter knock-in mice, we have determined that a subset of tumor-associated macrophages represent the major Arg1-expressing cell type following poly(I:C)/IFN stimulation. More detailed analyses from in vitro and in vivo models demonstrate a surprising IFN-to-IL-4 cytokine axis in transitional monocytes, which can subsequently stimulate IL-4 target genes, including Arg1, in macrophages. Intriguingly, IFN stimulation of transitional monocytes yielded concurrent M2 (YFP+)- and M1 (YFP-)-skewed macrophage subsets, correlated with an inhibitory crosstalk between IFN-I and IL-4. Genetic abrogation of IL-4 signaling in mice diminished poly(I:C)/IFN-induced ARG1 in tumors, leading to enhanced activation of CD8+ T cells and an improved therapeutic effect. The present work uncovered a monocyte-orchestrated macrophage phenotype conversion mechanism that may have broad implications.


Assuntos
Citocinas/metabolismo , Interferons/metabolismo , Interleucina-4/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , Poli I-C/metabolismo , Animais , Arginase/imunologia , Arginase/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/imunologia , Citocinas/imunologia , Feminino , Interferons/imunologia , Interleucina-4/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Neoplasias/imunologia , Neoplasias/metabolismo , Fenótipo , Poli I-C/imunologia , Transdução de Sinais/imunologia , Transdução de Sinais/fisiologia
3.
Mol Immunol ; 136: 128-137, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34139553

RESUMO

Transcription factor small mothers against decapentaplegic (Smad) family SMAD proteins are the essential intracellular signal mediators and transcription factors for transforming growth factor ß (TGF-ß) signal transduction pathway, which usually exert pleiotropic actions on cell physiology, including immune response, cell migration and differentiation. In this study, the Smad family was identified in the most primitive vertebrates through the investigation of the transcriptome data of lampreys. The topology of phylogenetic tree showed that the four Smads (Smad1, Smad3, Smad4 and Smad6) in lampreys were subdivided into four different groups. Meanwhile, homology analysis indicated that most Smads were conserved with typical Mad Homology (MH) 1 and MH2 domains. In addition, Lethenteron reissneri Smads (Lr-Smads) adopted general Smads folding structure and had high tertiary structural similarity with human Smads (H-Smads). Genomic synteny analysis revealed that the large-scale duplication blocks were not found in lamprey genome and neighbor genes of lamprey Smads presented dramatic differences compared with jawed vertebrates. Importantly, quantitative real-time PCR analysis demonstrated that Smads were widely expressed in lamprey, and the expression level of Lr-Smads mRNA was up-regulated with different pathogenic stimulations. Moreover, depending on the weighted gene co-expression network analysis (WGCNA), four Lr-Smads were identified as two meaningful modules (green and gray). The functional analysis of these two modules showed that they might have a correlation with ployI:C. And these genes presented strong positive correlation during the immune response from the results of Pearson's correlation analysis. In conclusion, our results would not only enrich the information of Smad family in jawless vertebrates, but also lay the foundation for immunity in further study.


Assuntos
Lampreias/genética , Lampreias/imunologia , Proteínas Smad/genética , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Sequência de Aminoácidos , Animais , Evolução Molecular , Regulação da Expressão Gênica/genética , Genoma/genética , Filogenia , Poli I-C/imunologia , Conformação Proteica , Transdução de Sinais/genética , Proteína Smad1/genética , Proteína Smad1/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Proteína Smad6/genética , Proteína Smad6/metabolismo
4.
Front Immunol ; 12: 652923, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34163470

RESUMO

Previously, we constructed a library of Ligilactobacillus salivarius strains from the intestine of wakame-fed pigs and reported a strain-dependent capacity to modulate IFN-ß expression in porcine intestinal epithelial (PIE) cells. In this work, we further characterized the immunomodulatory activities of L. salivarius strains from wakame-fed pigs by evaluating their ability to modulate TLR3- and TLR4-mediated innate immune responses in PIE cells. Two strains with a remarkable immunomodulatory potential were selected: L. salivarius FFIG35 and FFIG58. Both strains improved IFN-ß, IFN-λ and antiviral factors expression in PIE cells after TLR3 activation, which correlated with an enhanced resistance to rotavirus infection. Moreover, a model of enterotoxigenic E. coli (ETEC)/rotavirus superinfection in PIE cells was developed. Cells were more susceptible to rotavirus infection when the challenge occurred in conjunction with ETEC compared to the virus alone. However, L. salivarius FFIG35 and FFIG58 maintained their ability to enhance IFN-ß, IFN-λ and antiviral factors expression in PIE cells, and to reduce rotavirus replication in the context of superinfection. We also demonstrated that FFIG35 and FFIG58 strains regulated the immune response of PIE cells to rotavirus challenge or ETEC/rotavirus superinfection through the modulation of negative regulators of the TLR signaling pathway. In vivo studies performed in mice models confirmed the ability of L. salivarius FFIG58 to beneficially modulate the innate immune response and protect against ETEC infection. The results of this work contribute to the understanding of beneficial lactobacilli interactions with epithelial cells and allow us to hypothesize that the FFIG35 or FFIG58 strains could be used for the development of highly efficient functional feed to improve immune health status and reduce the severity of intestinal infections and superinfections in weaned piglets.


Assuntos
Infecções por Escherichia coli/veterinária , Lactobacillus salivarius/imunologia , Probióticos/administração & dosagem , Infecções por Rotavirus/veterinária , Superinfecção/veterinária , Suínos/imunologia , Ração Animal/microbiologia , Animais , Modelos Animais de Doenças , Escherichia coli Enterotoxigênica/imunologia , Escherichia coli Enterotoxigênica/patogenicidade , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/prevenção & controle , Feminino , Imunidade Inata , Mucosa Intestinal/microbiologia , Camundongos , Poli I-C/administração & dosagem , Poli I-C/imunologia , Rotavirus/imunologia , Rotavirus/patogenicidade , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/virologia , Superinfecção/imunologia , Superinfecção/microbiologia , Superinfecção/prevenção & controle , Suínos/microbiologia , Undaria/imunologia , Desmame
5.
PLoS Genet ; 17(5): e1009578, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34014925

RESUMO

The Receptor Transporter Protein (RTP) family is present in most, if not all jawed vertebrates. Most of our knowledge of this protein family comes from studies on mammalian RTPs, which are multi-function proteins that regulate cell-surface G-protein coupled receptor levels, influence olfactory system development, regulate immune signaling, and directly inhibit viral infection. However, mammals comprise less than one-tenth of extant vertebrate species, and our knowledge about the expression, function, and evolution of non-mammalian RTPs is limited. Here, we explore the evolutionary history of RTPs in vertebrates. We identify signatures of positive selection in many vertebrate RTP clades and characterize multiple, independent expansions of the RTP family outside of what has been described in mammals. We find a striking expansion of RTPs in the African clawed frog, Xenopus laevis, with 11 RTPs in this species as opposed to 1 to 4 in most other species. RNA sequencing revealed that most X. laevis RTPs are upregulated following immune stimulation. In functional assays, we demonstrate that at least three of these X. laevis RTPs inhibit infection by RNA viruses, suggesting that RTP homologs may serve as antiviral effectors outside of Mammalia.


Assuntos
Antivirais , Evolução Molecular , Genômica , Proteínas de Membrana Transportadoras/genética , Proteínas de Xenopus/genética , Xenopus laevis/genética , Animais , Antivirais/imunologia , Proteínas de Membrana Transportadoras/imunologia , Poli I-C/imunologia , Sintenia , Proteínas de Xenopus/imunologia , Xenopus laevis/imunologia , Xenopus laevis/metabolismo
6.
Nat Commun ; 12(1): 2626, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976179

RESUMO

By conferring systemic protection and durable benefits, cancer immunotherapies are emerging as long-term solutions for cancer treatment. One such approach that is currently undergoing clinical testing is a therapeutic anti-cancer vaccine that uses two different viruses expressing the same tumor antigen to prime and boost anti-tumor immunity. By providing the additional advantage of directly killing cancer cells, oncolytic viruses (OVs) constitute ideal platforms for such treatment strategy. However, given that the targeted tumor antigen is encoded into the viral genomes, its production requires robust infection and therefore, the vaccination efficiency partially depends on the unpredictable and highly variable intrinsic sensitivity of each tumor to OV infection. In this study, we demonstrate that anti-cancer vaccination using OVs (Adenovirus (Ad), Maraba virus (MRB), Vesicular stomatitis virus (VSV) and Vaccinia virus (VV)) co-administered with antigenic peptides is as efficient as antigen-engineered OVs and does not depend on viral replication. Our strategy is particularly attractive for personalized anti-cancer vaccines targeting patient-specific mutations. We suggest that the use of OVs as adjuvant platforms for therapeutic anti-cancer vaccination warrants testing for cancer treatment.


Assuntos
Antígenos de Neoplasias/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Neoplasias/imunologia , Vírus Oncolíticos/genética , Poli I-C/administração & dosagem , Poli I-C/imunologia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/genética , Vacinas de Subunidades/imunologia , Vírus Vaccinia , Vírus da Estomatite Vesicular Indiana , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Fish Shellfish Immunol ; 116: 74-83, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34033910

RESUMO

CD226 interacts with its ligand Necl5 as a costimulatory signal. In this study, we cloned a CD226 from Nile tilapia (Oreochromis niloticus, named OnCD226) and a Necl5 (named OnNecl5). The open reading frame of OnCD226 was 1071 bp, encoding a protein of 356 amino acids. Sequence alignment analysis indicated that OnCD226 contained two Ig-like domains in ectodomain. The open reading frame of OnNecl5 was 1155 bp, encoding a protein of 384 amino acids, and there are three lg-like domains in the extracellular domain. In healthy tilapia, OnCD226 was distributed in all tested tissues and relatively higher in the brain, while OnNecl5 was relatively higher in the skin. After Streptococcus agalactiae infection, OnCD226 has the same up-regulated expression pattern as OnNecl5 in different tissues. After HKLs stimulation with S. agalactiae and Poly I:C, respectively. OnCD226 was significantly up-regulated (0.01 < p < 0.05) at 12 h and extremely significant up-regulation was observed (p < 0.01) at 48 h and 96 h, the peak was observed at 96 h after stimulation by S. agalactiae. After stimulation by Poly I:C, OnCD226 expression was extremely significant (p < 0.01) at 72 h and 96 h, the peak was observed at 96 h. After stimulation by Keyhole limpet hemocyanin (KLH), a classical T cell-dependent antigen, the expression of OnCD226 was significantly up-regulated in blood, head kidney, spleen, and thymus. Moreover, when compared with the first challenge, the gene expression of OnCD226 which response to the second challenge was up-regulated earlier. Subcellular co-localization studies showed that OnCD226 and OnNecl5 were distributed mainly in the cytomembrane. Yeast two-hybrid results, indicated a strong interaction between OnCD226 and OnNecl5. These results suggested that OnCD226 plays an important role during pathogens infection, and the interaction between CD226 and Necl5 is conserved in Nile tilapia.


Assuntos
Antígenos de Diferenciação de Linfócitos T , Ciclídeos , Proteínas de Peixes , Receptores Virais , Animais , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/imunologia , Ciclídeos/genética , Ciclídeos/imunologia , Doenças dos Peixes/imunologia , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Células HEK293 , Rim Cefálico/imunologia , Hemocianinas/imunologia , Humanos , Leucócitos/imunologia , Filogenia , Poli I-C/imunologia , Conformação Proteica , Receptores Virais/genética , Receptores Virais/imunologia , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/veterinária , Streptococcus agalactiae/imunologia , Técnicas do Sistema de Duplo-Híbrido
8.
Front Immunol ; 12: 613145, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33833752

RESUMO

Fish interferon (IFN) is a crucial cytokine for a host to resist external pathogens, conferring cells with antiviral capacity. Meanwhile, grass carp reovirus (GCRV) is a strong pathogen that causes high mortality in grass carp. Therefore, it is necessary to study the strategy used by GCRV to evade the cellular IFN response. In this study, we found that GCRV 35-kDa protein (VP35) inhibited the host IFN production by degrading mitochondrial antiviral signaling (MAVS) protein through the autophagy pathway. First, the overexpression of VP35 inhibited the IFN activation induced by polyinosinic-polycytidylic acid (poly I:C) and MAVS, and the expression of downstream IFN-stimulated genes (ISGs) was also decreased by using VP35 under the stimulation. Second, VP35 interacted with MAVS; the experiments of truncated mutants of MAVS demonstrated that the caspase recruitment domain (CARD) and proline-rich (PRO) domains of MAVS were not necessary for this binding. Then, MAVS was degraded by using VP35 in a dose-dependent manner, and 3-MA (the autophagy pathway inhibitor) significantly blocked the degradation, meaning that MAVS was degraded by using VP35 in the autophagy pathway. The result of MAVS degradation suggested that the antiviral capacity of MAVS was remarkably depressed when interrupted by VP35. Finally, in the host cells, VP35 reduced ifn transcription and made the cells vulnerable to virus infection. In conclusion, our results reveal that GCRV VP35 impairs the host IFN response by degrading MAVS through the autophagy pathway, supplying evidence of a fish virus immune evasion strategy.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doenças dos Peixes/metabolismo , Doenças dos Peixes/virologia , Interações Hospedeiro-Patógeno , Infecções por Reoviridae/veterinária , Reoviridae/fisiologia , Proteínas do Envelope Viral/metabolismo , Animais , Linhagem Celular , Proteína DEAD-box 58/metabolismo , Resistência à Doença , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interferons/genética , Interferons/metabolismo , Poli I-C/imunologia , Transdução de Sinais
9.
Cancer Immunol Immunother ; 70(11): 3081-3091, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33751208

RESUMO

The nanoparticle complex of cholesteryl pullulan (CHP) and NY-ESO-1 antigen protein (CHP-NY-ESO-1) presents multiple epitope peptides to MHC class I and II pathways, leading to CD8+ and CD4+ T cell responses. Poly-ICLC is a synthetic, double-stranded RNA, an agonist of toll-like receptor (TLR)-3, and a cytoplasmic receptor of melanoma differentiation-associated gene (MDA)-5. It should be a suitable immune adjuvant of cancer vaccine to overcome the inhibitory tumor microenvironment. We conducted a phase 1 clinical trial of CHP-NY-ESO-1 with poly-ICLC in patients with advanced or recurrent esophageal cancer. CHP-NY-ESO-1/poly-ICLC (µg/mg) was administered at a dose of 200/0.5 or 200/1.0 (cohorts 1 and 2, respectively) every 2 weeks for a total of six doses. The primary endpoints were safety and immune response. The secondary endpoint was tumor response. In total, 16 patients were enrolled, and six patients in each cohort completed the trial. The most common adverse event (AE) was injection site skin reaction (86.7%). No grade 3 or higher drug-related AEs were observed. No tumor responses were observed, and three patients (30%) had stable disease. The immune response was comparable between the two cohorts, and all patients (100%) achieved antibody responses with a median of 2.5 vaccinations. Comparing CHP-NY-ESO-1 alone to the poly-ICLC combination, all patients in both groups exhibited antibody responses, but the titers were higher in the combination group. In a mouse model, adding anti-PD-1 antibody to the combination of CHP-NY-ESO-1/poly-ICLC suppressed the growth of NY-ESO-1-expressing tumors. Combining the vaccine with PD-1 blockade holds promise in human trials.


Assuntos
Antígenos de Neoplasias/uso terapêutico , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Carboximetilcelulose Sódica/análogos & derivados , Neoplasias Esofágicas/tratamento farmacológico , Glucanos/uso terapêutico , Proteínas de Membrana/uso terapêutico , Poli I-C/uso terapêutico , Polilisina/análogos & derivados , Adjuvantes Imunológicos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos de Neoplasias/imunologia , Carboximetilcelulose Sódica/uso terapêutico , Neoplasias Esofágicas/imunologia , Feminino , Glucanos/imunologia , Humanos , Indutores de Interferon/imunologia , Indutores de Interferon/uso terapêutico , Masculino , Proteínas de Membrana/imunologia , Camundongos , Pessoa de Meia-Idade , Nanopartículas , Poli I-C/imunologia , Polilisina/imunologia , Polilisina/uso terapêutico
10.
J Innate Immun ; 13(3): 179-193, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33626545

RESUMO

Expression of host noncoding RNAs and coding mRNAs is significantly altered by viral infection. In the current study, we screened the transcriptional profile of human lung epithelial A549 cells infected with Zika virus (ZIKV) by microarray assay. Seventy-nine long noncoding RNAs (lncRNAs) and 140 mRNAs were differentially expressed (DE). The bioinformatics analysis revealed that the mRNAs adjacent to the DE lncRNAs were closely related to the host responses to viral infection. We selected 7 lncRNAs from the top 50 hits for validation. The quantitative real-time PCR data confirmed that expression of selected lncRNAs was induced by ZIKV infection. Moreover, the expression of 7 lncRNAs was induced by infection of dengue virus, Japanese encephalitis virus, or vesicular stomatitis virus, or by treatment of poly(I:C) and IFN-ß. Furthermore, loss of innate immune adaptor IPS-1 or receptor IFNAR1 resulted in lower induction levels of several lncRNAs by ZIKV. Overexpression of 3 lncRNAs (RPL27-OT1, OASL-IT1, and REC8-OT3) reduced the virus yields of ZIKV. Knockout of OASL-IT1 significantly enhanced ZIKV replication. In OASL-IT1 knockout cells, the levels of interferons (IFNs) and the activation of 3 innate immune signaling pathways triggered by ZIKV were dramatically reduced. Collectively, our work found a positive feedback loop in the IFN system, in which IFNs and OASL-IT1 regulate each other, thereby promoting establishment of antiviral defense.


Assuntos
RNA Longo não Codificante/genética , Mucosa Respiratória/imunologia , Viroses/imunologia , Infecção por Zika virus/imunologia , Zika virus/fisiologia , Células A549 , Biologia Computacional , Retroalimentação Fisiológica , Técnicas de Silenciamento de Genes , Humanos , Imunidade Inata , Interferon beta/metabolismo , Poli I-C/imunologia , Transdução de Sinais/imunologia , Replicação Viral
11.
Sci Rep ; 11(1): 1105, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441832

RESUMO

The C1q protein, which contains the globular C1q (gC1q) domain, is involved in the innate immune response, and is found abundantly in the shell, and it participates in the shell formation. In this study, a novel gC1q domain-containing gene was identified from Pinctada fucata martensii (P. f. martensii) and designated as PmC1qDC-1. The full-length sequence of PmC1qDC-1 was 902 bp with a 534 bp open reading frame (ORF), encoding a polypeptide of 177 amino acids. Quantitative real-time PCR (qRT-PCR) result showed that PmC1qDC-1 was widely expressed in all tested tissues, including shell formation-associated tissue and immune-related tissue. PmC1qDC-1 expression was significantly high in the blastula and gastrula and especially among the juvenile stage, which is the most important stage of dissoconch shell formation. PmC1qDC-1 expression was located in the outer epithelial cells of mantle pallial and mantle edge and irregular crystal tablets were observed in the nacre upon knockdown of PmC1qDC-1 expression at mantle pallial. Moreover, the recombined protein PmC1qDC-1 increased the rate of calcium carbonate precipitation. Besides, PmC1qDC-1 expression was significantly up-regulated in the mantle pallial at 6 h and was significantly up-regulated in the mantle edge at 12 h and 24 h after shell notching. The expression level of PmC1qDC-1 in mantle edge was significantly up-regulated at 48 h after LPS stimulation and was significantly up-regulated at 12 h, 24 h and 48 h after poly I:C stimulation. Moreover, PmC1qDC-1 expression was significantly up-regulated in hemocytes at 6 h after lipopolysaccharide (LPS) and poly I:C challenge. These findings suggest that PmC1qDC-1 plays a crucial role both in the shell formation and the innate immune response in pearl oysters, providing new clues for understanding the shell formation and defense mechanism in mollusk.


Assuntos
Exoesqueleto/crescimento & desenvolvimento , Complemento C1q/metabolismo , Padrões Moleculares Associados a Patógenos/imunologia , Pinctada/imunologia , Pinctada/metabolismo , Proteínas/metabolismo , Exoesqueleto/metabolismo , Animais , Carbonato de Cálcio/metabolismo , Precipitação Química , Complemento C1q/química , Complemento C1q/genética , Hemócitos/imunologia , Hemócitos/metabolismo , Lipopolissacarídeos/imunologia , Nácar/metabolismo , Filogenia , Pinctada/genética , Pinctada/crescimento & desenvolvimento , Poli I-C/imunologia , Domínios Proteicos , Proteínas/química , Proteínas/genética , Transcriptoma , Regulação para Cima
12.
Sci Rep ; 11(1): 1220, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441615

RESUMO

Infants and young children are the groups at greatest risk for severe disease resulting from Plasmodium falciparum infection. We previously demonstrated in mice that a protein vaccine composed of the chemokine macrophage inflammatory protein 3α genetically fused to the minimally truncated circumsporozoite protein of P. falciparum (MCSP) elicits high concentrations of specific antibody and significant reduction of liver sporozoite load in a mouse model system. In the current study, a squalene based adjuvant (AddaVax, InvivoGen, San Diego, Ca) equivalent to the clinically approved MF59 (Seqiris, Maidenhead, UK) elicited greater antibody responses in mice than the previously employed adjuvant polyinosinic:polycytidylic acid, ((poly(I:C), InvivoGen, San Diego, Ca) and the clinically approved Aluminum hydroxide gel (Alum, Invivogen, San Diego, Ca) adjuvant. Use of the AddaVax adjuvant also expanded the range of IgG subtypes elicited by mouse vaccination. Sera passively transferred into mice from MCSP/AddaVax immunized 1 and 6 month old macaques significantly reduced liver sporozoite load upon sporozoite challenge. Protective antibody concentrations attained by passive transfer in the mice were equivalent to those observed in infant macaques 18 weeks after the final immunization. The efficacy of this vaccine in a relevant non-human primate model indicates its potential usefulness for the analogous high risk human population.


Assuntos
Anticorpos Antiprotozoários/imunologia , Formação de Anticorpos/imunologia , Quimiocinas/imunologia , Células Dendríticas/imunologia , Macaca/imunologia , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Esporozoítos/imunologia , Adjuvantes Imunológicos/farmacologia , Animais , Células Dendríticas/parasitologia , Modelos Animais de Doenças , Feminino , Imunização/métodos , Macaca/parasitologia , Malária Falciparum/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Plasmodium falciparum/imunologia , Poli I-C/imunologia , Proteínas de Protozoários/imunologia , Vacinação/métodos
13.
J Innate Immun ; 13(3): 164-178, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33445177

RESUMO

To study the molecular interplay between TLRs and complement representing ancient danger-sensing mechanisms, we examined the regulation of the C3a/anaphylatoxin C3a receptor (C3aR) axis in normal human epidermal keratinocytes (NHEKs) by treatment with different TLR ligands. Protein staining followed by flow cytometry revealed highly constitutive intracellular expression levels of the C3aR in NHEKs. Stimulation with Poly I:C up-regulated C3aR mRNA and intra- and extracellular expression in NHEKs which showed functional relevance by up-regulating CXCL10 and down-regulating C3 expression in response to C3a. mRNA and protein levels of C3 and protease cathepsin L (CTSL) that can cleave C3 were up-regulated by the TLR3 ligand Poly I:C. Enhanced intracellular expression levels of the biologically active C3 fragment (C3a), in response to TLR3 stimulation were also detectable in NHEKs. Cathelicidin antimicrobial peptide LL-37 potentiated Poly I:C-induced C3aR, C3, and CTSL up-regulation. In conclusion, we point to a role of TLR3 to promote up-regulation of C3aR, C3, and CTSL expression levels and generation of C3a. Our data provide evidence that local generation and activation of complement components as described for T cells or myeloid cells represent a scenario which may take place in a similar way in NHEKs.


Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Complemento C3a/metabolismo , Células Epidérmicas/imunologia , Queratinócitos/imunologia , Receptores de Complemento/metabolismo , Receptor 3 Toll-Like/metabolismo , Catepsina L/metabolismo , Células Cultivadas , Quimiocina CXCL10/metabolismo , Ativação do Complemento , Citometria de Fluxo , Regulação da Expressão Gênica , Humanos , Poli I-C/imunologia , Cultura Primária de Células
15.
J Immunol ; 206(1): 154-163, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33219146

RESUMO

Viral RNA in the cytoplasm of mammalian host cells is recognized by retinoic acid-inducible protein-I-like receptors (RLRs), which localize to cytoplasmic stress granules (SGs). Activated RLRs associate with the mitochondrial adaptor protein IPS-1, which activates antiviral host defense mechanisms, including type I IFN induction. It has remained unclear, however, how RLRs in SGs and IPS-1 in the mitochondrial outer membrane associate physically and engage in information transfer. In this study, we show that NUDT21, an RNA-binding protein that regulates alternative transcript polyadenylation, physically associates with IPS-1 and mediates its localization to SGs in response to transfection with polyinosinic-polycytidylic acid [poly(I:C)], a mimic of viral dsRNA. We found that despite its well-established function in the nucleus, a fraction of NUDT21 localizes to mitochondria in resting cells and becomes localized to SGs in response to poly(I:C) transfection. NUDT21 was also found to be required for efficient type I IFN induction in response to viral infection in both human HeLa cells and mouse macrophage cell line RAW264.7 cells. Our results together indicate that NUDT21 links RLRs in SGs to mitochondrial IPS-1 and thereby activates host defense responses to viral infection.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Infecções por Cardiovirus/metabolismo , Fator de Especificidade de Clivagem e Poliadenilação/metabolismo , Proteína DEAD-box 58/metabolismo , Vírus da Encefalomiocardite/fisiologia , Mitocôndrias/metabolismo , Doença de Newcastle/metabolismo , Vírus da Doença de Newcastle/fisiologia , Receptores Imunológicos/metabolismo , Vesículas Secretórias/metabolismo , Animais , Fator de Especificidade de Clivagem e Poliadenilação/genética , Regulação da Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Camundongos , Poli I-C/imunologia , Transporte Proteico , Células RAW 264.7 , RNA Interferente Pequeno/genética , RNA Viral/imunologia , Estresse Fisiológico
16.
Biochem Biophys Res Commun ; 534: 59-66, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310189

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopmental disorder caused by genetic and environmental factors. Among the environmental factors, maternal infection is known as one of the principal risk factors for ASD. On the other hand, postmortem studies suggested the relationship of oxidative stress with ASD etiology. However, the role of oxidative stress in the development of ASD remains unclear. Here, we report the involvement of NOX1/NADPH oxidase, an enzyme generating reactive oxygen species (ROS), in behavioral and anatomical abnormalities in a maternal immune activation (MIA) model. In the MIA model of gestational polyinosinic-polycytidylic acid (poly(I:C)) exposure, increased serum levels of IL-6 were observed in both wild-type (WT) and Nox1-deficient mice (Nox1KO). Following the comparable induction of MIA in the two genotypes, impairment of social preference and defects in motor coordination were observed in WT offspring but not in offspring deficient in Nox1. MIA up-regulated NOX1 mRNA in the cerebral cortex and cerebellum of the fetus but not in the adult offspring. Although the development of cortical neurons was unaffected by MIA in either genotype, the dropout of Purkinje cells in lobule VII of MIA-affected offspring was significantly ameliorated in Nox1KO. Taken together, these results suggested that NOX1/NADPH oxidase plays an essential role in some behavioral phenotypes observed in ASD, possibly by promoting the loss of Purkinje cells in the cerebellum.


Assuntos
Transtorno do Espectro Autista/etiologia , Comportamento Animal/fisiologia , NADPH Oxidase 1/genética , Células de Purkinje/patologia , Animais , Transtorno do Espectro Autista/imunologia , Cerebelo/embriologia , Córtex Cerebral/embriologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 1/metabolismo , Poli I-C/imunologia , Poli I-C/farmacologia , Gravidez
17.
BMC Vet Res ; 16(1): 450, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33213475

RESUMO

BACKGROUND: Interferon (IFN) regulatory factors (IRFs), as transcriptional regulatory factors, play important roles in regulating the expression of type I IFN and IFN- stimulated genes (ISGs) in innate immune responses. In addition, they participate in cell growth and development and regulate oncogenesis. RESULTS: In the present study, the cDNA sequence of IRF10 in common carp (Cyprinus carpio L.) was characterized (abbreviation, CcIRF10). The predicted protein sequence of CcIRF10 shared 52.7-89.2% identity with other teleost IRF10s and contained a DNA-binding domain (DBD), a nuclear localization signal (NLS) and an IRF-associated domain (IAD). Phylogenetic analysis showed that CcIRF10 had the closest relationship with IRF10 of Ctenopharyngodon idella. CcIRF10 transcripts were detectable in all examined tissues, with the highest expression in the gonad and the lowest expression in the head kidney. CcIRF10 expression was upregulated in the spleen, head kidney, foregut and hindgut upon polyinosinic:polycytidylic acid (poly I:C) and Aeromonas hydrophila stimulation and induced by poly I:C, lipopolysaccharide (LPS) and peptidoglycan (PGN) in peripheral blood leucocytes (PBLs) and head kidney leukocytes (HKLs) of C. carpio. In addition, overexpression of CcIRF10 was able to decrease the expression of the IFN and IFN-stimulated genes PKR and ISG15. CONCLUSIONS: These results indicate that CcIRF10 participates in antiviral and antibacterial immunity and negatively regulates the IFN response, which provides new insights into the IFN system of C. carpio.


Assuntos
Carpas/genética , Carpas/imunologia , Fatores Reguladores de Interferon/genética , Aeromonas hydrophila/imunologia , Animais , Carpas/metabolismo , DNA Complementar , Proteínas de Peixes , Lipopolissacarídeos/imunologia , Peptidoglicano/imunologia , Filogenia , Poli I-C/imunologia , Análise de Sequência de DNA , Distribuição Tecidual
18.
Proc Natl Acad Sci U S A ; 117(44): 27502-27508, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33087577

RESUMO

Cyclic dinucleotides (CDNs) are secondary messengers used by prokaryotic and eukaryotic cells. In mammalian cells, cytosolic CDNs bind STING (stimulator of IFN gene), resulting in the production of type I IFN. Extracellular CDNs can enter the cytosol through several pathways but how CDNs work from outside eukaryotic cells remains poorly understood. Here, we elucidate a mechanism of action on intestinal epithelial cells for extracellular CDNs. We found that CDNs containing adenosine induced a robust CFTR-mediated chloride secretory response together with cAMP-mediated inhibition of Poly I:C-stimulated IFNß expression. Signal transduction was strictly polarized to the serosal side of the epithelium, dependent on the extracellular and sequential hydrolysis of CDNs to adenosine by the ectonucleosidases ENPP1 and CD73, and occurred via activation of A2B adenosine receptors. These studies highlight a pathway by which microbial and host produced extracellular CDNs can regulate the innate immune response of barrier epithelial cells lining mucosal surfaces.


Assuntos
Adenosina/metabolismo , Células Epiteliais/metabolismo , Imunidade Inata , Imunidade nas Mucosas , Nucleotídeos Cíclicos/metabolismo , 5'-Nucleotidase/metabolismo , Linhagem Celular Tumoral , Cloretos/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Células Epiteliais/imunologia , Proteínas Ligadas por GPI/metabolismo , Humanos , Interferon beta/metabolismo , Mucosa Intestinal/citologia , Diester Fosfórico Hidrolases/metabolismo , Poli I-C/imunologia , Pirofosfatases/metabolismo , Receptor A2B de Adenosina/metabolismo , Transdução de Sinais/imunologia
19.
Nat Commun ; 11(1): 5236, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33067431

RESUMO

The etiology of major neurodevelopmental disorders such as schizophrenia and autism is unclear, with evidence supporting a combination of genetic factors and environmental insults, including viral infection during pregnancy. Here we utilized a mouse model of maternal immune activation (MIA) with the viral mimic PolyI:C infection during early gestation. We investigated the transcriptional changes in the brains of mouse fetuses following MIA during the prenatal period, and evaluated the behavioral and biochemical changes in the adult brain. The results reveal an increase in RNA editing levels and dysregulation in brain development-related gene pathways in the fetal brains of MIA mice. These MIA-induced brain editing changes are not observed in adulthood, although MIA-induced behavioral deficits are observed. Taken together, our findings suggest that MIA induces transient dysregulation of RNA editing at a critical time in brain development.


Assuntos
Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/genética , Complicações na Gravidez/imunologia , Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/genética , Edição de RNA , Animais , Comportamento Animal , Encéfalo/crescimento & desenvolvimento , Encéfalo/imunologia , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Imunidade Materno-Adquirida , Camundongos , Camundongos Endogâmicos C57BL , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/psicologia , Poli I-C/efeitos adversos , Poli I-C/imunologia , Complicações na Gravidez/etiologia , Complicações na Gravidez/genética , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/psicologia
20.
Semin Immunol ; 49: 101414, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-33011064

RESUMO

Immunotherapies have become the first line of treatment for many cancer types. Unfortunately, only a small fraction of patients benefits from these therapies. This low rate of success can be attributed to 3 main barriers: 1) low frequency of anti-tumor specific T cells; 2) lack of infiltration of the anti-tumor specific T cells into the tumor parenchyma and 3) accumulation of highly suppressive cells in the tumor mass that inhibit the effector function of the anti-tumor specific T cells. Thus, the identification of immunomodulators that can increase the frequency and/or the infiltration of antitumor specific T cells while reducing the suppressive capacity of the tumor microenvironment is necessary to ensure the effectiveness of T cell immunotherapies. In this review, we discuss the potential of poly-ICLC as a multi-functional immune modulator for treating cancer and its impact on the 3 above mentioned barriers. We describe the unique capacity of poly-ICLC in stimulating 2 separate pattern recognition receptors, TLR3 and cytosolic MDA5 and the consequences of these activations on cytokines and chemokines production. We emphasize the role of poly-ICLC as an adjuvant in the setting of peptide-based cancer vaccines and in situ tumor vaccination by mimicking natural immune responses to infections. Finally, we summarize the impact of poly-ICLC in enhancing T infiltration into the tumor parenchyma and address the implication of this finding in the clinic.


Assuntos
Antineoplásicos/farmacologia , Carboximetilcelulose Sódica/análogos & derivados , Fatores Imunológicos/farmacologia , Imunomodulação , Poli I-C/imunologia , Poli I-C/farmacologia , Polilisina/análogos & derivados , Animais , Antineoplásicos/uso terapêutico , Carboximetilcelulose Sódica/farmacologia , Carboximetilcelulose Sódica/uso terapêutico , Citocinas/metabolismo , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Imunomodulação/efeitos dos fármacos , Helicase IFIH1 Induzida por Interferon/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Poli I-C/uso terapêutico , Polilisina/imunologia , Polilisina/farmacologia , Polilisina/uso terapêutico , Receptores de Reconhecimento de Padrão/metabolismo , Receptor 3 Toll-Like/metabolismo
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