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1.
PLoS Pathog ; 16(1): e1008288, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961911

RESUMO

Insects rely on the innate immune system for defense against pathogens, some aspects of which are under hormonal control. Here we provide direct experimental evidence showing that the juvenile hormone-binding protein (mJHBP) of Aedes aegypti is required for the regulation of innate immune responses and the development of mosquito blood cells (hemocytes). Using an mJHBP-deficient mosquito line generated by means of CRISPR-Cas9 gene editing technology we uncovered a mutant phenotype characterized by immunosuppression at the humoral and cellular levels, which profoundly affected susceptibility to bacterial infection. Bacteria-challenged mosquitoes exhibited significantly higher levels of septicemia and mortality relative to the wild type (WT) strain, delayed expression of antimicrobial peptides (AMPs), severe developmental dysregulation of embryonic and larval hemocytes (reduction in the total number of hemocytes) and increased differentiation of the granulocyte lineage. Interestingly, injection of recombinant wild type mJHBP protein into adult females three-days before infection was sufficient to restore normal immune function. Similarly, injection of mJHBP into fourth-instar larvae fully restored normal larval/pupal hemocyte populations in emerging adults. More importantly, the recovery of normal immuno-activation and hemocyte development requires the capability of mJHBP to bind JH III. These results strongly suggest that JH III functions in mosquito immunity and hemocyte development in a manner that is perhaps independent of canonical JH signaling, given the lack of developmental and reproductive abnormalities. Because of the prominent role of hemocytes as regulators of mosquito immunity, this novel discovery may have broader implications for the understanding of vector endocrinology, hemocyte development, vector competence and disease transmission.


Assuntos
Aedes/crescimento & desenvolvimento , Aedes/imunologia , Proteínas de Transporte/imunologia , Proteínas de Insetos/imunologia , Aedes/genética , Aedes/microbiologia , Animais , Proteínas de Transporte/genética , Feminino , Hemócitos/imunologia , Hemócitos/microbiologia , Imunidade Inata , Proteínas de Insetos/genética , Hormônios Juvenis/imunologia , Larva/genética , Larva/crescimento & desenvolvimento , Larva/imunologia , Larva/microbiologia , Masculino , Serratia marcescens/fisiologia
2.
Int J Cancer ; 146(5): 1396-1408, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31525266

RESUMO

Chitinase-like proteins (CLP) are chitin-binding proteins that lack chitin hydrolyzing activity, but possess cytokine-like and growth factor-like properties, and play crucial role in intercellular crosstalk. Both human and mice express two members of CLP family: YKL-40 and stabilin-1 interacting chitinase-like protein (SI-CLP). Despite numerous reports indicating the role of YKL-40 in the support of angiogenesis, tumor cell proliferation, invasion and metastasis, the role of its structurally related protein SI-CLP in cancer was not reported. Using gain-of-function approach, we demonstrate in the current study that the expression of recombinant SI-CLP in mouse TS/A mammary adenocarcinoma cells results in significant and persistent inhibition of in vivo tumor growth. Using quantitative immunohistochemistry, we show that on the cellular level this phenomenon is associated with reduced infiltration of tumor-associated macrophages (TAMs), CD4+ and FoxP3+ cells in SI-CLP expressing tumors. Gene expression analysis in TAM isolated from SI-CLP-expressing and control tumors demonstrated that SI-CLP does not affect macrophage phenotype. However, SI-CLP significantly inhibited migration of murine bone-marrow derived macrophages and human primary monocytes toward monocyte-recruiting chemokine CCL2 produced in the tumor microenvironment (TME). Mechanistically, SI-CLP did not affect CCL2/CCR2 interaction, but suppressed cytoskeletal rearrangements in response to CCL2. Altogether, our data indicate that SI-CLP functions as a tumor growth inhibitor in mouse breast cancer by altering cellular composition of TME and blocking cytokine-induced TAM recruitment. Taking into consideration weak to absent expression of SI-CLP in human breast cancer, it can be considered as a therapeutic protein to block TAM-mediated support of breast tumor growth.


Assuntos
Proteínas de Ligação ao Cálcio/imunologia , Proteínas de Transporte/imunologia , Macrófagos/imunologia , Neoplasias Mamárias Experimentais/imunologia , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Processos de Crescimento Celular/imunologia , Movimento Celular/imunologia , Feminino , Células HEK293 , Humanos , Ativação de Macrófagos , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade
3.
Fish Shellfish Immunol ; 94: 81-89, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31476389

RESUMO

Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1), one of the interferon stimulated genes (ISGs), is strongly induced by type I interferon (IFN), double-stranded RNAs and virus infection. To investigate the actions of fish IFIT1 in response to virus infection, we cloned an IFIT1 homolog from orange spotted grouper (EcIFIT1) and clarified its function in this study. The full-length cDNA of EcIFIT1 is 1839 bp, which is composed of 436 amino acid (aa) residues, with 77.8% and 22.8% identity to IFIT1 homolog of yellow perch (Perca flavescens) and humans (homo sapiens), respectively. Sequence alignment analysis showed that EcIFIT1 contained three tetratricopeptide repeats (TPRs). Tissue distribution analysis indicated that EcIFIT1 was abundant in intestine, spleen, liver, and heart. Moreover, EcIFIT1 was significantly up-regulated by Singapore grouper iridovirus (SGIV) or red-spotted grouper nervous necrosis virus (RGNNV) infection, and polyinosinic-polycytidylic acid (poly I:C) or lipopolysaccharide (LPS) treatment in vitro. Under fluorescence microscopy, EcIFIT1 was found to localize throughout the cytoplasm in transfected cells. EcIFIT1 overexpression significantly suppressed the replication of SGIV and RGNNV, demonstrated by decreasing the cytopathic effect (CPE) severity, viral gene transcription and the virus titers. Further studies showed that the ectopic expression of EcIFIT1 increased the transcription level of IFN related molecules, including IFN regulatory factor (IRF) 3, IRF7, IFN stimulated gene (ISG) 15 and myxovirus resistance gene (MX) I. Meanwhile, the expression levels of pro-inflammation cytokines were differently regulated by the ectopic expression of EcIFIT1. In addition, flow cytometry analysis suggested that EcIFIT1 overexpression affected cell cycle progression by mediating S/G2 transition. Taken together, our results indicated that EcIFIT1 might exert antiviral function against fish virus by up-regulating interferon response or affecting cell cycle.


Assuntos
Bass/genética , Bass/imunologia , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Doenças dos Peixes/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Sequência de Aminoácidos , Animais , Proteínas de Transporte/química , Infecções por Vírus de DNA/imunologia , Infecções por Vírus de DNA/veterinária , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , Lipopolissacarídeos/farmacologia , Nodaviridae/fisiologia , Filogenia , Poli I-C/farmacologia , Infecções por Vírus de RNA/imunologia , Infecções por Vírus de RNA/veterinária , Ranavirus/fisiologia , Alinhamento de Sequência/veterinária
4.
Fish Shellfish Immunol ; 93: 815-822, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31419535

RESUMO

In symbiotic systems in which symbionts are transmitted horizontally, hosts must accept symbionts from the environment while defending themselves against invading pathogenic microorganisms. How they distinguish pathogens from symbionts and how the latter evade host immune defences are not clearly understood. Recognition of foreign materials is one of the most critical steps in stimulating immune responses, and pattern recognition receptors (PRRs) play vital roles in this process. In this study, we focused on a group of highly conserved PRRs, peptidoglycan recognition proteins (PGRPs), in the deep-sea mussel, Bathymodiolus septemdierum, which harbours chemosynthetic bacteria in their gill epithelial cells. We isolated B. septemdierum PGRP genes BsPGRP-S and BsPGRP-L, which encode a short- and a long-type PGRP, respectively. The short-type PGRP has a signal peptide and was expressed in the asymbiotic goblet mucous cells in the gill epithelium, whereas the long-type PGRP was predicted to include a transmembrane domain and was expressed in gill bacteriocytes. Based on these findings, we hypothesize that the secreted and transmembrane PGRPs are engaged in host defence against pathogenic bacteria and/or in the regulation of symbiosis via different cellular localizations and mechanisms.


Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Imunidade Inata/genética , Mytilidae/genética , Mytilidae/imunologia , Sequência de Aminoácidos , Animais , Proteínas de Transporte/química , Perfilação da Expressão Gênica , Brânquias/imunologia , Filogenia , Alinhamento de Sequência
5.
Cell Host Microbe ; 26(2): 193-201, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31415752

RESUMO

Plant innate immunity is triggered via direct or indirect recognition of pathogen effectors by the NLR family immune receptors. Mechanistic understanding of plant NLR function has relied on structural information from individual NLR domains and inferences from studies on animal NLRs. Recent reports of the cryo-EM structures of the Arabidopsis plant immune receptor ZAR1 in monomeric inactive and transition states, as well as the active oligomeric state or the "resistosome," have afforded a quantum leap in our understanding of how plant NLRs function. In this Review, we outline the recent structural findings and examine their implications for the activation of plant immune receptors more broadly. We also discuss how NLR signaling in plants, as illustrated by the ZAR1 structure, is analogous to innate immune receptor signaling mechanisms across kingdoms, drawing particular attention to the concept of signaling by cooperative assembly formation.


Assuntos
Proteínas de Arabidopsis , Proteínas de Transporte , Imunidade Vegetal/imunologia , Receptores Imunológicos , Transdução de Sinais , Difosfato de Adenosina , Trifosfato de Adenosina/metabolismo , Arabidopsis/imunologia , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/imunologia , Proteínas de Arabidopsis/metabolismo , Proteínas de Transporte/química , Proteínas de Transporte/imunologia , Proteínas de Transporte/metabolismo , Imunidade Inata , Proteínas NLR/química , Proteínas NLR/metabolismo , Imunidade Vegetal/fisiologia , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Domínios Proteicos , Receptores Imunológicos/química , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo
6.
PLoS One ; 14(7): e0219817, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31335868

RESUMO

The success of staphylococci as pathogens has been attributed, in part, to their ability to evade their hosts' immune systems. Although the proteins involved in evasion have been extensively studied in staphylococci affecting humans little characterization has been done with Staphylococcus pseudintermedius, an important cause of pyoderma in dogs. Staphylococcus aureus binder of immunoglobulin (Sbi) interferes with innate immune recognition by interacting with multiple host proteins. In this study, a S. pseudintermedius gene that shares 38% similarity to S. aureus Sbi was cloned from S. pseudintermedius strains representative of major clonal lineages bearing two paralogs of the protein. Binding of immunoglobulins and Fab and Fc fragments as well as interaction with complement was measured. S. pseudintermedius Sbi protein bound IgG from multiple species and canine complement C3, neutralized complement activity and bound to canine IgM and B cells. Evidence from this work suggests Sbi may play an important role in S. pseudintermedius immune evasion.


Assuntos
Proteínas de Bactérias/genética , Proteínas de Transporte/genética , Proteínas do Sistema Complemento/imunologia , Fragmentos Fab das Imunoglobulinas/imunologia , Fragmentos Fc das Imunoglobulinas/imunologia , Imunoglobulina M/imunologia , Staphylococcus/imunologia , Animais , Proteínas de Bactérias/imunologia , Proteínas de Transporte/imunologia , Cães , Homologia de Sequência de Aminoácidos , Staphylococcus/genética
7.
PLoS Negl Trop Dis ; 13(7): e0007511, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31269021

RESUMO

The prevalence of rheumatic heart disease (RHD) in the Aboriginal population of the Australian Northern Territory is high, and Streptococcus pyogenes skin infections likely contribute to this. A promising candidate S. pyogenes "30mer" vaccine is composed of 30 pharyngitis associated type-specific antigens from the S. pyogenes M protein. Cross opsonisation experiments suggest that 30mer vaccine protection may extend to non-cognate emm types. A new "emm cluster" scheme for classifying M protein is based on the full-length coding sequence, and correlates with functional and immunological properties, and anatomical tropism. Twenty-seven years of research in the Northern Territory has yielded 1810 S. pyogenes isolates with clinical and emm type data. The primary aim was to analyse these data with reference to the emm cluster scheme and cross opsonisation information, to inform estimation of 30mer vaccine efficacy in the Northern Territory. The isolates encompass 101 emm types. Variants of cluster A-C were enriched in throat isolates, and variants of emm cluster D enriched in skin isolates. Throat isolates were enriched for 30mer vaccine cognate emm types in comparison with skin isolates of which only 25% were vaccine emm types. While cross opsonisation data indicates potential for enhancing 30mer vaccine coverage, more than one third of skin isolates were within 38 emm types untested for cross opsonisation. Emm cluster D variants, in particular emm cluster D4, were not only all non-cognate with the vaccine, but were abundant and diverse, and less likely to be cross-opsonisation positive than other emm clusters. Long term persistence of many emm types in the study area was revealed. It was concluded that the 30mer vaccine efficacy in the Northern Territory will likely require both cross protection, and additional measures to elicit immunity against variants of emm cluster D.


Assuntos
Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas de Transporte/imunologia , Cardiopatia Reumática/microbiologia , Infecções Estreptocócicas/prevenção & controle , Vacinas Estreptocócicas/uso terapêutico , Streptococcus pyogenes , Humanos , Northern Territory/epidemiologia , Faringite/epidemiologia , Faringite/microbiologia , Prevalência , Cardiopatia Reumática/epidemiologia , Cardiopatia Reumática/prevenção & controle , Pele/microbiologia , Infecções Estreptocócicas/complicações , Infecções Estreptocócicas/epidemiologia , Vacinas Estreptocócicas/imunologia
8.
PLoS Pathog ; 15(7): e1007900, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31269090

RESUMO

The Pseudomonas syringae acetyltransferase HopZ1a is delivered into host cells by the type III secretion system to promote bacterial growth. However, in the model plant host Arabidopsis thaliana, HopZ1a activity results in an effector-triggered immune response (ETI) that limits bacterial proliferation. HopZ1a-triggered immunity requires the nucleotide-binding, leucine-rich repeat domain (NLR) protein, ZAR1, and the pseudokinase, ZED1. Here we demonstrate that HopZ1a can acetylate members of a family of 'receptor-like cytoplasmic kinases' (RLCK family VII; also known as PBS1-like kinases, or PBLs) and promote their interaction with ZED1 and ZAR1 to form a ZAR1-ZED1-PBL ternary complex. Interactions between ZED1 and PBL kinases are determined by the pseudokinase features of ZED1, and mutants designed to restore ZED1 kinase motifs can (1) bind to PBLs, (2) recruit ZAR1, and (3) trigger ZAR1-dependent immunity in planta, all independently of HopZ1a. A ZED1 mutant that mimics acetylation by HopZ1a also triggers immunity in planta, providing evidence that effector-induced perturbations of ZED1 also activate ZAR1. Overall, our results suggest that interactions between these two RLCK families are promoted by perturbations of structural features that distinguish active from inactive kinase domain conformations. We propose that effector-induced interactions between ZED1/ZRK pseudokinases (RLCK family XII) and PBL kinases (RLCK family VII) provide a sensitive mechanism for detecting perturbations of either kinase family to activate ZAR1-mediated ETI.


Assuntos
Proteínas de Arabidopsis/imunologia , Proteínas de Arabidopsis/metabolismo , Arabidopsis/imunologia , Arabidopsis/metabolismo , Fosfotransferases/imunologia , Fosfotransferases/metabolismo , Imunidade Vegetal , Acetilação , Arabidopsis/genética , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Proteínas de Transporte/química , Proteínas de Transporte/imunologia , Proteínas de Transporte/metabolismo , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Modelos Imunológicos , Mutação , Fosfotransferases/genética , Domínios e Motivos de Interação entre Proteínas , Proteínas Quinases/química , Proteínas Quinases/metabolismo , Pseudomonas syringae/imunologia , Pseudomonas syringae/metabolismo , Pseudomonas syringae/patogenicidade
9.
N Engl J Med ; 381(1): 47-54, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31269365

RESUMO

A 37-year-old man with a history of seminoma presented with vertigo, ataxia, and diplopia. An autoantibody specific for kelch-like protein 11 (KLHL11) was identified with the use of programmable phage display. Immunoassays were used to identify KLHL11 IgG in 12 other men with similar neurologic features and testicular disease. Immunostaining of the patient's IgG on mouse brain tissue showed sparse but distinctive points of staining in multiple brain regions, with enrichment in perivascular and perimeningeal tissues. The onset of the neurologic syndrome preceded the diagnosis of seminoma in 9 of the 13 patients. An age-adjusted estimate of the prevalence of autoimmune KLHL11 encephalitis in Olmsted County, Minnesota, was 2.79 cases per 100,000 men. (Funded by the Rochester Epidemiology Project and others.).


Assuntos
Autoanticorpos/análise , Encéfalo/imunologia , Proteínas de Transporte/imunologia , Técnicas de Visualização da Superfície Celular , Encefalite/imunologia , Doença de Hashimoto/imunologia , Síndromes Paraneoplásicas do Sistema Nervoso/imunologia , Seminoma/complicações , Neoplasias Testiculares/complicações , Adulto , Idoso , Encefalite/epidemiologia , Doença de Hashimoto/epidemiologia , Humanos , Imunoensaio , Masculino , Pessoa de Meia-Idade , Minnesota/epidemiologia , Prevalência
11.
Int Immunopharmacol ; 75: 105774, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31351363

RESUMO

BACKGROUND: The purpose of the present study was to evaluate the protective effect of Magnesium Isoglycyrrhizinate (MI) on Epirubicin (EPI)-induced hepatic encephalopathy (HE) and explore its underlying mechanism. METHODS: Mice were divided randomly into groups for treatments as follows: control group, EPI group (Model group), EPI + MI (25, 50 mg/kg) group. Morris water maze test were conducted to evaluate the spatial learning and memory ability. The serum and hippocampus levels of oxidative stress or inflammation were uncovered with the detection of superoxide dismutase (SOD), malondialdehyde (MDA), and pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α). RESULTS: As a result, treatment with MI effectively ameliorated the EPI-induced decline in the ability of spatial learning and memory. MI also significantly relieved the severity of oxidative stress or inflammation in serum and hippocampus, which was accompanied with regulating liver functional parameters. Western blot data demonstrated that administration of MI could regulate the redox-related expressions of Txnip, Trx, Nrf2, HO-1, p-IκB-α, p-NF-κB, Caspase-3, Caspase-9, Bax and Bcl-2 in EPI-stimulated hepatic encephalopathy (HE). And the potency of MI treatments on Nrf2, NF-κB expression was also confirmed with immunohistochemical analysis. CONCLUSIONS: Taken together, the protective effect of Magnesium Isoglycyrrhizinate on EPI-induced hepatic encephalopathy might be mediated via the Txnip/Nrf2/NF-κB signaling pathway.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Epirubicina/efeitos adversos , Encefalopatia Hepática/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Saponinas/uso terapêutico , Triterpenos/uso terapêutico , Animais , Proteínas de Transporte/imunologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/imunologia , Citocinas/sangue , Citocinas/imunologia , Encefalopatia Hepática/induzido quimicamente , Encefalopatia Hepática/imunologia , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Masculino , Malondialdeído/sangue , Malondialdeído/imunologia , Memória/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/imunologia , Fármacos Neuroprotetores/farmacologia , Saponinas/farmacologia , Aprendizagem Espacial/efeitos dos fármacos , Superóxido Dismutase/sangue , Superóxido Dismutase/imunologia , Tiorredoxinas/imunologia , Triterpenos/farmacologia
12.
Fish Shellfish Immunol ; 93: 216-222, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31336155

RESUMO

gC1qR is a multifunctional and multiligand binding protein that plays important roles in inflammation and infection. In this study, a novel gC1qR homolog called AjgC1qR from the invertebrate sea cucumber Apostichopus japonicus was cloned and characterized. The open reading frame of AjgC1qR encoded 292 amino acid residues with a conserved mitochondrial targeting sequence and MAM33 domain. Multiple sequence alignment and phylogenetic analyses proved that AjgC1qR is a homolog of the gC1qR family. Spatial mRNA transcription in five tissues revealed the ubiquitous expression of AjgC1qR. The highest and lowest levels of expression were found in the tentacle and muscle, respectively, and AjgC1qR expression was remarkably up-regulated in coelomocytes after Vibrio splendidus challenge. Moreover, the recombinant rAjgC1qR protein exhibited high binding activity toward pathogen-associated molecules, such as lipopolysaccharides, peptidoglycan, and mannan. These findings demonstrate that AjgC1qR may play important roles in innate immunity and function as a pathogen recognition receptor.


Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Stichopus/genética , Stichopus/imunologia , Sequência de Aminoácidos , Animais , Proteínas de Transporte/química , Perfilação da Expressão Gênica , Lipopolissacarídeos/farmacologia , Mananas/farmacologia , Peptidoglicano/farmacologia , Filogenia , Alinhamento de Sequência , Vibrio/fisiologia
13.
PLoS Pathog ; 15(6): e1007817, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31163079

RESUMO

Schistosome infection persists for decades. Parasites are in close contact with host peripheral blood immune cells, yet little is known about the regulatory interactions between parasites and these immune cells. Here, we report that extracellular vesicles (EVs) released from Schistosoma japonicum are taken up primarily by macrophages and other host peripheral blood immune cells and their miRNA cargo transferred into recipient cells. Uptake of S. japonicum EV miR-125b and bantam miRNAs into host cells increased macrophage proliferation and TNF-α production by regulating the corresponding targets including Pros1, Fam212b, and Clmp. Mice infected with S. japonicum exhibit an increased population of monocytes and elevated levels of TNF-α. Reduction of host monocytes and TNF-α level in S. japonicum infected mice led to a significant reduction in worm and egg burden and pathology. Overall, we demonstrate that S. japonicum EV miRNAs can regulate host macrophages illustrating parasite modulation of the host immune response to facilitate parasite survival. Our findings provide valuable insights into the schistosome-host interaction which may help to develop novel intervention strategies against schistosomiasis.


Assuntos
Vesículas Extracelulares/imunologia , Macrófagos/imunologia , MicroRNAs/imunologia , RNA de Helmintos/imunologia , Schistosoma japonicum/imunologia , Animais , Proteínas de Transporte/imunologia , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/imunologia , Macrófagos/parasitologia , Camundongos , Monócitos/imunologia , Monócitos/parasitologia , Células RAW 264.7 , Coelhos , Fator de Necrose Tumoral alfa/imunologia
14.
Mol Biol Rep ; 46(4): 3991-3999, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31168669

RESUMO

Mesenchymal stem cells (MSCs) are self-renewing multipotent cells with immunoregulatory function, which makes them attractive candidates for regenerative medicine. However, the detailed mechanisms of their immunomodulatory capacity are not fully characterized. Here, we found that casein kinase 2 interacting protein-1 (CKIP-1) expression was induced in the murine MSC cell line C3H/10T1/2 by LPS. Knockdown of CKIP-1 did not cause significant differences on the cell cycle or immunophenotype of MSCs. However, MSCs with CKIP-1 knockdown showed enhanced immunosuppressive capacity. Real-time PCR and western blot analyses revealed that compared with the control group, MSCs with CKIP-1-knockdown exhibited higher IL-10 production and p38 MAPK phosphorylation following LPS treatment. Interestingly, the expression of CKIP-1 was decreased in MSCs following high glucose treatment. Furthermore, MSCs became more immunosuppressive after high glucose treatment, as shown by higher IL-10 production and enhanced inhibition of T cell proliferation. Collectively, our data reveal a novel role for CKIP-1 in regulating MSC-mediated immunomodulation, and indicate that MSCs become more immunosuppressive under high glucose conditions. These new insights may help in the development of future applications of MSCs.


Assuntos
Proteínas de Transporte/imunologia , Fatores Imunológicos/metabolismo , Células-Tronco Mesenquimais/imunologia , Animais , Proteínas de Transporte/metabolismo , Diferenciação Celular/imunologia , Linhagem Celular , Proliferação de Células/fisiologia , Citocinas/imunologia , Glucose/imunologia , Glucose/metabolismo , Imunomodulação/imunologia , Imunofenotipagem/métodos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
15.
mBio ; 10(3)2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31213564

RESUMO

MenB-4C (Bexsero; GlaxoSmithKline Biologicals) is a licensed meningococcal vaccine for capsular B strains. The vaccine contains detergent-extracted outer membrane vesicles (dOMV) and three recombinant proteins, of which one is factor H binding protein (FHbp). In previous studies, overexpression of FHbp in native OMV (NOMV) with genetically attenuated endotoxin (LpxL1) and/or by the use of mutant FHbp antigens with low factor H (FH) binding increased serum bactericidal antibody (SBA) responses. In this study, we immunized 13 infant macaques with 2 doses of NOMV with overexpressed mutant (R41S) FHbp with low binding to macaque FH (NOMV-FHbp). Control macaques received MenB-4C (n = 13) or aluminum hydroxide adjuvant alone (n = 4). NOMV-FHbp elicited a 2-fold higher IgG anti-FHbp geometric mean titer (GMT) than MenB-4C (P = 0.003), and the anti-FHbp repertoire inhibited binding of FH to FHbp, whereas anti-FHbp antibodies to MenB-4C enhanced FH binding. MenB-4C elicited a 10-fold higher GMT against strain NZ98/254, which was used to prepare the dOMV component, whereas NOMV-FHbp elicited an 8-fold higher GMT against strain H44/76, which was the parent of the mutant NOMV-FHbp vaccine strain. Against four strains with PorA mismatched to both of the vaccines and different FHbp sequence variants, NOMV-FHbp elicited 6- to 14-fold higher SBA GMTs than MenB-4C (P ≤ 0.0002). Two of 13 macaques immunized with MenB-4C but 0 of 17 macaques immunized with NOMV-FHbp or adjuvant developed serum anti-FH autoantibodies (P = 0.18). Thus, the mutant NOMV-FHbp approach has the potential to elicit higher and broader SBA responses than a licensed group B vaccine that contains wild-type FHbp that binds FH. The mutant NOMV-FHbp also might pose less of a risk of eliciting anti-FH autoantibodies.IMPORTANCE There are two licensed meningococcal capsular B vaccines. Both contain recombinant factor H binding protein (FHbp), which can bind to host complement factor H (FH). The limitations of these vaccines include a lack of protection against some meningococcal strains and the potential to elicit autoantibodies to FH. We immunized infant macaques with a native outer membrane vesicle (NOMV) vaccine with genetically attenuated endotoxin and overproduced mutant FHbp with low binding to FH. The NOMV-FHbp vaccine stimulated higher levels of protective serum antibodies than a licensed meningococcal group B vaccine against five of six genetically diverse meningococcal strains tested. Two of 13 macaques immunized with the licensed vaccine, which contains FHbp that binds macaque FH, but 0 of 17 macaques given NOMV-FHbp or the negative control developed serum anti-FH autoantibodies Thus, in a relevant nonhuman primate model, the NOMV-FHbp vaccine elicited greater protective antibodies than the licensed vaccine and may pose less of a risk of anti-FH autoantibody.


Assuntos
Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas de Bactérias/imunologia , Fator H do Complemento/imunologia , Vacinas Meningocócicas/imunologia , Animais , Antígenos de Bactérias/genética , Autoanticorpos/imunologia , Proteínas da Membrana Bacteriana Externa/genética , Proteínas de Bactérias/genética , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Macaca mulatta , Meningite Meningocócica/imunologia , Meningite Meningocócica/prevenção & controle , Proteínas Mutantes/imunologia , Neisseria meningitidis/genética , Neisseria meningitidis/imunologia , Neisseria meningitidis Sorogrupo B/genética , Neisseria meningitidis Sorogrupo B/imunologia , Ensaios de Anticorpos Bactericidas Séricos
16.
Nat Commun ; 10(1): 2678, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31213601

RESUMO

Myeloid cells contribute to tumor progression, but how the constellation of receptors they express regulates their functions within the tumor microenvironment (TME) is unclear. We demonstrate that Fcmr (Toso), the putative receptor for soluble IgM, modulates myeloid cell responses to cancer. In a syngeneic melanoma model, Fcmr ablation in myeloid cells suppressed tumor growth and extended mouse survival. Fcmr deficiency increased myeloid cell population density in this malignancy and enhanced anti-tumor immunity. Single-cell RNA sequencing of Fcmr-deficient tumor-associated mononuclear phagocytes revealed a unique subset with enhanced antigen processing/presenting properties. Conversely, Fcmr activity negatively regulated the activation and migratory capacity of myeloid cells in vivo, and T cell activation by bone marrow-derived dendritic cells in vitro. Therapeutic targeting of Fcmr during oncogenesis decreased tumor growth when used as a single agent or in combination with anti-PD-1. Thus, Fcmr regulates myeloid cell activation within the TME and may be a potential therapeutic target.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Transporte/metabolismo , Melanoma Experimental/imunologia , Proteínas de Membrana/metabolismo , Monócitos/imunologia , Neoplasias Cutâneas/imunologia , Animais , Apresentação do Antígeno/efeitos dos fármacos , Apresentação do Antígeno/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/imunologia , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Linhagem Celular Tumoral/transplante , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Feminino , Ativação Linfocitária/imunologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/mortalidade , Melanoma Experimental/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
17.
PLoS Pathog ; 15(6): e1007898, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31251784

RESUMO

Attaching/Effacing (A/E) bacteria include human pathogens enteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli (EHEC), and their murine equivalent Citrobacter rodentium (CR), of which EPEC and EHEC are important causative agents of foodborne diseases worldwide. While A/E pathogen infections cause mild symptoms in the immunocompetent hosts, an increasing number of studies show that they produce more severe morbidity and mortality in immunocompromised and/or immunodeficient hosts. However, the pathogenic mechanisms and crucial host-pathogen interactions during A/E pathogen infections under immunocompromised conditions remain elusive. We performed a functional screening by infecting interleukin-22 (IL-22) knockout (Il22-/-) mice with a library of randomly mutated CR strains. Our screen reveals that interruption of the espF gene, which encodes the Type III Secretion System effector EspF (E. coli secreted protein F) conserved among A/E pathogens, completely abolishes the high mortality rates in CR-infected Il22-/- mice. Chromosomal deletion of espF in CR recapitulates the avirulent phenotype without impacting colonization and proliferation of CR, and EspF complement in ΔespF strain fully restores the virulence in mice. Moreover, the expression levels of the espF gene are elevated during CR infection and CR induces disruption of the tight junction (TJ) strands in colonic epithelium in an EspF-dependent manner. Distinct from EspF, chromosomal deletion of other known TJ-damaging effector genes espG and map failed to impede CR virulence in Il22-/- mice. Hence our findings unveil a critical pathophysiological function for EspF during CR infection in the immunocompromised host and provide new insights into the complex pathogenic mechanisms of A/E pathogens.


Assuntos
Proteínas de Bactérias/imunologia , Proteínas de Transporte/imunologia , Citrobacter rodentium/imunologia , Infecções por Enterobacteriaceae/imunologia , Hospedeiro Imunocomprometido , Mucosa Intestinal/imunologia , Junções Íntimas/imunologia , Animais , Proteínas de Bactérias/genética , Proteínas de Transporte/genética , Linhagem Celular , Citrobacter rodentium/genética , Citrobacter rodentium/patogenicidade , Colo/imunologia , Colo/microbiologia , Colo/patologia , Infecções por Enterobacteriaceae/genética , Infecções por Enterobacteriaceae/patologia , Interleucinas/deficiência , Interleucinas/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Camundongos , Camundongos Knockout , Junções Íntimas/genética , Junções Íntimas/patologia
18.
APMIS ; 127(8): 588-593, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31233243

RESUMO

Microfibrillar-associated protein 4 (MFAP4) is a non-structural matrix protein with cell regulatory activities and a potential as seromarker for fibrosis. We aimed to study the occurrence of MFAP4 in the synovial membrane from patients with rheumatoid arthritis (RA) vs osteoarthritis (OA). Formaldehyde-fixed synovial tissue sections, from patients with RA (N = 6) and OA (N = 6) undergoing total hip arthroplasty, were deparaffinized and immunostained with monoclonal antibodies against MFAP4. Elastin was detected using ElastiKit. MFAP4 in serum (sMFAP4) and synovial fluid was measured by an immunoassay. MFAP4 was present in synovial biopsies from both RA and OA patients, particularly prominent in deep arterioles where it colocalized with elastin. Notably however, MFAP4 was absent from the internal elastic lamina in RA arterioles irrespective of disease duration and synovitis activity, while present although with irregular staining patterns in OA specimens. sMFAP4 was increased in RA and OA serum vs healthy controls: median (interquartile range) 29.8 (25.3-39.1) and 25.5 U/L (18.1-43.3) vs 17.7 U/L (13.7-21.2), p = 0.006 and p = 0.02, respectively The concentration of synovial fluid was lower than in serum in both RA and OA. These findings may suggest that MFAP4 is involved in adaptive vessel wall remodeling associated with chronic joint disease.


Assuntos
Artrite Reumatoide/imunologia , Proteínas de Transporte/análise , Proteínas da Matriz Extracelular/análise , Glicoproteínas/análise , Osteoartrite/imunologia , Membrana Sinovial/imunologia , Idoso , Anticorpos Monoclonais/imunologia , Biomarcadores/análise , Proteínas de Transporte/imunologia , Estudos de Casos e Controles , Proteínas da Matriz Extracelular/imunologia , Feminino , Glicoproteínas/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Líquido Sinovial/química , Membrana Sinovial/patologia
19.
Fish Shellfish Immunol ; 92: 460-468, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31233778

RESUMO

Autophagy plays an important role in the immune defense systems of vertebrates through the interaction between the lethal with SEC13 protein 8 (lst8) and the mechanistic target of rapamycin. In the present study, a novel invertebrate lst8 homologue is identified from Apostichopus japonicus (designated as Ajlst8) via polymerase chain reaction. The full-length complementary DNA of Ajlst8 comprises a 5'-untranslated region (UTR) of 78 base pair (bp), a 3'-UTR of 479 bp, and a putative open reading frame of 951 bp; hence, 316 amino acids are encoded. Structural analysis shows that the deduced amino acid of Ajlst8 shares six typical WD40 domains (28 aa-248 aa). Spatial expression analysis indicates that Ajlst8 is ubiquitously expressed in all the examined tissues, with a larger magnitude in coelomocytes. Vibrio splendidus infection in vivo and lipopolysaccharide exposure in vitro can significantly upregulate the messenger RNA expression of Ajlst8 by 2.39-fold and 1.93-fold compared with the control group, respectively. LPS exposure could also significantly induced the protein level of Ajlst8 to 2.38-fold and the autophagy level was markedly increased by 3.08-fold under same condition. The RNA interference of Ajlst8 in primary coelomocytes also reduces the relative expression of autophagy with a 0.71-fold decrease in the ratio of LC3-II/LC3-I compared with that in the control group. These results indicate that Ajlst8 is a novel immune regulator that may be involved in the antibacterial response process of sea cucumber by regulating autophagy.


Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Stichopus/genética , Stichopus/imunologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Proteínas de Transporte/química , Perfilação da Expressão Gênica , Filogenia , Alinhamento de Sequência , Vibrio/fisiologia
20.
Microbiol Spectr ; 7(3)2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31111819

RESUMO

Streptococcal pharyngitis (or strep throat) is a common childhood disease affecting millions of children each year, but it is one of the only childhood diseases for which a vaccine does not exist. While for decades the development of a vaccine has been the center of attention in many laboratories worldwide, with some successes, no corporate development has yet to be initiated. The reason for this probably lies in our inability to conclusively identify the streptococcal molecule or molecules responsible for the heart cross-reactive antibodies observed in the serum of rheumatic fever patients. Without this specific knowledge, any streptococcal vaccine antigen is suspect and thus not the target for a billion-dollar investment, despite the fact that the exact role of cross-reactive antibodies in rheumatic fever is still questionable. This article will describe the development of several approaches to protect against Streptococcus pyogenes infections over the past several decades.


Assuntos
Faringite/imunologia , Faringite/prevenção & controle , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/prevenção & controle , Vacinas Estreptocócicas/imunologia , Streptococcus pyogenes/imunologia , Animais , Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas de Transporte/imunologia , Criança , Reações Cruzadas/imunologia , Bactérias Gram-Positivas/imunologia , Humanos , Imunidade nas Mucosas , Febre Reumática/imunologia , Vacinação , Vírus Vaccinia
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