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1.
PLoS One ; 15(12): e0242438, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33362211

RESUMO

BACKGROUND: Mannose-binding lectin (MBL) plays a pivotal role in innate immunity; however, its impact on susceptibility to opportunistic infections (OIs) has not yet been examined in a natural history cohort of people living with HIV/AIDS. METHODS: We used archived samples to analyze the association between MBL expression types and risk of major OIs including Pneumocystis jirovecii pneumonia (PCP), cryptococcosis, talaromycosis, toxoplasmosis, and tuberculosis in a prospective cohort in Northern Thailand conducted from 1 July 2000 to 15 October 2002 before the national antiretroviral treatment programme was launched. RESULTS: Of 632 patients, PCP was diagnosed in 96 (15.2%) patients, including 45 patients with new episodes during the follow-up period (1006.5 person-years). The total history of PCP was significantly associated with low MBL expression type: high/intermediate (81/587, 13.8%), low (10/33, 30.3%) and deficient (5/12, 41.7%) (p = 0.001), whereas the history of other OIs showed no relation with any MBL expression type. Kaplan-Meier analysis (n = 569; log-rank p = 0.011) and Cox's proportional hazards model revealed that deficient genotype dramatically increased the risk of PCP, which is independent upon sex, age, CD4 count, HIV-1 viral load and hepatitis B and C status (adjusted hazard ratio 7.93, 95% confidence interval 2.19-28.67, p = 0.002). CONCLUSIONS: Deficiency of MBL expression is a strong risk factor determining the incidence of PCP but not other major OIs.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Lectina de Ligação a Manose/deficiência , Pneumocystis carinii/isolamento & purificação , Pneumonia por Pneumocystis/epidemiologia , Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/genética , Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Adolescente , Adulto , Feminino , Seguimentos , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Imunidade Inata/genética , Incidência , Masculino , Lectina de Ligação a Manose/genética , Lectina de Ligação a Manose/imunologia , Pessoa de Meia-Idade , Pneumocystis carinii/imunologia , Pneumonia por Pneumocystis/diagnóstico , Pneumonia por Pneumocystis/genética , Pneumonia por Pneumocystis/microbiologia , Estudos Prospectivos , Fatores de Risco , Tailândia/epidemiologia , Adulto Jovem
2.
Infect Genet Evol ; 84: 104498, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32771700

RESUMO

New coronavirus SARS-CoV-2 is capable to infect humans and cause a novel disease COVID-19. Aiming to understand a host genetic component of COVID-19, we focused on variants in genes encoding proteases and genes involved in innate immunity that could be important for susceptibility and resistance to SARS-CoV-2 infection. Analysis of sequence data of coding regions of FURIN, PLG, PRSS1, TMPRSS11a, MBL2 and OAS1 genes in 143 unrelated individuals from Serbian population identified 22 variants with potential functional effect. In silico analyses (PolyPhen-2, SIFT, MutPred2 and Swiss-Pdb Viewer) predicted that 10 variants could impact the structure and/or function of proteins. These protein-altering variants (p.Gly146Ser in FURIN; p.Arg261His and p.Ala494Val in PLG; p.Asn54Lys in PRSS1; p.Arg52Cys, p.Gly54Asp and p.Gly57Glu in MBL2; p.Arg47Gln, p.Ile99Val and p.Arg130His in OAS1) may have predictive value for inter-individual differences in the response to the SARS-CoV-2 infection. Next, we performed comparative population analysis for the same variants using extracted data from the 1000 Genomes project. Population genetic variability was assessed using delta MAF and Fst statistics. Our study pointed to 7 variants in PLG, TMPRSS11a, MBL2 and OAS1 genes with noticeable divergence in allelic frequencies between populations worldwide. Three of them, all in MBL2 gene, were predicted to be damaging, making them the most promising population-specific markers related to SARS-CoV-2 infection. Comparing allelic frequencies between Serbian and other populations, we found that the highest level of genetic divergence related to selected loci was observed with African, followed by East Asian, Central and South American and South Asian populations. When compared with European populations, the highest divergence was observed with Italian population. In conclusion, we identified 4 variants in genes encoding proteases (FURIN, PLG and PRSS1) and 6 in genes involved in the innate immunity (MBL2 and OAS1) that might be relevant for the host response to SARS-CoV-2 infection.


Assuntos
Infecções por Coronavirus/genética , Resistência à Doença/genética , Predisposição Genética para Doença , Interações Hospedeiro-Patógeno/genética , Metagenômica , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Glicoproteína da Espícula de Coronavírus/genética , Alelos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Proteínas do Olho/genética , Proteínas do Olho/imunologia , Furina/genética , Furina/imunologia , Frequência do Gene , Variação Genética , Genoma Humano , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Lectina de Ligação a Manose/genética , Lectina de Ligação a Manose/imunologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Pandemias , Peptidil Dipeptidase A/imunologia , Plasminogênio/genética , Plasminogênio/imunologia , Pneumonia Viral/imunologia , Ligação Proteica , Glicoproteína da Espícula de Coronavírus/imunologia , Tripsina/genética , Tripsina/imunologia
3.
Fish Shellfish Immunol ; 98: 25-33, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31904539

RESUMO

Mannose-binding lectin (MBL) is a crucial pattern recognition receptor in the host innate immune system. Previously, we reported the biological function of Ctenopharyngodon idella MBL (CiMBL) in initiating the lectin pathway of the complement system. In the present study, we further explored its biological function including the agglutinating ability, binding capacity and protective role in vitro and in vivo. After Aeromonas hydrophila infection, western blot analysis revealed that the CiMBL were fluctuated and expressed in the serum and major immune-related tissues. The result of quantitative PCR (qPCR) showed that the recombinant CiMBL (rCiMBL) significantly inhibited the mRNA expression of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in liver, spleen and hepatic cells. Due to rCiMBL bound to d-mannose, d-galactose, d-glucose, N-acetyl-d-glucosamine (GlcNAc), lipopolysaccharide (LPS), peptidoglycan (PGN) and Agar in the presence of Ca2+, herein gram-positive (Staphylococcus aureus and Micrococcus luteus) and gram-negative (A. hydrophila and Vibrio anguillarum) bacteria were agglutinated by rCiMBL in a Ca2+-dependent manner. More importantly, rCiMBL enhanced the survival rate of grass carp following bacterial infection. Overall, the results provide an evidence that CiMBL can protect grass carp against A. hydrophila infection in aquaculture.


Assuntos
Aglutinação , Carpas/imunologia , Doenças dos Peixes/imunologia , Lectina de Ligação a Manose/imunologia , Monossacarídeos/metabolismo , Polissacarídeos/metabolismo , Aeromonas hydrophila/fisiologia , Animais , Carpas/metabolismo , Proteínas de Peixes/imunologia , Proteínas de Peixes/farmacologia , Bactérias Gram-Negativas/fisiologia , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , Bactérias Gram-Positivas/fisiologia , Lectina de Ligação a Manose/farmacologia , Substâncias Protetoras/farmacologia
4.
J Virol ; 94(6)2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31852794

RESUMO

We covalently attached human immunodeficiency virus type 1 (HIV-1) Env SOSIP trimers to iron oxide nanoparticles (IO-NPs) to create a particulate immunogen for neutralizing antibody (NAb) induction. The attached trimers, ∼20 per particle, retained native-like antigenicity, judged by reactivity with NAbs and non-NAbs. Bivalent (BG505 and B41) trimer IO-NPs were made, as were IO-NPs displaying B41 trimers carrying a PADRE T-cell helper epitope (TCHE). We immunized mice with B41 soluble or IO-NP trimers after PADRE peptide priming. After two immunizations, IO-NP presentation and the TCHE tag independently and substantially increased anti-trimer antibody responses, but titer differences waned after two further doses. Notable and unexpected findings were that autologous NAbs to the N289 glycan hole epitope were consistently induced in mice given soluble but not IO-NP trimers. Various recombinant mannose binding lectins (MBLs) and MBLs in sera of both murine and human origin bound to soluble and IO-NP trimers. MBL binding occluded the autologous NAb epitope on the B41 IO-NP trimers, which may contribute to its poor immunogenicity. The exposure of a subset of broadly active NAb epitopes was also impaired by MBL binding, which could have substantial implications for the utility of trimer-bearing nanoparticles in general and perhaps also for soluble Env proteins.IMPORTANCE Recombinant trimeric SOSIP proteins are vaccine components intended to induce neutralizing antibodies (NAbs) that prevent cells from infection by human immunodeficiency virus type 1 (HIV-1). A way to increase the strength of antibody responses to these proteins is to present them on the surface of nanoparticles (NPs). We chemically attached about 20 SOSIP trimers to NPs made of iron oxide (IO). The resulting IO-NP trimers had appropriate properties when we studied them in the laboratory but, unexpectedly, were less able to induce NAbs than nonattached trimers when used to immunize mice. We found that mannose binding lectins, proteins naturally present in the serum of mice and other animals, bound strongly to the soluble and IO-NP trimers, blocking access to antibody epitopes in a way that may impede the development of NAb responses. These findings should influence how trimer-bearing NPs of various designs are made and used.


Assuntos
Anticorpos Neutralizantes/imunologia , Epitopos de Linfócito T/imunologia , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Nanopartículas de Magnetita , Lectina de Ligação a Manose/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Animais , Humanos , Camundongos , Multimerização Proteica/imunologia
5.
PLoS One ; 14(12): e0220483, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31881024

RESUMO

E. coli associated Hemolytic Uremic Syndrome (epidemic hemolytic uremic syndrome, eHUS) caused by Shiga toxin-producing bacteria is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury that cause acute renal failure in up to 65% of affected patients. We hypothesized that the mannose-binding lectin (MBL) pathway of complement activation plays an important role in human eHUS, as we previously demonstrated that injection of Shiga Toxin-2 (Stx-2) led to fibrin deposition in mouse glomeruli that was blocked by co-injection of the anti-MBL-2 antibody 3F8. However, the markers of platelet thrombosis in affected mouse glomeruli were not delineated. To investigate the effect of 3F8 on markers of platelet thrombosis, we used kidney sections from our mouse model (MBL-2+/+ Mbl-A/C-/-; MBL2 KI mouse). Mice in the control group received PBS, while mice in a second group received Stx-2, and those in a third group received 3F8 and Stx-2. Using double immunofluorescence (IF) followed by digital image analysis, kidney sections were stained for fibrin(ogen) and CD41 (marker for platelets), von-Willebrand factor (marker for endothelial cells and platelets), and podocin (marker for podocytes). Electron microscopy (EM) was performed on ultrathin sections from mice and human with HUS. Injection of Stx-2 resulted in an increase of both fibrin and platelets in glomeruli, while administration of 3F8 with Stx-2 reduced both platelet and fibrin to control levels. EM studies confirmed that CD41-positive objects observed by IF were platelets. The increases in platelet number and fibrin levels by injection of Stx-2 are consistent with the generation of platelet-fibrin thrombi that were prevented by 3F8.


Assuntos
Síndrome Hemolítico-Urêmica/metabolismo , Lectina de Ligação a Manose/metabolismo , Trombose/metabolismo , Lesão Renal Aguda/metabolismo , Animais , Plaquetas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Escherichia coli/metabolismo , Escherichia coli/patogenicidade , Infecções por Escherichia coli/microbiologia , Síndrome Hemolítico-Urêmica/microbiologia , Humanos , Rim/metabolismo , Glomérulos Renais/metabolismo , Lectina de Ligação a Manose/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Toxina Shiga/metabolismo , Toxina Shiga II/metabolismo , Tromboembolia/metabolismo
6.
Nature ; 574(7777): 264-267, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31578522

RESUMO

Bacterial dysbiosis accompanies carcinogenesis in malignancies such as colon and liver cancer, and has recently been implicated in the pathogenesis of pancreatic ductal adenocarcinoma (PDA)1. However, the mycobiome has not been clearly implicated in tumorigenesis. Here we show that fungi migrate from the gut lumen to the pancreas, and that this is implicated in the pathogenesis of PDA. PDA tumours in humans and mouse models of this cancer displayed an increase in fungi of about 3,000-fold compared to normal pancreatic tissue. The composition of the mycobiome of PDA tumours was distinct from that of the gut or normal pancreas on the basis of alpha- and beta-diversity indices. Specifically, the fungal community that infiltrated PDA tumours was markedly enriched for Malassezia spp. in both mice and humans. Ablation of the mycobiome was protective against tumour growth in slowly progressive and invasive models of PDA, and repopulation with a Malassezia species-but not species in the genera Candida, Saccharomyces or Aspergillus-accelerated oncogenesis. We also discovered that ligation of mannose-binding lectin (MBL), which binds to glycans of the fungal wall to activate the complement cascade, was required for oncogenic progression, whereas deletion of MBL or C3 in the extratumoral compartment-or knockdown of C3aR in tumour cells-were both protective against tumour growth. In addition, reprogramming of the mycobiome did not alter the progression of PDA in Mbl- (also known as Mbl2) or C3-deficient mice. Collectively, our work shows that pathogenic fungi promote PDA by driving the complement cascade through the activation of MBL.


Assuntos
Adenocarcinoma/microbiologia , Adenocarcinoma/patologia , Carcinogênese , Carcinoma Ductal Pancreático/microbiologia , Carcinoma Ductal Pancreático/patologia , Microbioma Gastrointestinal/imunologia , Lectina de Ligação a Manose/imunologia , Micobioma/imunologia , Adenocarcinoma/imunologia , Animais , Carcinoma Ductal Pancreático/imunologia , Estudos de Casos e Controles , Ativação do Complemento , Complemento C3/deficiência , Complemento C3/imunologia , Progressão da Doença , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
7.
Exp Dermatol ; 28(9): 1017-1024, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31260126

RESUMO

Psoriasis is a chronic, relapsing inflammatory skin disorder. Numerous experimental evidence and therapeutic evidence have shown that the innate immune response is critical for the pathogenesis and development of psoriasis. Mannan-binding lectin (MBL), a prototypic pattern recognition molecule of the innate immune system, plays an essential role in the host defense against certain infections and also appears to be a major regulator of inflammation. In this study, we investigated the function of MBL on the course of experimental murine imiquimod (IMQ)-induced psoriasis. Our data showed that MBL-deficient (MBL-/- ) mice exhibited attenuated skin damage characterized by greatly decreased erythema compared with wild-type control mice during the early stages of IMQ-induced psoriasis-like skin inflammation. The reduced skin inflammation in MBL-/- mice was associated with the decreased infiltration of neutrophils. Furthermore, we have determined that MBL deficiency limited the chemokine CXCL1 production from skin keratinocytes upon IMQ stimulation, which might be responsible for the impaired skin recruitment of neutrophils. Additionally, we have provided the data that MBL protein promotes the IMQ-induced expression of CXCL1 and activation of MAPK/NF-κB signalling pathway in human keratinocyte HaCaT cells in vitro. In summary, our study revealed an unexpected role of MBL on keratinocyte function in skin, thus offering a new insight into the pathogenic mechanisms of psoriasis.


Assuntos
Quimiocina CXCL1/biossíntese , Quimiotaxia de Leucócito , Queratinócitos/metabolismo , Lectina de Ligação a Manose/fisiologia , Neutrófilos/fisiologia , Psoríase/imunologia , Animais , Linhagem Celular Transformada , Quimiocina CXCL1/genética , Derme/imunologia , Derme/patologia , Feminino , Humanos , Imiquimode/toxicidade , Inflamação , Queratinócitos/efeitos dos fármacos , Lectina de Ligação a Manose/deficiência , Lectina de Ligação a Manose/genética , Lectina de Ligação a Manose/imunologia , Lectina de Ligação a Manose/farmacologia , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/imunologia , Camundongos , Camundongos Knockout , Psoríase/induzido quimicamente , Psoríase/metabolismo , Organismos Livres de Patógenos Específicos , Regulação para Cima
8.
Dev Comp Immunol ; 99: 103408, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31173786

RESUMO

Mannose-binding lectin (MBL) is a vital component in host's innate immune system and the initiator of the lectin pathway of complement cascade. However, its opsonic role has rarely been reported. In this study, we revealed the biological function of Ctenopharyngodon idella MBL (CiMBL) in regulating monocytes/macrophages (MO/MФ) in the grass carp (C. idella). Flow cytometry results indicated that recombinant CiMBL (rCiMBL) significantly enhanced the phagocytotic activity of MO/MФ. Recombinant CiMBL also enhanced bactericidal activity and respiratory burst capacity in Aeromonas hydrophila-infected MO/MФ, regulated A. hydrophila-induced polarization of MO/MФ including down- and up-regulated pro- and anti-inflammatory cytokines, respectively, suppressed the inducible nitric oxide synthase activity, and enhanced the arginase activity. In addition, rCiMBL suppressed the bacteria burden in tissues and blood in vivo and enhanced the survival rate of juvenile A. hydrophila-infected grass carp. We provide evidence that CiMBL was synthesized by MO/MФ, regulating the biological function of MO/MФ against A. hydrophila infection.


Assuntos
Carpas/imunologia , Doenças dos Peixes/imunologia , Proteínas de Peixes/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , Macrófagos/imunologia , Lectina de Ligação a Manose/imunologia , Monócitos/imunologia , Aeromonas hydrophila/fisiologia , Animais , Carga Bacteriana , Carpas/microbiologia , Células Cultivadas , Doenças dos Peixes/microbiologia , Proteínas de Peixes/antagonistas & inibidores , Proteínas de Peixes/genética , Perfilação da Expressão Gênica , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/microbiologia , Imunidade Inata , Macrófagos/microbiologia , Lectina de Ligação a Manose/antagonistas & inibidores , Lectina de Ligação a Manose/genética , Viabilidade Microbiana , Monócitos/microbiologia , Fagocitose , Explosão Respiratória , Análise de Sobrevida
9.
J Immunol ; 203(2): 408-417, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31175160

RESUMO

Recent thymic emigrants that fail postpositive selection maturation are targeted by complement proteins. T cells likely acquire complement resistance during maturation in the thymus, a complement-privileged organ. To test this, thymocytes and fresh serum were separately obtained and incubated together in vitro to assess complement deposition. Complement binding decreased with development and maturation. Complement binding decreased from the double-positive thymocyte to the single-positive stage, and within single-positive thymocytes, complement binding gradually decreased with increasing intrathymic maturation. Binding of the central complement protein C3 to wild-type immature thymocytes required the lectin but not the classical pathway. Specifically, MBL2 but not MBL1 was required, demonstrating a unique function for MBL2. Previous studies demonstrated that the loss of NKAP, a transcriptional regulator of T cell maturation, caused peripheral T cell lymphopenia and enhanced complement susceptibility. To determine whether complement causes NKAP-deficient T cell disappearance, both the lectin and classical pathways were genetically ablated. This blocked C3 deposition on NKAP-deficient T cells but failed to restore normal cellularity, indicating that complement contributes to clearance but is not the primary cause of peripheral T cell lymphopenia. Rather, the accumulation of lipid peroxides in NKAP-deficient T cells was observed. Lipid peroxidation is a salient feature of ferroptosis, an iron-dependent nonapoptotic cell death. Thus, wild-type thymocytes naturally acquire the ability to protect themselves from complement targeting by MBL2 with maturation. However, NKAP-deficient immature peripheral T cells remain scarce in complement-deficient mice likely due to ferroptosis.


Assuntos
Diferenciação Celular/imunologia , Complemento C3/imunologia , Lectina de Ligação a Manose/imunologia , Proteínas Repressoras/imunologia , Linfócitos T/imunologia , Animais , Linfopenia/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Timócitos/imunologia , Timo/imunologia , Transcrição Genética/imunologia
10.
Front Immunol ; 10: 1005, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31139182

RESUMO

Background: Mannose-binding lectin (MBL) is an innate immune protein with strong biologic plausibility for protecting against influenza virus-related sepsis and bacterial co-infection. In an autopsy cohort of 105 influenza-infected young people, carriage of the deleterious MBL gene MBL2_Gly54Asp("B") mutation was identified in 5 of 8 individuals that died from influenza-methicillin-resistant Staphylococcus aureus (MRSA) co-infection. We evaluated MBL2 variants known to influence MBL levels with pediatric influenza-related critical illness susceptibility and/or severity including with bacterial co-infections. Methods: We enrolled children and adolescents with laboratory-confirmed influenza infection across 38 pediatric intensive care units from November 2008 to June 2016. We sequenced MBL2 "low-producer" variants rs11003125("H/L"), rs7096206("Y/X"), rs1800450Gly54Asp("B"), rs1800451Gly57Glu("C"), rs5030737Arg52Cys("D") in patients and biologic parents. We measured serum levels and compared complement activity in low-producing homozygotes ("B/B," "C/C") to HYA/HYA controls. We used a population control of 1,142 healthy children and also analyzed family trios (PBAT/HBAT) to evaluate disease susceptibility, and nested case-control analyses to evaluate severity. Results: We genotyped 420 patients with confirmed influenza-related sepsis: 159 (38%) had acute lung injury (ALI), 165 (39%) septic shock, and 30 (7%) died. Although bacterial co-infection was diagnosed in 133 patients (32%), only MRSA co-infection (n = 33, 8% overall) was associated with death (p < 0.0001), present in 11 of 30 children that died (37%). MBL2 variants predicted serum levels and complement activation as expected. We found no association between influenza-related critical illness susceptibility and MBL2 variants using family trios (633 biologic parents) or compared to population controls. MBL2 variants were not associated with admission illness severity, septic shock, ALI, or bacterial co-infection diagnosis. Carriage of low-MBL producing MBL2 variants was not a risk factor for mortality, but children that died did have higher carriage of one or more B alleles (OR 2.3; p = 0.007), including 7 of 11 with influenza MRSA-related death (vs. 2 of 22 survivors: OR 14.5, p = 0.0002). Conclusions: MBL2 variants that decrease MBL levels were not associated with susceptibility to pediatric influenza-related critical illness or with multiple measures of critical illness severity. We confirmed a prior report of higher B allele carriage in a relatively small number of young individuals with influenza-MRSA associated death.


Assuntos
Coinfecção , Predisposição Genética para Doença , Vírus da Influenza A , Influenza Humana , Lectina de Ligação a Manose , Staphylococcus aureus Resistente à Meticilina , Mutação de Sentido Incorreto , Infecções Estafilocócicas , Adolescente , Substituição de Aminoácidos , Criança , Pré-Escolar , Coinfecção/sangue , Coinfecção/genética , Coinfecção/imunologia , Coinfecção/mortalidade , Estado Terminal , Feminino , Humanos , Lactente , Vírus da Influenza A/imunologia , Vírus da Influenza A/metabolismo , Influenza Humana/sangue , Influenza Humana/genética , Influenza Humana/imunologia , Influenza Humana/mortalidade , Masculino , Lectina de Ligação a Manose/sangue , Lectina de Ligação a Manose/genética , Lectina de Ligação a Manose/imunologia , Staphylococcus aureus Resistente à Meticilina/imunologia , Staphylococcus aureus Resistente à Meticilina/metabolismo , Infecções Estafilocócicas/sangue , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/mortalidade
11.
Fish Shellfish Immunol ; 89: 448-457, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30974220

RESUMO

Mannose-binding lectin (MBL) is a pattern recognition receptor (PRR) that plays an important role in the innate immune response. In this study, a novel mannose-binding lectin was cloned from the swimmimg crab Portunus trituberculatus (designated as PtMBL). The complete cDNA of PtMBL gene was 1208 bp in length with an open reading frame (ORF) of 732 bp that encoded 244 amino acid proteins. PtMBL shared lower amino acid similarity with other MBLs, yet it contained the conserved carbohydrate-recognition domain (CRD) with QPD motif and was clearly member of the collectin family. PtMBL transcripts were mainly detected in eyestalk and gill with sexually dimorphic expression. The temporal expression of PtMBL in hemocytes showed different activation times after challenged with Vibrio alginolyticus, Micrococcus luteus and Pichia pastoris. The recombinant PtMBL protein revealed antimicrobial activity against the tested Gram-negative and Gram-positive bacteria. It could also bind and agglutinate (Ca2+-dependent) both bacteria and yeast. Furthermore, the agglutinating activity could be inhibited by both d-galactose and d-mannose, suggesting the broader pathogen-associated molecular patterns (PAMPs) recognition spectrum of PtMBL. These results together indicate that PtMBL could serve as not only a PRR in immune recognition but also a potential antibacterial protein in the innate immune response of crab.


Assuntos
Braquiúros/genética , Braquiúros/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Lectina de Ligação a Manose/genética , Lectina de Ligação a Manose/imunologia , Sequência de Aminoácidos , Animais , Proteínas de Artrópodes/química , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/imunologia , Sequência de Bases , Feminino , Perfilação da Expressão Gênica , Masculino , Lectina de Ligação a Manose/química , Micrococcus luteus/fisiologia , Filogenia , Pichia/fisiologia , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Alinhamento de Sequência , Vibrio alginolyticus/fisiologia
12.
Nutrients ; 11(3)2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30836628

RESUMO

(1) Background: High iron associates with inflammation and type 1 diabetes (T1D). Iron is essential not only for neonatal development but also for infectious microorganisms. The neonatal immune system is immature, and innate immunity prevails before immunocompetence develops. (2) Methods: In 398 newborns from the Danish Newborn Screening Biobank, we examined if whole blood iron (WB-Iron) content were associated with cytokines, adipokines, C-reactive protein (CRP), and mannose-binding lectin (MBL) in non-infected healthy neonates, and if these associations differed in newborns who later developed T1D (cases) (n = 199). WB-Iron was quantified using laser ablation inductively coupled plasma mass spectrometry on the neonatal dried blood spots. For each analyte, the relative change (RC) in the mean level was modeled by robust log-normal regression. (3) Results: A one unit increase in neonatal WB-Iron was associated with a 38% decrease in mean interleukin (IL)-6 levels (0.62; 95% CI: 0.40⁻0.95, p = 0.03), and a 37% decrease in mean MBL levels (0.63; 95% CI: 0.41⁻0.95, p = 0.03), but was not statistically significant after correction for multiple testing. (4) Conclusions: In summary, we found that higher neonatal WB-iron content was inversely associated with IL-6 and MBL, which may increase susceptibility to infections.


Assuntos
Adipocinas/sangue , Citocinas/sangue , Doenças do Recém-Nascido/imunologia , Ferro/sangue , Lectina de Ligação a Manose/sangue , Adipocinas/imunologia , Bancos de Espécimes Biológicos , Biomarcadores/sangue , Proteína C-Reativa/análise , Proteína C-Reativa/imunologia , Citocinas/imunologia , Dinamarca , Diabetes Mellitus Tipo 1/sangue , Feminino , Voluntários Saudáveis , Humanos , Imunidade Inata/imunologia , Recém-Nascido , Doenças do Recém-Nascido/sangue , Interleucina-6/sangue , Interleucina-6/imunologia , Ferro/imunologia , Masculino , Lectina de Ligação a Manose/imunologia , Análise de Regressão
13.
Fish Shellfish Immunol ; 87: 265-274, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30654028

RESUMO

Mannose-binding lectin (MBL), a soluble pattern recognition receptor, is able to recognize antigen and participate in non-specific cell immunity, such as regulation of inflammation, migration, opsonization, phagocytosis and killing, which plays an important role in innate immunity. In this study, we have investigated the contributing mechanisms and effects of MBL on the cell immunity of Nile tilapia (Oreochromis niloticus) monocytes/macrophages. The mRNA expression level of OnMBL was significantly up-regulated in monocytes/macrophages after in vitro bacterial infection (Streptococcus agalactiae and Aeromonas hydrophila). Recombinant OnMBL ((r)OnMBL) protein could participate in the regulation of inflammation, migration, and enhancement of phagocytosis and respiratory burst activity in monocytes/macrophages. Moreover, the (r)OnMBL could induce the apoptosis of monocytes/macrophages. Taken together, the results of this study indicated that OnMBL is likely to involve in immune regulation, which may play an important role in host defense of innate immunity in Nile tilapia.


Assuntos
Apoptose/imunologia , Ciclídeos/imunologia , Proteínas de Peixes/imunologia , Imunidade Celular/imunologia , Macrófagos/imunologia , Lectina de Ligação a Manose/imunologia , Monócitos/imunologia , Animais
14.
Fish Shellfish Immunol ; 84: 91-99, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30273652

RESUMO

Lectins are a group of carbohydrate-binding proteins, which play an important role in innate immune system against pathogen infection. In this study, a B-type mannose-binding lectin (OnBML) was identified from Nile tilapia (Oreochromis niloticus), and characterized at expression patterns against bacterial infection and capability to promote phagocytosis by macrophages. The open reading frame of OnBML is 354 bp of nucleotide sequence encoding polypeptides of 117 amino acids. The deduced protein is highly homologous to other teleost BMLs, containing two repeats of the conserved mannose-binding motif QXDXNXVXY. Expression of OnBML was widely exhibited in all examined tissues, with the most abundance in spleen and following gill, peripheral blood, and head kidney. The OnBML expressions were significantly up-regulated following two major bacterial infections including a Gram-positive bacterium (Streptococcus agalactiae) and a Gram-negative bacterium (Aeromonas hydrophila) in vivo and in vitro. Recombinant OnBML protein possessed capacities of mannose-binding and calcium-dependent agglutination to S. agalactiae and A. hydrophila, and promoted the phagocytosis by macrophages. Taken together, the present study indicated that OnBML is likely to get involved in host defense against bacterial infection in Nile tilapia.


Assuntos
Ciclídeos/imunologia , Doenças dos Peixes/imunologia , Proteínas de Peixes/imunologia , Lectina de Ligação a Manose/imunologia , Infecções Estreptocócicas/imunologia , Aeromonas hydrophila , Animais , Ciclídeos/microbiologia , Proteínas de Peixes/genética , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , Macrófagos/imunologia , Lectina de Ligação a Manose/genética , Monócitos/imunologia , Infecções Estreptocócicas/veterinária , Streptococcus agalactiae
15.
J Cell Biol ; 218(1): 333-349, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30366943

RESUMO

Collectins such as mannose-binding lectin (MBL) and surfactant protein D (SP-D) become temporarily deposited in extravascular compartments after tissue injury and perform immune-stimulatory or inflammation-limiting functions. However, their turnover mechanisms, necessary to prevent excessive tissue damage, are virtually unknown. In this study, we show that fibroblasts in injured tissues undertake the clearance of collectins by using the endocytic collagen receptor uPARAP. In cellular assays, several types of collectins were endocytosed in a highly specific uPARAP-dependent process, not shared by the closely related receptor MR/CD206. When introduced into dermis or bleomycin-injured lungs of mice, collectins MBL and SP-D were endocytosed and routed for lysosomal degradation by uPARAP-positive fibroblasts. Fibroblast-specific expression of uPARAP governed endogenous SP-D levels and overall survival after lung injury. In lung tissue from idiopathic pulmonary fibrosis patients, a strong up-regulation of uPARAP was observed in fibroblasts adjacent to regions with SP-D secretion. This study demonstrates a novel immune-regulatory function of fibroblasts and identifies uPARAP as an endocytic receptor in immunity.


Assuntos
Fibroblastos/imunologia , Lesão Pulmonar/imunologia , Lectina de Ligação a Manose/imunologia , Lectinas de Ligação a Manose/imunologia , Glicoproteínas de Membrana/imunologia , Fibrose Pulmonar/imunologia , Proteína D Associada a Surfactante Pulmonar/imunologia , Receptores de Superfície Celular/imunologia , Animais , Bleomicina/administração & dosagem , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Endocitose , Fibroblastos/patologia , Expressão Gênica , Humanos , Imunidade Inata , Interleucina-6/genética , Interleucina-6/imunologia , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Pulmão/imunologia , Pulmão/patologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/genética , Lesão Pulmonar/mortalidade , Lisossomos/imunologia , Lisossomos/metabolismo , Lectina de Ligação a Manose/genética , Lectinas de Ligação a Manose/genética , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteólise , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/mortalidade , Proteína D Associada a Surfactante Pulmonar/genética , Receptores de Superfície Celular/genética , Análise de Sobrevida
16.
Science ; 363(6427): 649-654, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30573546

RESUMO

In vaccine design, antigens are often arrayed in a multivalent nanoparticle form, but in vivo mechanisms underlying the enhanced immunity elicited by such vaccines remain poorly understood. We compared the fates of two different heavily glycosylated HIV antigens, a gp120-derived mini-protein and a large, stabilized envelope trimer, in protein nanoparticle or "free" forms after primary immunization. Unlike monomeric antigens, nanoparticles were rapidly shuttled to the follicular dendritic cell (FDC) network and then concentrated in germinal centers in a complement-, mannose-binding lectin (MBL)-, and immunogen glycan-dependent manner. Loss of FDC localization in MBL-deficient mice or via immunogen deglycosylation significantly affected antibody responses. These findings identify an innate immune-mediated recognition pathway promoting antibody responses to particulate antigens, with broad implications for humoral immunity and vaccine design.


Assuntos
Vacinas contra a AIDS/imunologia , Formação de Anticorpos , Centro Germinativo/imunologia , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/imunologia , Imunidade Inata , Polissacarídeos/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Testes de Fixação de Complemento , Proteínas do Sistema Complemento/imunologia , Células Dendríticas/imunologia , Feminino , Anticorpos Anti-HIV/imunologia , Infecções por HIV/prevenção & controle , Lipossomos , Lectina de Ligação a Manose/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Complexos Multiproteicos , Nanopartículas , Receptores de Complemento/imunologia
17.
J Cereb Blood Flow Metab ; 39(5): 794-807, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-29425056

RESUMO

We explored the involvement of the lectin pathway of complement in post-traumatic brain injury (TBI) pathophysiology in humans. Brain samples were obtained from 28 patients who had undergone therapeutic contusion removal, within 12 h (early) or from >12 h until five days (late) from injury, and from five non-TBI patients. Imaging analysis indicated that lectin pathway initiator molecules (MBL, ficolin-1, ficolin-2 and ficolin-3), the key enzymes MASP-2 and MASP-3, and the downstream complement components (C3 fragments and TCC) were present inside and outside brain vessels in all contusions. Only ficolin-1 was found in the parenchyma of non-TBI tissues. Immunoassays in brain homogenates showed that MBL, ficolin-2 and ficolin-3 increased in TBI compared to non-TBI (2.0, 2.2 and 6.0-times) samples. MASP-2 increased with subarachnoid hemorrhage and abnormal pupil reactivity, two indicators of structural and functional damage. C3 fragments and TCC increased, respectively, by 3.5 - and 4.0-fold in TBI compared to non-TBI tissue and significantly correlated with MBL, ficolin-2, ficolin-3, MASP-2 and MASP-3 levels in the homogenates. In conclusion, we show for the first time the direct presence of lectin pathway components in human cerebral contusions and their association with injury severity, suggesting a central role for the lectin pathway in the post-traumatic pathophysiology of human TBI.


Assuntos
Lesões Encefálicas Traumáticas/imunologia , Lectina de Ligação a Manose da Via do Complemento , Lesões Encefálicas Traumáticas/patologia , Ativação do Complemento , Complemento C3/análise , Complemento C3/imunologia , Feminino , Humanos , Lectinas/análise , Lectinas/imunologia , Masculino , Lectina de Ligação a Manose/análise , Lectina de Ligação a Manose/imunologia , Pessoa de Meia-Idade
18.
Proc Natl Acad Sci U S A ; 115(45): 11573-11578, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30337484

RESUMO

Invasive microbes causing diseases such as sudden oak death negatively affect ecosystems and economies around the world. The deployment of resistant genotypes for combating introduced diseases typically relies on breeding programs that can take decades to complete. To demonstrate how this process can be accelerated, we employed a genome-wide association mapping of ca 1,000 resequenced Populus trichocarpa trees individually challenged with Sphaerulina musiva, an invasive fungal pathogen. Among significant associations, three loci associated with resistance were identified and predicted to encode one putative membrane-bound L-type receptor-like kinase and two receptor-like proteins. A susceptibility-associated locus was predicted to encode a putative G-type D-mannose-binding receptor-like kinase. Multiple lines of evidence, including allele analysis, transcriptomics, binding assays, and overexpression, support the hypothesized function of these candidate genes in the P. trichocarpa response to S. musiva.


Assuntos
Regulação da Expressão Gênica de Plantas , Interações Hospedeiro-Patógeno/genética , Doenças das Plantas/genética , Proteínas de Plantas/genética , Populus/genética , Saccharomycetales/patogenicidade , Transcriptoma , Alelos , Mapeamento Cromossômico , Cromossomos de Plantas/química , Resistência à Doença/genética , Perfilação da Expressão Gênica , Loci Gênicos , Interações Hospedeiro-Patógeno/imunologia , Lectina de Ligação a Manose/genética , Lectina de Ligação a Manose/imunologia , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Imunidade Vegetal/genética , Proteínas de Plantas/imunologia , Populus/imunologia , Populus/microbiologia , Proteínas Quinases/genética , Proteínas Quinases/imunologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Saccharomycetales/fisiologia
19.
J Immunol Methods ; 460: 101-106, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30056939

RESUMO

The aim of this study was to develop an assay to analyze the serum profile of Mannose-binding lectin (MBL) through a simple and "in-house" method (called "dot-N-man"). Furthermore, the study attempted to associate molecular masses of MBL to the profile of MBL gene polymorphisms in patients with hepatitis C. Heterogeneity in molecular masses of MBL is due to the impairment of oligomers formation, which is linked to genetic polymorphisms in the MBL gene. Individuals with AA genotype (wild-type) produce high-molecular-mass proteins, whereas AO and OO individuals produce intermediate and low-molecular-mass proteins, respectively. Sera of thirty patients carrying the hepatitis C virus (HCV) were investigated using MBL binding assay with mannan-coated nitrocellulose (dot-N-man). Purified MBL was evaluated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting. Dot-N-Man assay yielded MBL with molecular masses ranging between 55 and 320 kDa, comparable to low and high molecular mass forms of MBL. Nonreducing SDS-PAGE showed high molecular mass bands in all AA individuals while bands of 270 and 205 kDa were observed in sera for a number of patients with AO and OO genotypes, respectively. Immunoblotting confirmed the MBL samples obtained from the dot-N-man. These results provide new insights to understand the MBL molecular forms profile in patients infected with HCV- which could be useful in future investigations on the influence of the MBL structure/genotype on both the progression of infection and the response to hepatitis C therapy.


Assuntos
Hepacivirus/imunologia , Hepatite C , Immunoblotting/métodos , Lectina de Ligação a Manose , Polimorfismo Genético , Colódio/química , Feminino , Hepatite C/genética , Hepatite C/imunologia , Humanos , Masculino , Mananas/química , Lectina de Ligação a Manose/genética , Lectina de Ligação a Manose/imunologia
20.
Thromb Res ; 169: 50-56, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30015228

RESUMO

INTRODUCTION: Deep vein thrombosis (DVT) originates in the valvular sinuses of large veins in a local milieu characterized by stasis and severe hypoxia. This may induce complement- and coagulation activation, which potentially increases the risk of venous thromboembolism (VTE). The aim of the present study was to investigate whether the activity of the complement pathways, the level of mannose-binding lectin (MBL) and tissue-factor (TF) induced thrombin generation were associated with risk of unprovoked VTE. METHODS: A case-control study was performed in patients with unprovoked VTE (n = 24) and age- and sex-matched healthy controls (n = 24). Serum complement pathway activity was measured by the total complement screen assay (Wieslab®). MBL was quantified by ELISA. Plasma TF-induced thrombin generation was measured using the CAT-assay. RESULTS: Activity in the highest quintile of the classical pathway was associated with increased odds of unprovoked VTE (OR 4.5, 95% CI; 0.8-24.7). Moreover, MBL deficiency (≤100 ng/ml) was associated with unprovoked VTE (OR 3.5, 95% Cl; 0.8-15.3). VTE patients had shortened TF-induced lag-time (4.8 ±â€¯0.6 min vs. 5.8 ±â€¯2.1 min, p < 0.001) and a higher endogenous thrombin potential (ETP) (1383 ±â€¯267 nM∗h vs. 1265 ±â€¯247 nM∗h, p = 0.07) than controls. No association between the classical complement pathway activity or MBL deficiency, and parameters of TF-induced thrombin generation was observed. CONCLUSION: Our findings suggest that high activity of the classical complement pathway, and MBL deficiency, might be associated with an increased odds of unprovoked VTE, independent of activation of TF-induced coagulation.


Assuntos
Ativação do Complemento , Lectina de Ligação a Manose/deficiência , Lectina de Ligação a Manose/imunologia , Erros Inatos do Metabolismo/complicações , Tromboembolia Venosa/etiologia , Adulto , Idoso , Coagulação Sanguínea , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Lectina de Ligação a Manose/sangue , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/imunologia , Pessoa de Meia-Idade , Trombina/imunologia , Tromboplastina/imunologia , Tromboembolia Venosa/sangue , Tromboembolia Venosa/imunologia
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