Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 279
Filtrar
1.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 31(5): 560-564, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31713396

RESUMO

Hookworm infection remains a global health concern, which threatens human health. Hookworm infection is widely prevalent across the world, notably in tropical and subtropical areas. Recently, with the in-depth study of the immunity of parasitic infections, the"bidirectional effect"of host immune responses induced by helminth infections (including hookworm infections) has become increasingly prominent. On one hand, an immune response is induced in the host to kill the infected worms; on the other hand, the host produces a series of immunological changes that are conducive to the maintenance of parasite survival. The immune state of the host is regulated by various complicated mechanisms, and this may lead to the reduction in the incidence of allergic and autoimmune diseases or alleviation of the disease symptoms, which provide new insights into the management of these allergic and autoimmune diseases. The present article reviewed the advances of host immune responses induced by hook-worm infection and its potential values in the treatment of allergic asthma, inflammatory bowel disease and rheumatoid arthritis.


Assuntos
Infecções por Uncinaria , Interações Hospedeiro-Parasita , Infecções por Uncinaria/imunologia , Interações Hospedeiro-Parasita/imunologia , Humanos , Prevalência , Pesquisa/tendências
2.
Acta Trop ; 196: 52-59, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31078470

RESUMO

INTRODUCTION: HLA-G plays a key role on immune tolerance. Pathogens can induce soluble HLA-G (sHLA-G) production to down-regulate the host immune response, creating a tolerogenic environment favorable for their dissemination. To our knowledge, no study has yet been conducted to assess the relationship between sHLA-G and geohelminth infections. METHODS: The study was conducted in Allada, Southeastern Benin, from 2011-2014. The study population encompassed 400 pregnant women, included before the end of the 28th week of gestation and followed-up until delivery. At two antenatal care visits and at delivery, stool and blood samples were collected. Helminths were diagnosed by means of the Kato-Katz concentration technique. We used quantile regression to analyze the association between helminth infections and sHLA-G levels during pregnancy. RESULTS: sHLA-G levels gradually increased during pregnancy and reached maximal levels at delivery. Prevalence of helminth infections was low, with a majority of hookworm infections. We found significantly more hookworm-infected women above the 80th quantile (Q80) of the distribution of the mean sHLA-G level (p < 0.03, multivariate quantile regression). Considering only women above the Q80 percentile, the mean sHLA-G level was significantly higher in hookworm-infected compared to uninfected women (p = 0.04). CONCLUSION: High levels of sHLA-G were associated with hookworm infection in pregnant women. This result is consistent with the potential involvement of sHLA-G in immune tolerance induced by helminths during pregnancy.


Assuntos
Antígenos HLA-G/metabolismo , Infecções por Uncinaria/metabolismo , Complicações Parasitárias na Gravidez/metabolismo , Adulto , Benin/epidemiologia , Feminino , Antígenos HLA-G/genética , Infecções por Uncinaria/epidemiologia , Infecções por Uncinaria/imunologia , Humanos , Gravidez , Complicações Parasitárias na Gravidez/epidemiologia , Prevalência , Adulto Jovem
3.
Elife ; 72018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30398149

RESUMO

Increases in ocean temperature are associated with changes in the distribution of fish stocks, and the foraging regimes and maternal attendance patterns of marine mammals. However, it is not well understood how these changes affect offspring health and survival. The maternal attendance patterns and immunity of South American fur seals were assessed in a rookery where hookworm disease is the main cause of pup mortality. Pups receiving higher levels of maternal attendance had a positive energy balance and a more reactive immune system. These pups were able to expel hookworms through a specific immune mediated mechanism and survived the infection. Maternal attendance was higher in years with low sea surface temperature, therefore, the mean hookworm burden and mortality increased with sea surface temperature over a 10-year period. We provide a mechanistic explanation regarding how changes in ocean temperature and maternal care affect infectious diseases dynamics in a marine mammal.


Assuntos
Ancylostomatoidea/imunologia , Doenças dos Animais/imunologia , Doenças dos Animais/mortalidade , Organismos Aquáticos , Otárias , Infecções por Uncinaria/veterinária , Animais , Aquecimento Global , Infecções por Uncinaria/imunologia , Infecções por Uncinaria/mortalidade , Comportamento Materno , Oceanos e Mares , Análise de Sobrevida , Temperatura Ambiente
4.
Front Immunol ; 9: 850, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29760697

RESUMO

Gastrointestinal (GI) parasites, hookworms in particular, have evolved to cause minimal harm to their hosts, allowing them to establish chronic infections. This is mediated by creating an immunoregulatory environment. Indeed, hookworms are such potent suppressors of inflammation that they have been used in clinical trials to treat inflammatory bowel diseases (IBD) and celiac disease. Since the recent description of helminths (worms) secreting extracellular vesicles (EVs), exosome-like EVs from different helminths have been characterized and their salient roles in parasite-host interactions have been highlighted. Here, we analyze EVs from the rodent parasite Nippostrongylus brasiliensis, which has been used as a model for human hookworm infection. N. brasiliensis EVs (Nb-EVs) are actively internalized by mouse gut organoids, indicating a role in driving parasitism. We used proteomics and RNA-Seq to profile the molecular composition of Nb-EVs. We identified 81 proteins, including proteins frequently present in exosomes (like tetraspanin, enolase, 14-3-3 protein, and heat shock proteins), and 27 sperm-coating protein-like extracellular proteins. RNA-Seq analysis revealed 52 miRNA species, many of which putatively map to mouse genes involved in regulation of inflammation. To determine whether GI nematode EVs had immunomodulatory properties, we assessed their potential to suppress GI inflammation in a mouse model of inducible chemical colitis. EVs from N. brasiliensis but not those from the whipworm Trichuris muris or control vesicles from grapes protected against colitic inflammation in the gut of mice that received a single intraperitoneal injection of EVs. Key cytokines associated with colitic pathology (IL-6, IL-1ß, IFNγ, and IL-17a) were significantly suppressed in colon tissues from EV-treated mice. By contrast, high levels of the anti-inflammatory cytokine IL-10 were detected in Nb-EV-treated mice. Proteins and miRNAs contained within helminth EVs hold great potential application in development of drugs to treat helminth infections as well as chronic non-infectious diseases resulting from a dysregulated immune system, such as IBD.


Assuntos
Colite/prevenção & controle , Exossomos/imunologia , Vesículas Extracelulares/fisiologia , Infecções por Uncinaria/imunologia , Interações Hospedeiro-Parasita , Nippostrongylus/fisiologia , Animais , Colite/induzido quimicamente , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Imunomodulação , Inflamação/genética , Interleucina-10/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Proteômica , Análise de Sequência de RNA , Trichuris/fisiologia
5.
Parasite Immunol ; 40(2)2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28369954

RESUMO

Hookworm is a major public health concern, yet still relatively little is known about the immunological responses involved in human infection. Animal studies are mainly confined to using the natural rodent helminth Nippostrongylus brasiliensis as this has been proposed as the most accurate model of hookworm infection in the mouse, with both its life cycle and the immune responses it invokes having been extremely well characterized. In this review, we examine the roles that type 2 innate lymphoid cells (ILC2s) play in immunity and host tolerance to hookworm infection, particularly N. brasiliensis. This includes their role in the initiation and regulation of immune responses, as well as in the resolution and limitation of tissue damage required after an infection with a large organism, such as a helminth.


Assuntos
Ancylostomatoidea/imunologia , Citocinas/imunologia , Infecções por Uncinaria/imunologia , Imunidade Inata/imunologia , Nippostrongylus/imunologia , Células Th2/imunologia , Animais , Modelos Animais de Doenças , Feminino , Infecções por Uncinaria/parasitologia , Humanos , Masculino , Camundongos , Doenças Negligenciadas/imunologia , Doenças Negligenciadas/parasitologia
6.
Front Immunol ; 9: 2893, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619265

RESUMO

Soil-transmitted helminths and Mycobacterium tuberculosis frequently coincide geographically and it is hypothesized that gastrointestinal helminth infection may exacerbate tuberculosis (TB) disease by suppression of Th1 and Th17 responses. However, few studies have focused on latent TB infection (LTBI), which predominates globally. We performed a large observational study of healthy adults migrating from Nepal to the UK (n = 645). Individuals were screened for LTBI and gastrointestinal parasite infections. A significant negative association between hookworm and LTBI-positivity was seen (OR = 0.221; p = 0.039). Hookworm infection treatment did not affect LTBI conversions. Blood from individuals with hookworm had a significantly greater ability to control virulent mycobacterial growth in vitro than from those without, which was lost following hookworm treatment. There was a significant negative relationship between mycobacterial growth and eosinophil counts. Eosinophil-associated differential gene expression characterized the whole blood transcriptome of hookworm infection and correlated with improved mycobacterial control. These data provide a potential alternative explanation for the reduced prevalence of LTBI among individuals with hookworm infection, and possibly an anti-mycobacterial role for helminth-induced eosinophils.


Assuntos
Ancylostomatoidea/imunologia , Infecções por Uncinaria/imunologia , Tuberculose Latente/imunologia , Mycobacterium tuberculosis/imunologia , Adolescente , Ancylostomatoidea/fisiologia , Animais , Eosinófilos/imunologia , Eosinófilos/metabolismo , Fezes/microbiologia , Fezes/parasitologia , Perfilação da Expressão Gênica/métodos , Infecções por Uncinaria/genética , Infecções por Uncinaria/parasitologia , Humanos , Tuberculose Latente/genética , Tuberculose Latente/microbiologia , Estudos Longitudinais , Masculino , Mycobacterium tuberculosis/fisiologia , Nepal , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
7.
Parasite Immunol ; 39(10)2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28796897

RESUMO

Approximately one billion people are currently infected with hookworm. Despite its high prevalence and the concomitant immune suppression seen in infected individuals, little research has been performed on the mechanism of immunosuppression by hookworm. Our study focused on characterizing mechanisms utilized by hookworm to suppress the host immune response. Splenocytes and draining lymph node cells from mice injected with hookworm excretory/secretory (ES) proteins showed decreased proliferation in response to both heterologous and species-specific antigens while also having increased nitric oxide secretion. Analysis by fluorescence-activated cell sorting revealed that mice injected with ES had reduced percentages of CD4+ T cells indicating potential effects of ES proteins on lymphocyte homeostasis. Antibody and cytokine response analyses demonstrated that immunization with ES proteins decreased IgG and IgG1 levels, also decreased interleukin (IL-)-4 and increased IL-12 and interferon-gamma (IFN-γ) cytokine production suggesting impairment of B-cell activation and a shift towards a nonhealing IL-12 directed T helper-1 immune response. Together, these data demonstrate for the first time that host immunosuppression by hookworms is orchestrated by ES proteins and provide mechanisms underlying the shift towards a nonhealing Th-1 profile as seen in humans suffering from hookworm infection.


Assuntos
Ancylostomatoidea/imunologia , Antígenos de Helmintos/imunologia , Proteínas de Helminto/imunologia , Infecções por Uncinaria/imunologia , Evasão da Resposta Imune/imunologia , Tolerância Imunológica/imunologia , Células Th1/imunologia , Animais , Anticorpos Anti-Helmínticos/imunologia , Linfócitos B/imunologia , Cricetinae , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Infecções por Uncinaria/parasitologia , Humanos , Imunoglobulina G/imunologia , Interferon gama/biossíntese , Interleucina-12/biossíntese , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Células Th2/imunologia
8.
PLoS Negl Trop Dis ; 11(5): e0005574, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28464026

RESUMO

Necator americanus Glutathione-S-Transferase-1 (Na-GST-1) plays a role in the digestion of host hemoglobin by adult N. americanus hookworms. Vaccination of laboratory animals with recombinant Na-GST-1 is associated with significant protection from challenge infection. Recombinant Na-GST-1 was expressed in Pichia pastoris and adsorbed to aluminum hydroxide adjuvant (Alhydrogel) according to current Good Manufacturing Practice. Two Phase 1 trials were conducted in 142 healthy adult volunteers in the United States and Brazil, first in hookworm-naïve individuals and then in residents of a N. americanus endemic area in Brazil. Volunteers received one of three doses of recombinant Na-GST-1 (10, 30, or 100 µg) adjuvanted with Alhydrogel, adjuvanted with Alhydrogel and co-administered with an aqueous formulation of Glucopyranosyl Lipid A (GLA-AF), or the hepatitis B vaccine. Vaccinations were administered via intramuscular injection on days 0, 56, and 112. Na-GST-1/Alhydrogel was well tolerated in both hookworm-naïve and hookworm-exposed adults, with the most common adverse events being mild to moderate injection site pain and tenderness, and mild headache and nausea; no vaccine-related severe or serious adverse events were observed. Antigen-specific IgG antibodies were induced in a dose-dependent fashion, with increasing levels observed after each vaccination in both trials. The addition of GLA-AF to Na-GST-1/Alhydrogel did not result in significant increases in specific IgG responses. In both the US and Brazil studies, the predominant IgG subclass induced against Na-GST-1 was IgG1, with lesser amounts of IgG3. Vaccination of both hookworm-naïve and hookworm-exposed adults with recombinant Na-GST-1 was safe, well tolerated, and resulted in significant antigen-specific IgG responses. Based on these results, this vaccine will be advanced into clinical trials in children and eventual efficacy studies. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01261130 for the Brazil trial and NCT01385189 for the US trial).


Assuntos
Ancylostomatoidea/imunologia , Antígenos de Helmintos/imunologia , Glutationa Transferase/imunologia , Infecções por Uncinaria/prevenção & controle , Vacinas Sintéticas/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Adulto , Hidróxido de Alumínio/administração & dosagem , Animais , Anticorpos Anti-Helmínticos/sangue , Brasil , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Glucosídeos/administração & dosagem , Voluntários Saudáveis , Vacinas contra Hepatite B/administração & dosagem , Infecções por Uncinaria/imunologia , Humanos , Imunoglobulina G/sangue , Injeções Intramusculares , Lipídeo A/administração & dosagem , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Estados Unidos , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Adulto Jovem
9.
BMC Infect Dis ; 17(1): 253, 2017 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-28390393

RESUMO

BACKGROUND: While the macrophage polarization is well characterized in helminth infections, the natural heterogeneity of monocytes with multiple cell phenotypes might influence the outcome of neglected diseases, such hookworm infection. Here, we report the profile of monocytes in human hookworm infections as a model to study the regulatory subpopulation of monocytes in helminth infections. METHODS: Blood samples were collected from 19 Necator americanus-infected individuals and 13 healthy individuals. Peripheral blood mononuclear cells (PBMCs) were isolated, and immunophenotyping was conducted by flow cytometry. The expressions of genes encoding human nitric oxide synthase (iNOS), interleukin 4 (IL-4), arginase-1 (Arg-1) and glyceraldehyde 3-phosphate dehydrogenase were quantified by qPCR. Plasma levels of IL-4 were determined by sandwich ELISA. Unpaired t-tests or Mann-Whitney tests were used depending on the data distribution. RESULTS: Hookworm infected individuals (HWI) showed a significant increase in the number of monocytes/mm3 (555.2 ± 191.0) compared to that of the non-infected (NI) individuals (120.4 ± 44.7) (p < 0.0001). While the frequencies of CD14+IL-10+ and CD14+IL-12+ cells were significantly reduced in the HWI compared to NI group (p = 0.0289 and p < 0.0001, respectively), the ratio between IL-10/IL-12 producing monocytes was significantly elevated in HWI (p = 0.0004), indicating the potential regulatory activity of these cells. Measurement of IL-4 levels and gene expression of IL-4 and Arg-1 (highly expressed in alternatively activated macrophages) revealed no significant differences between the NI and HWI groups. Interestingly, individuals from the HWI group had higher expression of the iNOS gene (associated with a regulatory profile) (20.27 ± 2.97) compared to the NI group (11.28 ± 1.18, p = 0.0409). Finally, individuals from the HWI group had a significantly higher frequency of CD206+CD23+IL-10+ (7.57 ± 1.96) cells compared to individuals from the NI group (0.35 ± 0.09) (p < 0.001), suggesting that activated monocytes are a potential source of regulatory cytokines during hookworm infection. CONCLUSIONS: Natural hookworm infection induces a high frequency of circulating monocytes that present a regulatory profile and promote the downmodulation of the proinflammatory response, which may contribute to prolonged survival of the parasite in the host.


Assuntos
Infecções por Uncinaria/imunologia , Monócitos/imunologia , Adulto , Idoso , Animais , Arginase/genética , Citocinas/metabolismo , Feminino , Gliceraldeído-3-Fosfato Desidrogenases/genética , Humanos , Imunofenotipagem , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Interleucina-4/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo II/genética , Fragmentos de Peptídeos/genética
11.
Am J Trop Med Hyg ; 95(4): 852-855, 2016 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-27549636

RESUMO

In the United States, infection with Fasciola hepatica has been identified as an emerging disease, primarily in immigrants, refugees, and travelers. The laboratory test of choice for diagnosis of fascioliasis is detection of disease specific antibodies, most commonly uses excretory-secretory antigens for detection of IgG antibodies. Recently, recombinant proteins such as F. hepatica antigen (FhSAP2) have been used to detect IgG antibodies. The glutathione S-transferase (GST)-FhSAP2 recombinant antigen was used to develop Western blot (WB) and fluorescent bead-based (Luminex) assays to detect F. hepatica total IgG and IgG4 antibodies. The sensitivity and specificity of GST-FhSAP2 total IgG and IgG4 WB were similar at 94% and 98%, respectively. For the IgG Luminex assay, the sensitivity and specificity were 94% and 97%, and for the IgG4, the values were 100% and 99%, respectively. In conclusion, the GST-FhSAP2 antigen performs well in several assay formats and can be used for clinical diagnosis.


Assuntos
Anticorpos Anti-Helmínticos/imunologia , Antígenos de Helmintos/imunologia , Fasciola hepatica/imunologia , Fasciolíase/diagnóstico , Imunoglobulina G/imunologia , Animais , Western Blotting , Estudos de Casos e Controles , Doença Crônica , Reações Cruzadas/imunologia , Fasciolíase/imunologia , Imunofluorescência , Glutationa Transferase , Infecções por Uncinaria/imunologia , Humanos , Esquistossomose Japônica/imunologia , Sensibilidade e Especificidade , Testes Sorológicos , Toxocaríase/imunologia
12.
J Immunol ; 196(11): 4632-40, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27183598

RESUMO

How the metabolic demand of parasitism affects immune-mediated resistance is poorly understood. Immunity against parasitic helminths requires M2 cells and IL-13, secreted by CD4(+) Th2 and group 2 innate lymphoid cells (ILC2), but whether certain metabolic enzymes control disease outcome has not been addressed. This study demonstrates that AMP-activated protein kinase (AMPK), a key driver of cellular energy, regulates type 2 immunity and restricts lung injury following hookworm infection. Mice with a selective deficiency in the AMPK catalytic α1 subunit in alveolar macrophages and conventional dendritic cells produced less IL-13 and CCL17 and had impaired expansion of ILC2 in damaged lung tissue compared with wild-type controls. Defective type 2 responses were marked by increased intestinal worm burdens, exacerbated lung injury, and increased production of IL-12/23p40, which, when neutralized, restored IL-13 production and improved lung recovery. Taken together, these data indicate that defective AMPK activity in myeloid cells negatively impacts type 2 responses through increased IL-12/23p40 production. These data support an emerging concept that myeloid cells and ILC2 can coordinately regulate tissue damage at mucosal sites through mechanisms dependent on metabolic enzyme function.


Assuntos
Proteínas Quinases Ativadas por AMP/imunologia , Infecções por Uncinaria/imunologia , Imunidade Inata/imunologia , Interleucina-12/imunologia , Interleucina-23/imunologia , Lesão Pulmonar/imunologia , Células Mieloides/imunologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Infecções por Uncinaria/metabolismo , Lesão Pulmonar/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/metabolismo
13.
Sci Rep ; 5: 13797, 2015 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-26381211

RESUMO

The intestinal microbiota plays a critical role in the development of the immune system. Recent investigations have highlighted the potential of helminth therapy for treating a range of inflammatory disorders, including celiac disease (CeD); however, the mechanisms by which helminths modulate the immune response of the human host and ameliorate CeD pathology are unknown. In this study, we investigated the potential role of alterations in the human gut microbiota in helminth-mediated suppression of an inflammatory disease. We assessed the qualitative and quantitative changes in the microbiota of human volunteers with CeD prior to and following infection with human hookworms, and following challenge with escalating doses of dietary gluten. Experimental hookworm infection of the trial subjects resulted in maintenance of the composition of the intestinal flora, even after a moderate gluten challenge. Notably, we observed a significant increase in microbial species richness over the course of the trial, which could represent a potential mechanism by which hookworms can regulate gluten-induced inflammation and maintain intestinal immune homeostasis.


Assuntos
Ancylostomatoidea , Biodiversidade , Doença Celíaca/etiologia , Microbioma Gastrointestinal , Glutens/metabolismo , Infecções por Uncinaria , Ancylostomatoidea/imunologia , Animais , Estudos de Casos e Controles , Doença Celíaca/terapia , Fezes/microbiologia , Microbioma Gastrointestinal/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Infecções por Uncinaria/imunologia , Humanos , Imunomodulação , Metagenoma , Metagenômica/métodos
14.
Ann Parasitol ; 61(2): 125-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26342510

RESUMO

Ancylostomum caninum larvae cause damage to the host at the point of entry through the skin leaving a wound vulnerable to secondary infections. As the larvae migrate through the skin an inflammatory response, dermatitis, is often stimulated which can be exacerbated in hosts which give hypersensitive responses. We assessed a 44-year-old man with contact dermatitis diagnosed as nickel allergy but caused by Ancylostoma caninum infection.


Assuntos
Ancylostoma , Dermatite de Contato/parasitologia , Infecções por Uncinaria/imunologia , Adulto , Animais , Antinematódeos/uso terapêutico , Dermatite de Contato/tratamento farmacológico , Dermatite de Contato/patologia , Fezes/parasitologia , Infecções por Uncinaria/tratamento farmacológico , Infecções por Uncinaria/patologia , Humanos , Masculino , Mebendazol/uso terapêutico
15.
ChemMedChem ; 10(10): 1647-54, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26269385

RESUMO

Necator americanus (hookworm) infects over half a billion people worldwide. Anthelminthic drugs are commonly used to treat the infection; however, vaccination is a more favorable strategy to combat this parasite. We designed new B-cell peptide epitopes based on the aspartic protease of N. americanus (Na-APR-1). The peptides were conjugated to self-adjuvanting lipid core peptide (LCP) systems via stepwise solid-phase peptide synthesis (SPPS) and copper catalyst azide-alkyne cycloaddition (CuAAC) reactions. The LCP vaccine candidates were able to self-assemble into nanoparticles, were administered to mice without the use of additional adjuvant, and generated antibodies that recognized the parent epitope. However, only one LCP derivative was able to produce a high titer of antibodies specific to Na-APR-1; circular dichroism analyses of this compound showed a ß-sheet conformation for the incorporated epitope. This study provides important insight in epitope and delivery system design for the development of a vaccine against hookworm infections.


Assuntos
Ácido Aspártico Proteases/imunologia , Infecções por Uncinaria/parasitologia , Lipopeptídeos/imunologia , Nanopartículas/química , Necator americanus/imunologia , Vacinas Sintéticas/química , Vacinas Sintéticas/imunologia , Animais , Anticorpos Anti-Helmínticos/imunologia , Ácido Aspártico Proteases/química , Feminino , Infecções por Uncinaria/imunologia , Lipopeptídeos/química , Camundongos , Camundongos Endogâmicos BALB C , Conformação Molecular , Necator americanus/enzimologia , Tamanho da Partícula , Relação Estrutura-Atividade
16.
J Helminthol ; 89(5): 540-4, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25850789

RESUMO

Approximately 440 million people globally are afflicted by hookworm disease, one of the 17 WHO-recognized neglected tropical diseases (NTDs). The iron-deficiency anaemia attributed to this disease contributes to at least 3.2 million disability-adjusted life years (DALYs) according to the Global Burden of Disease Study 2010. The current WHO-recommended control strategies rely primarily on mass drug administration or preventive chemotherapy. However, evidence is starting to accumulate confirming that preventive chemotherapy alone will not be sufficient to reduce the reinfection rates of hookworm, especially in areas of heavy transmission. The global health and research community is currently building a consensus stressing the need for the advancement of research and innovation to bridge the gaps and identify new public health interventions for diseases such as hookworm and other NTDs. This paper presents the strategies used by the Sabin Vaccine Institute Product Development Partnership (Sabin PDP) in their ongoing endeavour for the development of a human hookworm vaccine. Recent updates and the current prospects for success of an effective human hookworm vaccine, as a new technology to be linked to or combined with drug interventions, are presented.


Assuntos
Ancylostomatoidea/imunologia , Infecções por Uncinaria/prevenção & controle , Vacinas/administração & dosagem , Animais , Infecções por Uncinaria/imunologia , Infecções por Uncinaria/parasitologia , Humanos , Doenças Negligenciadas/imunologia , Doenças Negligenciadas/parasitologia , Doenças Negligenciadas/prevenção & controle , Vacinação , Vacinas/genética , Vacinas/imunologia
17.
Expert Rev Gastroenterol Hepatol ; 9(7): 913-27, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25864708

RESUMO

Celiac disease (CD) is a chronic, small intestinal, immune-mediated enteropathy triggered by exposure to dietary gluten in genetically susceptible individuals. Currently, lifelong adherence to a gluten-free diet (GFD) is the only available treatment. However, GFD alone is not sufficient to relieve symptoms, control small intestinal inflammation and prevent long-term complications in many patients. The GFD has its challenges including issues related to adherence, lifestyle restrictions and cost. As a result, there is growing interest in and a need for non-dietary therapies to manage this condition. In recent years, different targets in the immune-mediated cascade of CD have been identified in clinical and pre-clinical trials for potential therapies. This review will discuss the latest non-dietary therapies in CD, including endopeptidases, modulators of enterocyte tight junctions and agents involved in gluten tolerization and immunomodulation. We will also discuss the potential implications of approved therapeutics on CD clinical practice.


Assuntos
Doença Celíaca/imunologia , Doença Celíaca/terapia , Endopeptidases/uso terapêutico , Glutens/imunologia , Imunomodulação , Terapia Combinada , Dieta Livre de Glúten , Descoberta de Drogas , Enterócitos/efeitos dos fármacos , Proteínas de Ligação ao GTP/antagonistas & inibidores , Glutens/metabolismo , Infecções por Uncinaria/imunologia , Humanos , Terapia de Alvo Molecular , Oligopeptídeos/uso terapêutico , Probióticos/uso terapêutico , Junções Íntimas/efeitos dos fármacos , Transglutaminases/antagonistas & inibidores , Vacinas/uso terapêutico
18.
Am J Trop Med Hyg ; 92(5): 945-51, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25758654

RESUMO

In a study of children having polyparasitic infections in a Schistosoma haematobium-endemic area, we examined the hypothesis that S. haematobium-positive children, compared with S. haematobium-negative children (anti-soluble worm antigen preparation [SWAP] negative and egg negative) have increased systemic production of pro-inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor [TNF]-α) and decreased down-regulatory IL-10. A total of 804 children, 2-19 years of age, were surveyed between July and December 2009 and tested for S. haematobium, Plasmodium falciparum, filariasis, and soil-transmitted helminth infections. Plasma levels of IL-6, TNF-α, and IL-10 were compared for S. haematobium-positive and S. haematobium-negative children, adjusting for malaria, filaria, and hookworm co-infections, and for nutritional status, age group, sex, and geographic location. IL-10 was significantly elevated among children infected with S. haematobium, showing bimodal peaks in 7-8 and 13-14 years age groups. IL-10 was also higher among children who were acutely malnourished, whereas IL-10 levels were lower in the presence of S. haematobium-filaria co-infection. After adjustment for co-factors, IL-6 was significantly elevated among children of 5-6 years and among those with P. falciparum infection. Lower levels of IL-6 were found in malaria-hookworm co-infection. High levels of TNF-α were found in children aged 11-12 years regardless of infection status. In addition, village of residence was a strong predictor of IL-6 and IL-10 plasma levels. In adolescent children infected with S. haematobium, there is an associated elevation in circulating IL-10 that may reduce the risk of later morbidity. Although we did not find a direct link between S. haematobium infection and circulating pro-inflammatory IL-6 and TNF-α levels, future T-cell stimulation studies may provide more conclusive linkages between infection and cytokine responses in settings that are endemic for multiple parasites and multiple co-infections.


Assuntos
Citocinas/sangue , Infecções por Uncinaria/imunologia , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Schistosoma haematobium/imunologia , Esquistossomose Urinária/imunologia , Adolescente , Distribuição por Idade , Animais , Anticorpos Anti-Helmínticos/sangue , Anticorpos Antiprotozoários/sangue , Criança , Pré-Escolar , Coinfecção , Feminino , Geografia , Infecções por Uncinaria/epidemiologia , Infecções por Uncinaria/parasitologia , Humanos , Interleucina-10/sangue , Interleucina-6/sangue , Quênia/epidemiologia , Malária Falciparum/epidemiologia , Malária Falciparum/parasitologia , Masculino , Esquistossomose Urinária/epidemiologia , Esquistossomose Urinária/parasitologia , Fator de Necrose Tumoral alfa/sangue , Adulto Jovem
19.
Am J Clin Nutr ; 101(3): 462-70, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25733630

RESUMO

BACKGROUND: In sub-Saharan Africa, parasitic diseases and low bioavailable iron intake are major causes of anemia. Anemia results from inflammation, preventing iron recycling and decreasing dietary iron absorption. Hookworm, Plasmodium, and Schistosoma infections contribute to anemia, but their influence on dietary iron absorption and recycling is unknown. OBJECTIVE: The objective was to measure inflammation biomarkers, hepcidin, iron absorption, and utilization pre- and posttreatment in children with afebrile malaria, hookworm, and Schistosoma haematobium infection. DESIGN: Ivorian children aged 11-17 y with afebrile Plasmodium falciparum (n = 17), hookworm (n = 16), or S. haematobium infection (n = 8) consumed a syrup containing 3 mg 57Fe as ferrous sulfate and received an intravenous infusion of 50 µg 58Fe as ferrous citrate. Children were treated for their respective infection, and the iron studies were repeated 4 wk later. Iron and inflammation biomarkers and hepcidin were measured. RESULTS: Geometric mean iron absorptions in the afebrile malaria and hookworm groups were 12.9% and 32.2% (P < 0.001) before treatment and 23.6% and 30.0% (P = 0.113) after treatment, respectively. Treatment of afebrile malaria reduced inflammation (P < 0.001) and serum hepcidin (P = 0.004) and improved iron absorption (P = 0.003). Treatment of hookworm infection neither affected inflammation biomarkers nor altered iron absorption. Similarly, there was a lack of treatment effects in the S. haematobium-infected group; however, the small sample size limits conclusions. Geometric mean iron utilization ranged between 79.1% and 88.0% in the afebrile malaria and hookworm groups with no significant differences pre- and posttreatment. CONCLUSIONS: In school-age children, hookworm infection does not produce inflammation or increase serum hepcidin, and it does not influence iron absorption or utilization. In contrast, afebrile malaria causes inflammation, increases hepcidin, and reduces iron absorption but not utilization. These findings provide insights into the iron metabolism and the etiology of anemia in parasitic infections.


Assuntos
Anemia Ferropriva/etiologia , Regulação para Baixo , Infecções por Uncinaria/metabolismo , Absorção Intestinal , Mucosa Intestinal/metabolismo , Ferro na Dieta/metabolismo , Malária Falciparum/metabolismo , Adolescente , Anemia Ferropriva/prevenção & controle , Animais , Anti-Helmínticos/uso terapêutico , Antimaláricos/uso terapêutico , Biomarcadores/sangue , Criança , Estudos de Coortes , Costa do Marfim , Regulação para Baixo/efeitos dos fármacos , Feminino , Hepcidinas/sangue , Infecções por Uncinaria/tratamento farmacológico , Infecções por Uncinaria/imunologia , Infecções por Uncinaria/fisiopatologia , Humanos , Mediadores da Inflamação/sangue , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/parasitologia , Isótopos de Ferro , Malária Falciparum/tratamento farmacológico , Malária Falciparum/imunologia , Malária Falciparum/fisiopatologia , Masculino , Esquistossomose Urinária/tratamento farmacológico , Esquistossomose Urinária/imunologia , Esquistossomose Urinária/metabolismo , Esquistossomose Urinária/fisiopatologia
20.
J Infect Dis ; 211(3): 416-25, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25139017

RESUMO

Na-ASP-2 is an efficacious hookworm vaccine antigen. However, despite elucidation of its crystal structure and studies addressing its immunobiology, the function of Na-ASP-2 has remained elusive. We probed a 9000-protein human proteome microarray with Na-ASP-2 and showed binding to CD79A, a component of the B-cell antigen receptor complex. Na-ASP-2 bound to human B lymphocytes ex vivo and downregulated the transcription of approximately 1000 B-cell messenger RNAs (mRNAs), while only approximately 100 mRNAs were upregulated, compared with control-treated cells. The expression of a range of molecules was affected by Na-ASP-2, including factors involved in leukocyte transendothelial migration pathways and the B-cell signaling receptor pathway. Of note was the downregulated transcription of lyn and pi3k, molecules that are known to interact with CD79A and control B-cell receptor signaling processes. Together, these results highlight a previously unknown interaction between a hookworm-secreted protein and B cells, which has implications for helminth-driven immunomodulation and vaccine development. Further, the novel use of human protein microarrays to identify host-pathogen interactions, coupled with ex vivo binding studies and subsequent analyses of global gene expression in human host cells, demonstrates a new pipeline by which to explore the molecular basis of infectious diseases.


Assuntos
Ancylostomatoidea/imunologia , Linfócitos B/imunologia , Infecções por Uncinaria/imunologia , Receptores de Células Precursoras de Linfócitos B/imunologia , Proteoma/imunologia , Proteínas Recombinantes/imunologia , Transdução de Sinais/imunologia , Adulto , Animais , Antígenos de Helmintos/imunologia , Antígenos CD79/imunologia , Células Cultivadas , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Proteínas de Helminto/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Leucócitos Mononucleares/imunologia , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/imunologia , Análise Serial de Proteínas/métodos , Proteoma/genética , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Transdução de Sinais/genética , Transcrição Genética/genética , Transcrição Genética/imunologia , Regulação para Cima/genética , Regulação para Cima/imunologia , Quinases da Família src/genética , Quinases da Família src/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA