RESUMEN
B-cells play a critical role in the formation of immune responses against pathogens by acting as antigen-presenting cells, by modulating immune responses and by generating immune memory and antibody responses. Here, we studied B-cell subset distributions between regions with higher and lower microbial exposure, i.e. by comparing peripheral blood B-cells from people living in Indonesia or Ghana to those from healthy Dutch residents using a 36-marker mass cytometry panel. By applying an unbiased multidimensional approach, we observed differences in the balance between the naïve and memory compartments, with higher CD11c+ and double negative (DN-IgDnegCD27neg) memory (M)B-cells in individuals from rural tropical areas, and conversely lower naïve B-cells compared to residents from an area with less pathogen exposure. Furthermore, characterization of total B-cell populations, CD11c+, DN and Breg cells showed the emergence of specific memory clusters in individuals living in rural tropical areas. Some of these differences were more pronounced in children compared to adults and suggest that a higher microbial exposure accelerates memory B cell formation, which 'normalizes' with age.
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Schistosomiasis is an infection caused by contact with Schistosoma-contaminated water and affects more than 230 million people worldwide with varying morbidity. The roles of T helper 2 (TH2) cells and regulatory immune responses in chronic infection are well documented, but less is known about human immune responses during acute infection. Here, we comprehensively map immune responses during controlled human Schistosoma mansoni infection using male or female cercariae. Immune responses to male or female parasite single-sex infection were comparable. An early TH1-biased inflammatory response was observed at week 4 after infection, which was particularly apparent in individuals experiencing symptoms of acute schistosomiasis. By week 8 after infection, inflammatory responses were followed by an expansion of TH2 and regulatory cell subsets. This study demonstrates the shift from TH1 to both TH2 and regulatory responses, typical of chronic schistosomiasis, in the absence of egg production and provides immunological insight into the clinical manifestations of acute schistosomiasis.
Asunto(s)
Schistosoma mansoni , Esquistosomiasis mansoni , Células Th2 , Humanos , Femenino , Animales , Masculino , Células Th2/inmunología , Esquistosomiasis mansoni/inmunología , Schistosoma mansoni/inmunología , Inflamación/inmunología , Adulto , Células TH1/inmunología , Adulto Joven , Adolescente , Citocinas/inmunología , Esquistosomiasis/inmunología , Esquistosomiasis/parasitologíaRESUMEN
Hookworm infection remains a significant public health concern, particularly in low- and middle-income countries, where mass drug administration has not stopped reinfection. Developing a vaccine is crucial to complement current control measures, which necessitates a thorough understanding of host immune responses. By leveraging controlled human infection models and high-dimensional immunophenotyping, here we investigated the immune remodeling following infection with 50 Necator americanus L3 hookworm larvae in four naïve volunteers over two years of follow-up and compared the profiles with naturally infected populations in endemic areas. Increased plasmacytoid dendritic cell frequency and diminished responsiveness to Toll-like receptor 7/8 ligand were observed in both controlled and natural infection settings. Despite the increased CD45RA+ regulatory T cell (Tregs) frequencies in both settings, markers of Tregs function, including inducible T-cell costimulatory (ICOS), tumor necrosis factor receptor 2 (TNFR2), and latency-associated peptide (LAP), as well as in vitro Tregs suppressive capacity were higher in natural infections. Taken together, this study provides unique insights into the immunological trajectories following a first-in-life hookworm infection compared to natural infections.
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Células Dendríticas , Necator americanus , Linfocitos T Reguladores , Humanos , Linfocitos T Reguladores/inmunología , Animales , Células Dendríticas/inmunología , Necator americanus/inmunología , Masculino , Adulto , Necatoriasis/inmunología , Infecciones por Uncinaria/inmunología , Infecciones por Uncinaria/parasitología , Femenino , Enfermedades Endémicas , Adulto Joven , InmunofenotipificaciónRESUMEN
BACKGROUND: Vaccine development against hookworm is hampered by the absence of the development of protective immunity in populations repeatedly exposed to hookworm, limiting identification of mechanisms of protective immunity and new vaccine targets. Immunisation with attenuated larvae has proven effective in dogs and partial immunity has been achieved using an irradiated larvae model in healthy volunteers. We aimed to investigate the protective efficacy of immunisation with short-term larval infection against hookworm challenge. METHODS: We did a single-centre, placebo-controlled, randomised, controlled, phase 1 trial at Leiden University Medical Center (Leiden, Netherlands). Healthy volunteers (aged 18-45 years) were recruited using advertisements on social media and in publicly accessible areas. Volunteers were randomly assigned (2:1) to receive three short-term infections with 50 infectious Necator americanus third-stage filariform larvae (50L3) or placebo. Infection was abrogated with a 3-day course of albendazole 400 mg, 2 weeks after each exposure. Subsequently all volunteers were challenged with two doses of 50L3 at a 2-week interval. The primary endpoint was egg load (geometric mean per g faeces) measured weekly between weeks 12 and 16 after first challenge, assessed in the per-protocol population, which included all randomly assigned volunteers with available data on egg counts at week 12-16 after challenge. This study is registered with ClinicalTrials.gov, NCT03702530. FINDINGS: Between Nov 8 and Dec 14, 2018, 26 volunteers were screened, of whom 23 enrolled in the trial. The first immunisation was conducted on Dec 18, 2018. 23 volunteers were randomly assigned (15 to the intervention group and eight to the placebo group). Egg load after challenge was lower in the intervention group than the placebo group (geometric mean 571 eggs per g [range 372-992] vs 873 eggs per g [268-1484]); however, this difference was not statistically significant (p=0·10). Five volunteers in the intervention group developed a severe skin rash, which was associated with 40% reduction in egg counts after challenge (geometric mean 742 eggs per g [range 268-1484] vs 441 eggs per g [range 380-520] after challenge; p=0·0025) and associated with higher peak IgG1 titres. INTERPRETATION: To our knowledge, this is the first study to describe a protective effect of short-term exposure to hookworm larvae and show an association with skin response, eosinophilic response, and IgG1. These findings could inform future hookworm vaccine development. FUNDING: Dioraphte Foundation.
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Infecciones por Uncinaria , Necator americanus , Humanos , Animales , Perros , Voluntarios Sanos , Países Bajos , Infecciones por Uncinaria/tratamiento farmacológico , Infecciones por Uncinaria/prevención & control , Inmunoglobulina G , LarvaRESUMEN
BACKGROUND: A controlled human infection model for schistosomiasis (CHI-S) can speed up vaccine development and provides insight into early immune responses following schistosome exposure. Recently, we established CHI-S model using single-sex male-only Schistosoma mansoni (Sm) cercariae in Schistosoma-naïve individuals. Given important differences in antigenic profile and human immune responses to schistosomes of different sex, we pioneered a single-sex female-only CHI-S model for future use in vaccine development. METHODS: We exposed 13 healthy, Schistosoma-naïve adult participants to 10 (n = 3) or 20 (n = 10) female cercariae and followed for 20 weeks, receiving treatment with praziquantel (PZQ) 60 mg/kg at week 8 and 12 after exposure. FINDINGS: The majority (11/13) participants reported rash and/or itch at the site of exposure, 5/13 had transient symptoms of acute schistosomiasis. Exposure to 20 cercariae led to detectable infection, defined as serum circulating anodic antigen levels >1.0 pg/mL, in 6/10 participants. Despite two rounds of PZQ treatment, 4/13 participants showed signs of persistent infection. Additional one- or three-day PZQ treatment (1 × 60 mg/kg and 3 × 60 mg/kg) or artemether did not result in cure, but over time three participants self-cured. Antibody, cellular, and cytokine responses peaked at week 4 post infection, with a mixed Th1, Th2, and regulatory profile. Cellular responses were (most) discriminative for symptoms. INTERPRETATION: Female-only infections exhibit similar clinical and immunological profiles as male-only infections but are more resistant to PZQ treatment. This limits future use of this model and may have important implications for disease control programs. FUNDING: European Union's Horizon 2020 (grant no. 81564).
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Antihelmínticos , Esquistosomiasis mansoni , Adulto , Animales , Humanos , Masculino , Femenino , Esquistosomiasis mansoni/tratamiento farmacológico , Voluntarios Sanos , Schistosoma mansoni , Praziquantel/farmacología , Praziquantel/uso terapéutico , Citocinas , Antihelmínticos/farmacología , Antihelmínticos/uso terapéuticoRESUMEN
Controlled human malaria infection (CHMI) using cryopreserved non-attenuated Plasmodium falciparum sporozoites (PfSPZ) offers a unique opportunity to investigate naturally acquired immunity (NAI). By analyzing blood samples from 5 malaria-naïve European and 20 African adults with lifelong exposure to malaria, before, 5, and 11 days after direct venous inoculation (DVI) with SanariaR PfSPZ Challenge, we assessed the immunological patterns associated with control of microscopic and submicroscopic parasitemia. All (5/5) European individuals developed parasitemia as defined by thick blood smear (TBS), but 40% (8/20) of the African individuals controlled their parasitemia, and therefore remained thick blood smear-negative (TBS- Africans). In the TBS- Africans, we observed higher baseline frequencies of CD4+ T cells producing interferon-gamma (IFNγ) that significantly decreased 5 days after PfSPZ DVI. The TBS- Africans, which represent individuals with either very strong and rapid blood-stage immunity or with immunity to liver stages, were stratified into subjects with sub-microscopic parasitemia (TBS-PCR+) or those with possibly sterilizing immunity (TBS-PCR-). Higher frequencies of IFNγ+TNF+CD8+ γδ T cells at baseline, which later decreased within five days after PfSPZ DVI, were associated with those who remained TBS-PCR-. These findings suggest that naturally acquired immunity is characterized by different cell types that show varying strengths of malaria parasite control. While the high frequencies of antigen responsive IFNγ+CD4+ T cells in peripheral blood keep the blood-stage parasites to a sub-microscopic level, it is the IFNγ+TNF+CD8+ γδ T cells that are associated with either immunity to the liver-stage, or rapid elimination of blood-stage parasites.
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Vacunas contra la Malaria , Malaria Falciparum , Malaria , Adulto , Animales , Gabón , Humanos , Interferón gamma , Malaria Falciparum/parasitología , Parasitemia/parasitología , Plasmodium falciparum , Esporozoítos , VoluntariosRESUMEN
Systemic immune cell dynamics during coronavirus disease 2019 (COVID-19) are extensively documented, but these are less well studied in the (upper) respiratory tract, where severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates1-6. Here, we characterized nasal and systemic immune cells in individuals with COVID-19 who were hospitalized or convalescent and compared the immune cells to those seen in healthy donors. We observed increased nasal granulocytes, monocytes, CD11c+ natural killer (NK) cells and CD4+ T effector cells during acute COVID-19. The mucosal proinflammatory populations positively associated with peripheral blood human leukocyte antigen (HLA)-DRlow monocytes, CD38+PD1+CD4+ T effector (Teff) cells and plasmablasts. However, there was no general lymphopenia in nasal mucosa, unlike in peripheral blood. Moreover, nasal neutrophils negatively associated with oxygen saturation levels in blood. Following convalescence, nasal immune cells mostly normalized, except for CD127+ granulocytes and CD38+CD8+ tissue-resident memory T cells (TRM). SARS-CoV-2-specific CD8+ T cells persisted at least 2 months after viral clearance in the nasal mucosa, indicating that COVID-19 has both transient and long-term effects on upper respiratory tract immune responses.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Nasofaringe/inmunología , Nariz/citología , Mucosa Respiratoria/inmunología , SARS-CoV-2/inmunología , Anticuerpos Antivirales/sangre , COVID-19/inmunología , COVID-19/patología , Granulocitos/inmunología , Antígenos HLA-DR/metabolismo , Humanos , Células Asesinas Naturales/inmunología , Células T de Memoria/inmunología , Monocitos/inmunología , Nasofaringe/citología , Nasofaringe/virología , Neutrófilos/inmunología , Nariz/inmunología , Nariz/virología , Estudios Prospectivos , Mucosa Respiratoria/citología , Mucosa Respiratoria/virologíaRESUMEN
BACKGROUND: Hookworm is a major contributor to worldwide disease burden with over 230 million people infected. It has been identified as one of the Neglected Tropical Diseases that can be controlled and even eliminated through mass drug administration and other effective interventions. Mathematical models have shown that hookworm can only be eliminated via a vaccine. Controlled Hookworm Human Infection (CHHI) models can facilitate rapid development of vaccines and drugs. METHODS: As a first step towards the establishment of CHHI in Africa, we held a stakeholders meeting in Lamberene, Gabon from 10 to 11 November 2019. RESULTS: Discussions revolved around the roles of the different regulatory institutions concerned; the need to strengthen existing regulatory capacity and the role of legislation; creating Gabon-specific ethical guidelines to govern Controlled Human Infection (CHI) studies; development of a study protocol; consideration of cultural and social peculiarities; the need for regular joint review meetings between interested parties throughout the process of protocol implementation; and participant compensation. Moreover, operational considerations concerning the introduction of CHHI in Gabon include the use of the local strain of hookworm for the challenge infections, capacity building for the local production of challenge material, and the establishment of adequate quality assurance procedures. CONCLUSION: The workshop addressed several of the anticipated hurdles to the successful implementation of CHHI in Gabon. It is our aim that this report will stimulate interest in the implementation of this model in the sub-Saharan African setting.
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Controlled human infections provide opportunities to study the interaction between the immune system and malaria parasites, which is essential for vaccine development. Here, we compared immune signatures of malaria-naive Europeans and of Africans with lifelong malaria exposure using mass cytometry, RNA sequencing and data integration, before and 5 and 11 days after venous inoculation with Plasmodium falciparum sporozoites. We observed differences in immune cell populations, antigen-specific responses and gene expression profiles between Europeans and Africans and among Africans with differing degrees of immunity. Before inoculation, an activated/differentiated state of both innate and adaptive cells, including elevated CD161+CD4+ T cells and interferon-γ production, predicted Africans capable of controlling parasitemia. After inoculation, the rapidity of the transcriptional response and clusters of CD4+ T cells, plasmacytoid dendritic cells and innate T cells were among the features distinguishing Africans capable of controlling parasitemia from susceptible individuals. These findings can guide the development of a vaccine effective in malaria-endemic regions.
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Inmunidad Adaptativa/inmunología , Susceptibilidad a Enfermedades/inmunología , Malaria Falciparum/inmunología , Plasmodium falciparum/inmunología , Inmunidad Adaptativa/genética , Adolescente , Adulto , Anticuerpos Antiprotozoarios/sangre , Anticuerpos Antiprotozoarios/inmunología , Antígenos de Protozoos/inmunología , Población Negra/genética , Células Dendríticas/inmunología , Susceptibilidad a Enfermedades/sangre , Susceptibilidad a Enfermedades/parasitología , Femenino , Voluntarios Sanos , Interacciones Huésped-Parásitos/genética , Interacciones Huésped-Parásitos/inmunología , Humanos , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Interferón gamma/metabolismo , Malaria Falciparum/sangre , Malaria Falciparum/parasitología , Masculino , RNA-Seq , Análisis de Sistemas , Linfocitos T/inmunología , Linfocitos T/metabolismo , Población Blanca/genética , Adulto JovenRESUMEN
BACKGROUND: Controlled human hookworm infections could significantly contribute to the development of a hookworm vaccine. However, current models are hampered by low and unstable egg output, reducing generalizability and increasing sample sizes. This study aims to investigate the safety, tolerability, and egg output of repeated exposure to hookworm larvae. METHODS: Twenty-four healthy volunteers were randomized, double-blindly, to 1, 2, or 3 doses of 50 Necator americanus L3 larvae at 2-week intervals. Volunteers were monitored weekly and were treated with albendazole at week 20. RESULTS: There was no association between larval dose and number or severity of adverse events. Geometric mean egg loads stabilized at 697, 1668, and 1914 eggs per gram feces for the 1â ×â 50L3, 2â ×â 50L3, and 3â ×â 50L3 group, respectively. Bayesian statistical modeling showed that egg count variability relative to the mean was reduced with a second infectious dose; however, the third dose did not increase egg load or decrease variability. We therefore suggest 2â ×â 50L3 as an improved challenge dose. Model-based simulations indicates increased frequency of stool sampling optimizes the power of hypothetical vaccine trials. CONCLUSIONS: Repeated infection with hookworm larvae increased egg counts to levels comparable to the field and reduced relative variability in egg output without aggravating adverse events. CLINICAL TRIALS REGISTRATION: NCT03257072.
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Infecciones por Uncinaria , Recuento de Huevos de Parásitos , Albendazol/uso terapéutico , Animales , Teorema de Bayes , Heces/parasitología , Infecciones por Uncinaria/tratamiento farmacológico , Humanos , Larva , Necator americanusRESUMEN
Four healthy volunteers were infected with 50 Necator americanus infective larvae (L3) in a controlled human hookworm infection trial and followed for 52 weeks. The kinetics of fecal egg counts in volunteers was assessed with Bayesian multilevel analysis, which revealed an increase between weeks 7 and 13, followed by an egg density plateau of about 1000 eggs/g of feces. Variation in egg counts was minimal between same-day measurements but varied considerably between days, particularly during the plateau phase. These analyses pave the way for the controlled human hookworm model to accelerate drug and vaccine efficacy studies.
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Larva/fisiología , Modelos Biológicos , Necator americanus/citología , Necator americanus/fisiología , Necatoriasis/fisiopatología , Animales , Teorema de Bayes , Recuento de Células Sanguíneas , Eosinófilos , Heces/parasitología , Femenino , Estudios de Seguimiento , Voluntarios Sanos , Humanos , Cinética , Masculino , Necatoriasis/parasitología , Adulto JovenRESUMEN
Schistosoma mansoni is a parasitic helminth that infects millions of people mostly in tropical parts of the world. Different life cycle stages of S.mansoni, that infect or develop in the human host, promote distinct immune responses and are known for their ability to modulate host immune responses. However, the molecular mechanisms through which the parasites interact with, and modulate the host immune system remain incompletely understood. Despite the well-known ability of various lipids to modulate immune responses, a comprehensive analysis of the lipidome of the different life cycle stages has not been performed. Using three complementary MS-based platforms to detect and quantify around 350 lipid species, we here characterized the lipid profiles of S. mansoni cercariae, worms and eggs, as well as extracts and excretory/secretory (ES) products of different life cycle stages of S. mansoni. We identified life cycle stage specific signatures of lipid classes of which cercariae were found to have the most distinct profile. Moreover, we detected several immunolomodulatory oxylipids in the different life cycle stages. Specifically, prostaglandins were found to be most highly enriched in egg preparations, while resolvins were specifically detected in cercariae. Together, the generation of this detailed lipid database of the different life cycle stages of S. mansoni will not only be important for a better understanding of the biology of the parasite itself but also of host-parasite interactions and how that could result in immunomodulation.
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Lípidos/inmunología , Schistosoma mansoni/inmunología , Animales , Interacciones Huésped-Parásitos , Humanos , InmunomodulaciónRESUMEN
BACKGROUND: Chronic helminth infections typically induce an immunoregulatory environment, with markedly reduced immune responses to both parasite-specific and unrelated bystander antigens. Here we tested whether these changes are also observed in human infections with Mansonella ozzardi, a neglected filarial nematode widely distributed across Latin America. METHODS: CD4+ T cell populations from microfilaremic (Fil+) and uninfected (Fil-) inhabitants in M. ozzardi-endemic riverine communities in Brazil were characterized by flow cytometry analysis. Plasma concentrations of a wide range of cytokines and chemokines were measured. We examined whether M. ozzardi infection is associated with suppressed in vitro lymphoproliferative and inflammatory cytokine responses upon stimulation with filarial antigen, unrelated antigens or mitogens. PRINCIPAL FINDINGS/CONCLUSIONS: Fil+ subjects had lower plasma levels of selected inflammatory cytokines, such as TNF-α, IL-8, and IL-6, than their Fil- counterparts. However, we found no evidence for attenuated T-cell responses to filarial antigens or co-endemic pathogens, such as malaria parasites and Toxoplasma gondii. CD4+ T cells expressing CD39, an ectonucleosidase involved in the generation of the anti-inflammatory molecule adenosine, were increased in frequency in Fil+ subjects, compared to uninfected controls. Significantly, such an expansion was directly proportional to microfilarial loads. Surprisingly, CD39 blocking with a neutralizing antibody suppressed antigen-driven lymphoproliferation in vitro, while decreasing inflammatory cytokine responses, in Fil+ and Fil- individuals. These findings suggest that circulating CD4+ CD39+ T cells comprise subsets with both regulatory and stimulatory roles that contribute to the immune homeostasis in chronic M. ozzardi infection.
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Apirasa/inmunología , Linfocitos T CD4-Positivos/inmunología , Citocinas/sangre , Mansoneliasis/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antígenos Helmínticos/inmunología , Brasil , Niño , Femenino , Humanos , Inmunoglobulina G/sangre , Masculino , Mansonella , Microfilarias , Persona de Mediana Edad , Adulto JovenRESUMEN
In cross-sectional studies, chronic helminth infections have been associated with immunological hyporesponsiveness that can affect responses to unrelated antigens. To study the immunological effects of deworming, we conducted a cluster-randomized, double-blind, placebo-controlled trial in Indonesia and assigned 954 households to receive albendazole or placebo once every 3 mo for 2 y. Helminth-specific and nonspecific whole-blood cytokine responses were assessed in 1,059 subjects of all ages, whereas phenotyping of regulatory molecules was undertaken in 121 school-aged children. All measurements were performed before and at 9 and 21 mo after initiation of treatment. Anthelmintic treatment resulted in significant increases in proinflammatory cytokine responses to Plasmodium falciparum-infected red blood cells (PfRBCs) and mitogen, with the largest effect on TNF responses to PfRBCs at 9 mo-estimate [95% confidence interval], 0.37 [0.21-0.53], P value over time (Ptime) < 0.0001. Although the frequency of regulatory T cells did not change after treatment, there was a significant decline in the expression of the inhibitory molecule cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on CD4+ T cells of albendazole-treated individuals, -0.060 [-0.107 to -0.013] and -0.057 [-0.105 to -0.008] at 9 and 21 mo, respectively; Ptime = 0.017. This trial shows the capacity of helminths to up-regulate inhibitory molecules and to suppress proinflammatory immune responses in humans. This could help to explain the inferior immunological responses to vaccines and lower prevalence of inflammatory diseases in low- compared with high-income countries.
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Albendazol/uso terapéutico , Infecciones Comunitarias Adquiridas/prevención & control , Helmintiasis/tratamiento farmacológico , Helmintos/efectos de los fármacos , Adolescente , Adulto , Animales , Antihelmínticos/uso terapéutico , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Antígeno CTLA-4/inmunología , Antígeno CTLA-4/metabolismo , Niño , Infecciones Comunitarias Adquiridas/inmunología , Infecciones Comunitarias Adquiridas/parasitología , Estudios Transversales , Citocinas/sangre , Citocinas/inmunología , Método Doble Ciego , Femenino , Helmintiasis/epidemiología , Helmintiasis/inmunología , Helmintos/inmunología , Interacciones Huésped-Parásitos/efectos de los fármacos , Interacciones Huésped-Parásitos/inmunología , Humanos , Indonesia/epidemiología , Masculino , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/inmunología , Prevalencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Immunoglobulin G (IgG) Fc N-glycosylation affects antibody-mediated effector functions and varies with inflammation rooted in both communicable and non-communicable diseases. Worldwide, communicable and non-communicable diseases tend to segregate geographically. Therefore, we studied whether IgG Fc N-glycosylation varies in populations with different environmental exposures in different parts of the world. IgG Fc N-glycosylation was analysed in serum/plasma of 700 school-age children from different communities of Gabon, Ghana, Ecuador, the Netherlands and Germany. IgG1 galactosylation levels were generally higher in more affluent countries and in more urban communities. High IgG1 galactosylation levels correlated with low total IgE levels, low C-reactive protein levels and low prevalence of parasitic infections. Linear mixed modelling showed that only positivity for parasitic infections was a significant predictor of reduced IgG1 galactosylation levels. That IgG1 galactosylation is a predictor of immune activation is supported by the observation that asthmatic children seemed to have reduced IgG1 galactosylation levels as well. This indicates that IgG1 galactosylation levels could be used as a biomarker for immune activation of populations, providing a valuable tool for studies examining the epidemiological transition from communicable to non-communicable diseases.
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Enfermedades Transmisibles/inmunología , Inmunoglobulina G/química , Polisacáridos/química , Receptores Fc/química , Schistosoma/inmunología , Esquistosomiasis/inmunología , Adolescente , Animales , Biomarcadores/química , Proteína C-Reactiva/metabolismo , Niño , Preescolar , Ecuador , Femenino , Gabón , Alemania , Ghana , Glicosilación , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inflamación/inmunología , Masculino , Países Bajos , Esquistosomiasis/parasitologíaRESUMEN
BACKGROUND: Malaria and helminth co infection are common in tropical and subtropical areas where they affect the life of millions of people. While both helminth and malaria parasites have immunomodulatory activities, little is known about the consequence of co-infections on malaria antigen specific immune responses. METHOD/DESIGN: This study will be conducted in two rural areas of the Moyen Ogooué province in Gabon, endemic for both Plasmodium falciparum and Schistosoma haematobium infections. Participants, 5 to 50 years old, will be enrolled and grouped according to their infection status. S. haematobium and malaria parasites will be detected, demographic and clinical data will be recorded and blood will be collected for hematological as well as for immunological assays. The level of antibody specific to Plasmodium falciparum blood stage and gametocyte antigens will be measured using ELISA. PBMC will be isolated for phenotyping of different T cell subsets ex vivo by flow cytometry and for culture and cytokine response assessment. DISCUSSION: We will provide a comprehensive picture of the interaction between schistosomes and malaria parasites which co-localize in peripheral blood. We will test the hypothesis that schistosome infection has an impact on specific humoral as well as on cellular immune responses to malaria antigens.
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BACKGROUND: Helminth infections and allergies are associated with TH2 responses. Whereas the development of TH2 responses and allergic disorders in pediatric populations has been examined in affluent countries, no or little data exist from low income regions of the world. The aim of this study is to examine factors influencing the development of TH2 responses of children born in areas endemic for helminth infections and to relate these factors to atopic sensitization at 4 years of age. METHODS: Data were collected from pregnant mothers on helminth infections, education and socioeconomic status (SES). Total IgE, IL-5 in response to mitogen, and helminth antigens were measured in children at 2, 5, 12, 24 and 48 months of age. Skin prick testing (SPT) and allergen-specific IgE were determined at 4 years of age. RESULTS: Strong TH2 responses were seen at 5 months of age and increased with time. Although maternal filarial infection was associated with helminth-antigen specific TH2 responses, it was low maternal education or SES but not helminth infection, which was associated with the development of high total IgE and PHA-induced IL-5. At 4 years of age when allergen reactivity was assessed by SPT, the high general TH2 responses did not translate into higher prevalence of SPT. The risk factor for SPT reactivity was low maternal education which decreased the risk of SPT positivity to allergens (adjusted OR, 0.32; 95% CI, 0.12 - 0.87) independently of maternal filarial infection which tended to reduce the child's risk for being SPT positive (adjusted OR, 0.35; 95% CI, 0.07 - 1.70). CONCLUSIONS: In areas endemic for helminths, potent TH2 responses were seen early in life, but did not translate into a higher SPT reactivity to allergens. Therefore, in many parts of the world TH2 responses in general and IgE in particular cannot be used for diagnosis of allergic diseases.
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Chronic Schistosoma infection is often characterized by a state of T cell hyporesponsiveness of the host. Suppression of dendritic cell (DC) function could be one of the mechanisms underlying this phenomenon, since Schistosoma antigens are potent modulators of dendritic cell function in vitro. Yet, it remains to be established whether DC function is modulated during chronic human Schistosoma infection in vivo. To address this question, the effect of Schistosoma haematobium infection on the function of human blood DC was evaluated. We found that plasmacytoid (pDC) and myeloid DC (mDC) from infected subjects were present at lower frequencies in peripheral blood and that mDC displayed lower expression levels of HLA-DR compared to those from uninfected individuals. Furthermore, mDC from infected subjects, but not pDC, were found to have a reduced capacity to respond to TLR ligands, as determined by MAPK signaling, cytokine production and expression of maturation markers. Moreover, the T cell activating capacity of TLR-matured mDC from infected subjects was lower, likely as a result of reduced HLA-DR expression. Collectively these data show that S. haematobium infection is associated with functional impairment of human DC function in vivo and provide new insights into the underlying mechanisms of T cell hyporesponsiveness during chronic schistosomiasis.
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Células Dendríticas/inmunología , Tolerancia Inmunológica , Schistosoma haematobium/inmunología , Schistosoma haematobium/patogenicidad , Esquistosomiasis Urinaria/inmunología , Esquistosomiasis Urinaria/parasitología , Adolescente , Adulto , Animales , Citocinas/metabolismo , Femenino , Expresión Génica , Antígenos HLA-DR/biosíntesis , Humanos , Recuento de Leucocitos , Masculino , Transducción de Señal , Adulto JovenRESUMEN
Malaria and helminth infections often coincide in the same tropical regions. Studies of the consequences of helminth and malaria coinfection in humans have been few and are mainly epidemiological, with little information on cellular immune responses. In this study, we investigated the antimalarial immune responses of Ghanaian children living in a rural area with a high prevalence of both helminth infection and Plasmodium falciparum infection. Whole blood specimens were cultured with P. falciparum-infected red blood cells (iRBCs), and pro- and anti-inflammatory cytokines and immune regulatory molecules were measured. In response to iRBCs, levels of interleukin (IL)-10, but not tumor necrosis factor-alpha,were higher in samples from helminth-infected children than in those from uninfected children, as was expression of the regulatory molecules suppressor of cytokine signaling (SOCS)-3, Foxp3, and programmed death (PD)-1. Furthermore, a significant correlation was found between SOCS-3 gene expression and IL-10 production. These results indicate that the presence of helminth infection modulates the immune response to malarial parasites, making it more anti-inflammatory.
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Antígenos de Protozoos/inmunología , Malaria/inmunología , Animales , Niño , Femenino , Ghana , Helmintiasis , Humanos , Interferón gamma/sangre , Interleucina-10/sangre , Interleucina-6/sangre , Malaria/complicaciones , Masculino , Plasmodium falciparum , Esquistosomiasis mansoni/complicaciones , Esquistosomiasis mansoni/inmunología , Linfocitos T/inmunología , Clima Tropical , Factor de Necrosis Tumoral alfa/sangreRESUMEN
BACKGROUND: Helminth infections are prevalent in rural areas of developing countries and have in some studies been negatively associated with allergic disorders and atopy. In this context little is known of the molecular mechanisms of modulation involved. We have characterized the innate immune responses, at the molecular level, in children according to their helminth infection status and their atopic reactivity to allergens. METHODOLOGY/PRINCIPAL FINDINGS: The mRNA expression of several genes of the innate immune system that have been associated with microbial exposure and allergy was examined in 120 school children in a rural area in Ghana. Helminth infections were common and atopy rare in the study area. The analysis of gene expression in ex vivo whole blood samples reflected the levels of corresponding proteins. Using this approach in a population of school children in whom the presence of Schistosoma haematobium infection was associated with protection from atopic reactivity, we found that the level of TLR2 and SOCS-3, genes associated with atopy in the children, were significantly downregulated by presence of S. haematobium infection. CONCLUSIONS: S. haematobium infections modulate the expression of genes of the innate immune system (TLR2 and SOCS-3); these are genes that are associated with increased allergic inflammatory processes, providing a molecular link between the negative association of this infection and atopy in rural children in Ghana.