RESUMEN
Immunomodulation enhances parasite fitness by reducing inflammation-induced morbidity in the mammalian host, as well as by attenuating parasite-targeting immune responses. Using a whole-proteome differential screening method, we identified Schistosoma japonicum helminth defense molecule 1 (SjHDM-1) as a target of antibodies expressed by S. japonicum-resistant but not S. japonicum-susceptible individuals. In a longitudinal cohort study (n = 644) conducted in a S. japonicum-endemic region of the Philippines, antibody levels to SjHDM-1 did not predict resistance to reinfection but were associated with increased measures of inflammation. Individuals with high levels of anti-SjHDM-1 immunoglobulin G had higher levels of C-reactive protein than those with low anti-SjHDM-1. High anti-SjHDM-1 immunoglobulin G responses were also associated with reduced biomarkers of nutritional status (albumin), as well as decreased anthropometric measures of nutritional status (weight-for-age and height-for-age z scores) and increased measures of hepatomegaly. Our results suggest that anti-SjHDM-1 responses inhibit the immunomodulatory function of SjHDM-1, resulting in increased morbidity rates.
Asunto(s)
Anticuerpos Antihelmínticos , Inflamación , Estado Nutricional , Esquistosomiasis Japónica , Humanos , Anticuerpos Antihelmínticos/sangre , Anticuerpos Antihelmínticos/inmunología , Animales , Femenino , Esquistosomiasis Japónica/inmunología , Masculino , Filipinas/epidemiología , Inflamación/inmunología , Estudios Longitudinales , Adulto , Schistosoma japonicum/inmunología , Adolescente , Proteínas del Helminto/inmunología , Adulto Joven , Niño , Persona de Mediana Edad , Hepatomegalia/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunologíaRESUMEN
Schistosoma japonicum is endemic in the Philippines. The Kato-Katz (KK) method was used to diagnose S. japonicum. This is impractical, particularly when the sample size is limited. Knowledge on point-of-care circulating cathodic antigen (CCA) test performance for S. japonicum is limited. Determining the sensitivity and specificity of new diagnostics is difficult when the gold standard test is less effective or absent. Latent class analysis (LCA) can address some limitations. A total of 484 children and 572 adults from the Philippines were screened for S. japonicum. We performed Bayesian LCA to estimate the infection prevalence, sensitivity and specificity of each test by stratifying them into two age groups. Observed prevalence assessed by KK was 50.2% and 31.8%, and by CCA was 89.9% and 66.8%, respectively. Using Bayesian LCA, among children, the sensitivity and specificity of CCA were 94.8% (88.7-99.4) and 21.5% (10.5-36.1) while those of KK were 66.0% (54.2-83.3) and 78.1% (61.1-91.3). Among adults, the sensitivity and specificity of CCA were 86.4% (76.6-96.9) and 62.8% (49.1-81.1) while those of KK were 43.6% (35.1-53.9) and 85.5% (75.8-94.6). Overall, CCA was more sensitive than KK, regardless of the age group at diagnosis, as KK was more specific. KK and CCA have different diagnostic performance, which should inform their use in the planning and implementation of S. japonicum control programs.
Asunto(s)
Schistosoma japonicum , Esquistosomiasis mansoni , Niño , Adulto , Animales , Humanos , Schistosoma mansoni , Antígenos Helmínticos , Teorema de Bayes , Análisis de Clases Latentes , Sistemas de Atención de Punto , Heces/química , Sensibilidad y Especificidad , PrevalenciaRESUMEN
OBJECTIVES: The association between thrombocytopenia and parasite density or disease severity is described in numerous studies. In recent years, several studies described the protective role of platelets in directly killing Plasmodium parasites, mediated by platelet factor 4 (PF4) binding to Duffy antigen. This study aimed to evaluate the protective role of platelets in young children who are Duffy antigen-negative, such as those in sub-Saharan Africa. METHODS: A zero-inflated negative binomial model was used to relate platelet count and parasite density data collected in a longitudinal birth cohort. Platelet factors were measured by enzyme-linked immunosorbent assay in samples collected from malaria-infected children who participated in a cross-sectional study. RESULTS: We described that an increase of 10,000 platelets/µl was associated with a 2.76% reduction in parasite count. Increasing levels of PF4 and CXCL7 levels were also significantly associated with a reduction in parasite count. CONCLUSIONS: Platelets play a protective role in reducing parasite burden in Duffy-negative children, possibly mediated through activation of the innate immune system.
Asunto(s)
Malaria Falciparum , Malaria , Parásitos , Niño , Animales , Humanos , Preescolar , Plasmodium falciparum , Recuento de Plaquetas , Estudios Transversales , Malaria Falciparum/parasitologíaRESUMEN
BACKGROUND: The frequency and clinical presentation of malaria infections show marked heterogeneity in epidemiological studies. However, deeper understanding of this variability is hampered by the difficulty in quantifying all relevant factors. Here, we report the history of malaria infections in twins, who are exposed to the same in utero milieu, share genetic factors, and are similarly exposed to vectors. METHODS: Data were obtained from a Malian longitudinal birth cohort. Samples from 25 twin pairs were examined for malaria infection and antibody responses. Bayesian models were developed for the number of infections during follow-up. RESULTS: In 16 of 25 pairs, both children were infected and often developed symptoms. In 8 of 25 pairs, only 1 twin was infected, but usually only once or twice. Statistical models suggest that this pattern is not inconsistent with twin siblings having the same underlying infection rate. In a pair with discordant hemoglobin genotype, parasite densities were consistently lower in the child with hemoglobin AS, but antibody levels were similar. CONCLUSIONS: By using a novel design, we describe residual variation in malaria phenotypes in naturally matched children and confirm the important role of environmental factors, as suggested by the between-twin pair heterogeneity in malaria history.
Asunto(s)
Malaria , Gemelos Monocigóticos , Preescolar , Humanos , Teorema de Bayes , Malaria/epidemiología , Gemelos Monocigóticos/genéticaRESUMEN
BACKGROUND: We compared individuals' self-reported water contact from a questionnaire to direct observation of water contact. Questionnaires that accurately capture water contact are necessary to risk-stratify individuals and communities at high risk for schistosomiasis. METHODS: Individuals (N=677) ages 7-30 y were included from three Schistosoma japonicum-endemic villages in Leyte, The Philippines. Each individual was observed for 12 d over the course of the 18-month study and the questionnaire was administered six times. A questionnaire index was derived that captured the number of self-reported contacts with water bodies for any purpose. An exposure index was created based on the sum of contacts that was weighted by the percentage of body surface area (BSA) exposed and exposure duration. RESULTS: Of 16 water contact activities, only bathing and washing clothes exhibited a significant, positive correlation between self-reported contacts and the observed exposure index related to those contacts. CONCLUSIONS: We found that only the reported frequencies of bathing and washing clothes were significantly related to an individual's overall observed exposure index, while use of all reported contacts was not related to the observed exposure. This study further supports the need for questionnaires to be augmented by some measure of how much BSA is exposed and/or time is spent in the water on average for a specific activity.
Asunto(s)
Schistosoma japonicum , Esquistosomiasis Japónica , Esquistosomiasis , Adolescente , Adulto , Animales , Niño , Humanos , Filipinas/epidemiología , Esquistosomiasis/epidemiología , Esquistosomiasis/prevención & control , Esquistosomiasis Japónica/epidemiología , Esquistosomiasis Japónica/prevención & control , Autoinforme , Agua , Adulto JovenRESUMEN
Children diagnosed with endemic Burkitt lymphoma (eBL) are deficient in interferon-γ (IFN-γ) responses to Epstein-Barr Nuclear Antigen1 (EBNA1), the viral protein that defines the latency I pattern in this B cell tumor. However, the contributions of immune-regulatory cytokines and phenotypes of the EBNA1-specific T cells have not been characterized for eBL. Using a bespoke flow cytometry assay we measured intracellular IFN-γ, IL-10, IL-17A expression and phenotyped CD4+ and CD8+ T cell effector memory subsets specific to EBNA1 for eBL patients compared to two groups of healthy children with divergent malaria exposures. In response to EBNA1 and a malaria antigen (PfSEA-1A), the three study groups exhibited strikingly different cytokine expression and T cell memory profiles. EBNA1-specific IFN-γ-producing CD4+ T cell response rates were lowest in eBL (40%) compared to children with high malaria (84%) and low malaria (66%) exposures (p < 0.0001 and p = 0.0004, respectively). However, eBL patients did not differ in CD8+ T cell response rates or the magnitude of IFN-γ expression. In contrast, eBL children were more likely to have EBNA1-specific CD4+ T cells expressing IL-10, and less likely to have polyfunctional IFN-γ+IL-10+ CD4+ T cells (p = 0.02). They were also more likely to have IFN-γ+IL-17A+, IFN-γ+ and IL-17A+ CD8+ T cell subsets compared to healthy children. Cytokine-producing T cell subsets were predominantly CD45RA+CCR7+ TNAIVE-LIKE cells, yet PD-1, a marker of persistent activation/exhaustion, was more highly expressed by the central memory (TCM) and effector memory (TEM) T cell subsets. In summary, our study suggests that IL-10 mediated immune regulation and depletion of IFN-γ+ EBNA1-specific CD4+ T cells are complementary mechanisms that contribute to impaired T cell cytotoxicity in eBL pathogenesis.
RESUMEN
In the past decade, ecological surveys emphasized rats and dogs as the most significant animal reservoirs for Schistosoma japonicum (S.j) in the Philippines. However, recent studies demonstrated 51-91% prevalence of schistosomiasis among water buffalo using qPCR in the Sj endemic regions in the Philippines. In order to resolve the inconsistency of reported surveys regarding Sj endemicity among carabao, a domestic water buffalo that is the most important draught animal, we introduced 42 schistosome negative water buffalo to Macanip, Jaro municipality, Leyte, the Philippines, a subsistence rice-farming village that has been the focus of schistosomiasis japonica studies of our group for the past 20 years. We conducted perfusion to the remaining 34 buffalo that survived 10 months of nature exposure and Typhoon Haiyan. Thirty-three water buffalo were found to be positive with at least 1 pair of worms from the mesenteric vein. The infection rate is 97%, with the worm burden of 94 (95% confidence interval, 49-138 worms) worms. To our knowledge, this is the first report about S. japonicum worm burden in naturally infected water buffalo in the Philippines. The fact that with less than one-year of exposure, in this human schistosomiasis endemic area, only 1 out of 34 water buffalo was uninfected is striking. Urgent attention is needed for a cost-effective technique for monitoring Sj infection in animals and humans. Meanwhile, intervention implementation, including water buffalo treatment and vaccination, should be taken into consideration.
Asunto(s)
Búfalos , Perfusión/efectos adversos , Schistosoma japonicum , Esquistosomiasis Japónica/epidemiología , Esquistosomiasis Japónica/veterinaria , Animales , Bovinos , Enfermedades de los Bovinos , Heces/parasitología , Humanos , Filipinas/epidemiología , Prevalencia , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
We previously identified a Plasmodium falciparum (Pf) protein of unknown function encoded by a single-copy gene, PF3D7_1134300, as a target of antibodies in plasma of Tanzanian children in a whole-proteome differential screen. Here we characterize this protein as a blood-stage antigen that localizes to the surface membranes of both parasitized erythrocytes and merozoites, hence its designation as Pf erythrocyte membrane and merozoite antigen 1 (PfEMMA1). Mouse anti-PfEMMA1 antisera and affinity-purified human anti-PfEMMA1 antibodies inhibited growth of P. falciparum strains by up to 68% in growth inhibition assays. Following challenge with uniformly fatal Plasmodium berghei (Pb) ANKA, up to 40% of mice immunized with recombinant PbEMMA1 self-cured, and median survival of lethally infected mice was up to 2.6-fold longer than controls (21 vs. 8 d, P = 0.005). Furthermore, high levels of naturally acquired human anti-PfEMMA1 antibodies were associated with a 46% decrease in parasitemia over 2.5 yr of follow-up of Tanzanian children. Together, these findings suggest that antibodies to PfEMMA1 mediate protection against malaria.
Asunto(s)
Antígenos de Protozoos/metabolismo , Membrana Eritrocítica/parasitología , Malaria Falciparum/parasitología , Merozoítos/metabolismo , Plasmodium falciparum/fisiología , Proteínas Protozoarias/genética , Animales , Anticuerpos Antiprotozoarios/inmunología , Antígenos de Protozoos/genética , Antígenos de Protozoos/inmunología , Preescolar , Femenino , Interacciones Huésped-Parásitos/fisiología , Humanos , Lactante , Vacunas contra la Malaria/genética , Vacunas contra la Malaria/inmunología , Malaria Falciparum/inmunología , Malaria Falciparum/mortalidad , Merozoítos/inmunología , Ratones Endogámicos BALB C , Plasmodium falciparum/inmunología , Plasmodium falciparum/patogenicidad , Polimorfismo de Nucleótido Simple , Proteínas Protozoarias/química , Proteínas Protozoarias/inmunología , Proteínas Protozoarias/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/metabolismo , TanzaníaRESUMEN
Fetal anemia is common in malaria-endemic areas and a risk factor for anemia as well as mortality during infancy. Placental malaria (PM) and red cell abnormalities have been proposed as possible etiologies, but the relationship between PM and fetal anemia has varied in earlier studies, and the role of red cell abnormalities has not been studied in malaria-endemic areas. In a Tanzanian birth cohort study designed to elucidate the pathogenesis of severe malaria in young infants, we performed a cross-sectional analysis of risk factors for fetal anemia. We determined PM status, newborn red cell abnormalities, and maternal and cord blood levels of iron regulatory proteins, erythropoietin (EPO), cytokines and cytokine receptors. We examined the relationship between these factors and fetal anemia. Fetal anemia was present in 46.2% of the neonates but was not related to PM. Maternal iron deficiency was common (81.6%), most frequent in multigravidae, and interacted with parity to modify risk of fetal anemia, but it was not directly related to risk. Among offspring of iron-deficient women, the odds of fetal anemia increased with fetal α+-thalassemia, as well as these patterns of cord blood cytokines: increased cord IL-6, decreased TNF-RI, and decreased sTfR. The EPO response to fetal anemia was low or absent and EPO levels were significantly decreased in newborns with the most severe anemia. This study from an area of high malaria transmission provides evidence that 1) fetal α+-thalassemia and cytokine balance, but not PM at delivery, are related to fetal anemia; 2) maternal iron deficiency increases the risk that other factors may cause fetal anemia; and 3) fetal anemia has a multifactorial etiology that may require a variety of interventions, although measures that reduce maternal iron deficiency may be generally beneficial.
Asunto(s)
Anemia/etiología , Citocinas/sangre , Eritropoyetina/sangre , Enfermedades Fetales/etiología , Feto/metabolismo , Malaria/parasitología , Placenta/parasitología , Complicaciones Parasitarias del Embarazo/parasitología , Talasemia alfa/complicaciones , Adulto , Anemia/sangre , Anemia/inmunología , Anemia/parasitología , Biomarcadores/sangre , Estudios Transversales , Femenino , Enfermedades Fetales/sangre , Enfermedades Fetales/inmunología , Enfermedades Fetales/parasitología , Feto/inmunología , Hemoglobinas/metabolismo , Humanos , Recién Nacido , Hierro/sangre , Deficiencias de Hierro , Malaria/sangre , Malaria/inmunología , Masculino , Salud Materna , Paridad , Placenta/inmunología , Placenta/metabolismo , Embarazo , Complicaciones Parasitarias del Embarazo/sangre , Complicaciones Parasitarias del Embarazo/inmunología , Medición de Riesgo , Factores de Riesgo , Tanzanía , Transferrina/metabolismo , Adulto Joven , Talasemia alfa/sangre , Talasemia alfa/inmunologíaRESUMEN
In areas endemic to schistosomiasis, fetal exposure to schistosome antigens prime the offspring before potential natural infection. Praziquantel (PZQ) treatment for Schistosoma japonicum infection in pregnant women has been demonstrated to be safe and effective. Our objectives were to evaluate whether maternal PZQ treatment modifies the process of in utero sensitization to schistosome antigens potentially impacting later risk of infection, as well as immune response to S. japonicum. We enrolled 295 children at age six, born to mothers with S. japonicum infection who participated in a randomized control trial of PZQ versus placebo given at 12-16 weeks gestation in Leyte, The Philippines. At enrollment, we assessed and treated current S. japonicum infection and measured serum cytokines. During a follow-up visit four weeks later, we assessed peripheral blood mononuclear cell (PBMC) cytokine production in response to soluble worm antigen preparation (SWAP) or soluble egg antigen (SEA). Associations between maternal treatment group and the child's S. japonicum infection status and immunologic responses were determined using multivariate linear regression analysis. PZQ treatment during pregnancy did not impact the prevalence (P = 0.12) or intensity (P = 0.59) of natural S. japonicum infection among children at age six. Among children with infection at enrollment (12.5%) there were no significant serum cytokine concentration differences between maternal treatment groups. Among children with infection at enrollment, IL-1 production by PBMCs stimulated with SEA was higher (P = 0.03) in the maternal PZQ group compared to placebo. Among children without infection, PBMCs stimulated with SEA produced greater IL-12 (P = 0.03) and with SWAP produced less IL-4 (P = 0.01) in the maternal PZQ group compared to placebo. Several cytokines produced by PBMCs in response to SWAP and SEA were significantly higher in children with S. japonicum infection irrespective of maternal treatment: IL-4, IL-5, IL-10, and IL-13. We report that maternal PZQ treatment for S. japonicum shifted the PBMC immune response to a more inflammatory signature but had no impact on their offspring's likelihood of infection or serum cytokines at age six, further supporting the safe use of PZQ in pregnant women. Trial Registration: ClinicalTrials.gov NCT00486863.
Asunto(s)
Citocinas/metabolismo , Inmunidad Materno-Adquirida , Praziquantel/administración & dosificación , Complicaciones Parasitarias del Embarazo/tratamiento farmacológico , Esquistosomiasis Japónica/tratamiento farmacológico , Animales , Antiprotozoarios/administración & dosificación , Niño , Estudios de Cohortes , Citocinas/sangre , Método Doble Ciego , Femenino , Humanos , Leucocitos Mononucleares/inmunología , Modelos Lineales , Masculino , Análisis Multivariante , Filipinas , Embarazo , Complicaciones Parasitarias del Embarazo/inmunología , Schistosoma japonicum/efectos de los fármacos , Esquistosomiasis Japónica/inmunología , Resultado del TratamientoRESUMEN
In 2011, faculty from the University of Rhode Island (URI)'s Institute for Immunology and Informatics and Lifespan's Center for International Health Research collaborated to develop a successful application for a Phase I Center of Biomedical Research Excellence around the scientific theme of translational infectious diseases immunology. From 2013 to 2020, this COBRE supported significant discoveries in research on dengue, HIV, and malaria, among other diseases, and facilitated the career development of several independent Rhode Island (RI)-based early-stage investigators. Our experience illustrates both the potential and challenges for investigators with shared scientific interests to leverage the NIH COBRE program to enhance cross-institutional interactions.
Asunto(s)
Investigación Biomédica , Enfermedades Transmisibles , Enfermedades Transmisibles/terapia , Docentes , Salud Global , Humanos , Rhode IslandRESUMEN
Schistosomiasis remains a leading cause of chronic morbidity in endemic regions despite decades of widespread mass chemotherapy with praziquantel. Using our whole proteome differential screening approach, and plasma and epidemiologic data from a longitudinal cohort of individuals living in a Schistosoma japonicum-endemic region of the Philippines, we interrogated the parasite proteome to identify novel vaccine candidates for Schistosoma japonicum. We identified 16 parasite genes which encoded proteins that were recognized by immunoglobulin G or immunoglobulin E antibodies in the plasma of individuals who had developed resistance to reinfection, but were not recognized by antibodies in the plasma of individuals who remained susceptible to reinfection. Antibody levels to Sj6-8 and Sj4-1 measured in the entire cohort (Nâ =â 505) 1 month after praziquantel treatment were associated with significantly decreased risk of reinfection and lower intensity of reinfection over 18 months of follow-up.
Asunto(s)
Anticuerpos Antihelmínticos , Schistosoma japonicum , Esquistosomiasis Japónica , Vacunas , Animales , Anticuerpos Antihelmínticos/inmunología , Resistencia a la Enfermedad , Humanos , Recurrencia Local de Neoplasia , Praziquantel/uso terapéutico , Proteoma , Reinfección/prevención & control , Schistosoma japonicum/genética , Esquistosomiasis Japónica/prevención & controlAsunto(s)
Infecciones Asintomáticas , COVID-19/diagnóstico , COVID-19/prevención & control , Transmisión de Enfermedad Infecciosa de Paciente a Profesional/prevención & control , Transmisión de Enfermedad Infecciosa de Profesional a Paciente/prevención & control , Nasofaringe/virología , SARS-CoV-2 , Procedimientos Quirúrgicos Operativos , Prueba de Ácido Nucleico para COVID-19 , Femenino , Humanos , Tamizaje Masivo , Equipo de Protección Personal , Embarazo , Cuidados Preoperatorios , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rhode IslandRESUMEN
Malaria caused by Plasmodium falciparum remains the leading single-agent cause of mortality in children1, yet the promise of an effective vaccine has not been fulfilled. Here, using our previously described differential screening method to analyse the proteome of blood-stage P. falciparum parasites2, we identify P. falciparum glutamic-acid-rich protein (PfGARP) as a parasite antigen that is recognized by antibodies in the plasma of children who are relatively resistant-but not those who are susceptible-to malaria caused by P. falciparum. PfGARP is a parasite antigen of 80 kDa that is expressed on the exofacial surface of erythrocytes infected by early-to-late-trophozoite-stage parasites. We demonstrate that antibodies against PfGARP kill trophozoite-infected erythrocytes in culture by inducing programmed cell death in the parasites, and that vaccinating non-human primates with PfGARP partially protects against a challenge with P. falciparum. Furthermore, our longitudinal cohort studies showed that, compared to individuals who had naturally occurring anti-PfGARP antibodies, Tanzanian children without anti-PfGARP antibodies had a 2.5-fold-higher risk of severe malaria and Kenyan adolescents and adults without these antibodies had a twofold-higher parasite density. By killing trophozoite-infected erythrocytes, PfGARP could synergize with other vaccines that target parasite invasion of hepatocytes or the invasion of and egress from erythrocytes.
Asunto(s)
Apoptosis/inmunología , Péptidos y Proteínas de Señalización Intercelular/inmunología , Malaria Falciparum/inmunología , Malaria Falciparum/prevención & control , Parásitos/inmunología , Plasmodium falciparum/citología , Plasmodium falciparum/inmunología , Proteínas Protozoarias/inmunología , Adolescente , Adulto , Animales , Anticuerpos Antiprotozoarios/inmunología , Antígenos de Protozoos/química , Antígenos de Protozoos/inmunología , Aotidae/inmunología , Aotidae/parasitología , Caspasas/metabolismo , Niño , Estudios de Cohortes , ADN Protozoario/química , ADN Protozoario/metabolismo , Activación Enzimática , Eritrocitos/parasitología , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/química , Kenia , Vacunas contra la Malaria/inmunología , Malaria Falciparum/parasitología , Masculino , Ratones , Parásitos/citología , Parásitos/crecimiento & desarrollo , Plasmodium falciparum/crecimiento & desarrollo , Proteínas Protozoarias/química , Tanzanía , Trofozoítos/citología , Trofozoítos/crecimiento & desarrollo , Trofozoítos/inmunología , Vacuolas/inmunologíaRESUMEN
BACKGROUND: Our objective was to quantify the risk of acquiring malaria among progeny of women with malaria during pregnancy. METHODS: We searched MEDLINE, EMBASE, CINAHL, and the Cochrane Library for eligible prospective studies. The primary predictor was malaria during pregnancy defined as placental malaria, parasitemia, clinical malaria, or pregnancy-associated malaria. Primary outcomes were parasitemia or clinically defined malaria of young children. We performed meta-analyses to pool adjusted risk estimates using a random-effects model. RESULTS: Nineteen of 2053 eligible studies met inclusion criteria for the systemic review. Eleven of these studies were quantitative and were included in the meta-analyses. The pooled adjusted odds ratio (aOR) or adjusted hazard ratio (aHR) of malaria during pregnancy for detection of parasitemia in young children were 1.94 (95% confidence interval [CI], 0.93-4.07; P = .08) and 1.46 (95% CI, 1.07-2.00; P < .001), respectively. The pooled aOR or aHR for clinically defined malaria in young children were 2.82 (95% CI, 1.82-4.38; P < .001) and 1.31 (95% CI, 0.96-1.79; P = .09), respectively. CONCLUSIONS: Our results confirmed that malaria during pregnancy significantly increased the overall risk of malaria in young children via indeterminate mechanisms and emphasize the urgent need to implement safe and highly effective strategies to prevent malaria during pregnancy.
Asunto(s)
Número de Embarazos , Transmisión Vertical de Enfermedad Infecciosa , Malaria/transmisión , Femenino , Humanos , Lactante , Parasitemia , Placenta/parasitología , Embarazo , Factores de RiesgoRESUMEN
BACKGROUND: We evaluated whether maternally-derived antibodies to a malarial vaccine candidate, Plasmodium falciparum Schizont Egress Antigen-1 (PfSEA-1), in cord blood interfered with the development of infant anti-PfSEA-1 antibodies in response to natural exposure. METHODS: We followed 630 Tanzanian infants who were measured their antibodies against PfSEA-1 (aa 810-1023; PfSEA-1A) at birth and 6, 12, 18, and 24â¯months of age, and examined the changes in anti-PfSEA-1A antibody levels in response to parasitemia, and evaluated whether maternally-derived anti-PfSEA-1A antibodies in cord blood modified infant anti-PfSEA-1A immune responses. RESULTS: Infants who experienced parasitemia during the first 6â¯months of life had significantly higher anti-PfSEA-1A antibodies at 6 and 12â¯months of age compared to uninfected infants. Maternally-derived anti-PfSEA-1A antibodies in cord blood significantly modified this effect during the first 6â¯months. During this period, infant anti-PfSEA-1A antibody levels were significantly associated with their P. falciparum exposure when they were born with low, but not higher, maternally-derived anti-PfSEA-1A antibody levels in cord blood. Nevertheless, during the first 6â¯months of life, maternally-derived anti-PfSEA-1A antibodies in cord blood did not abrogate the parasitemia driven development of infant anti-PfSEA-1A: parasitemia were significantly correlated with anti-PfSEA-1A antibody levels at 6â¯months of age in the infants born with low maternally-derived anti-PfSEA-1A antibody levels in cord blood and borderline significantly correlated in those infants born with middle and high levels. CONCLUSIONS: Maternal vaccination with PfSEA-1A is unlikely to interfere with the development of naturally acquired anti-PfSEA-1A immune responses following exposure during infancy.
Asunto(s)
Anticuerpos Antiprotozoarios/sangre , Antígenos de Protozoos/inmunología , Sangre Fetal/inmunología , Inmunidad Materno-Adquirida , Proteínas Protozoarias/inmunología , Preescolar , Estudios de Cohortes , Humanos , Inmunoglobulina G/sangre , Lactante , Recién Nacido , Malaria Falciparum/prevención & control , Parasitemia/inmunología , Plasmodium falciparumRESUMEN
BACKGROUND: The objectives of this study were to 1) evaluate the influence of treatment with praziquantel on the inflammatory milieu in maternal, placental, and cord blood, 2) assess the extent to which proinflammatory signatures in placental and cord blood impacts birth outcomes, and 3) evaluate the impact of other helminths on the inflammatory micro environment. METHODS/FINDINGS: This was a secondary analysis of samples from 369 mother-infant pairs participating in a randomized controlled trial of praziquantel given at 12-16 weeks' gestation. We performed regression analysis to address our study objectives. In maternal peripheral blood, the concentrations of CXCL8, and TNF receptor I and II decreased from 12 to 32 weeks' gestation, while IL-13 increased. Praziquantel treatment did not significantly alter the trajectory of the concentration of any of the cytokines examined. Hookworm infection was associated with elevated placental IL-1, CXCL8 and IFN-γ. The risk of small-for-gestational age increased with elevated IL-6, IL-10, and CXCL8 in cord blood. The risk of prematurity was increased when cord blood sTNFRI and placental IL-5 were elevated. CONCLUSIONS: Our study suggests that fetal cytokines, which may be related to infectious disease exposures, contribute to poor intrauterine growth. Additionally, hookworm infection influences cytokine concentrations at the maternal-fetal interface. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE: ClinicalTrials.gov (NCT00486863).
Asunto(s)
Antihelmínticos/administración & dosificación , Citocinas/sangre , Sangre Fetal/química , Placenta/patología , Praziquantel/administración & dosificación , Complicaciones Parasitarias del Embarazo/patología , Esquistosomiasis Japónica/patología , Adulto , Femenino , Humanos , Recién Nacido de Bajo Peso , Recién Nacido , Recién Nacido Pequeño para la Edad Gestacional , Masculino , Filipinas , Embarazo , Complicaciones Parasitarias del Embarazo/tratamiento farmacológico , Esquistosomiasis Japónica/complicaciones , Esquistosomiasis Japónica/tratamiento farmacológico , Adulto JovenRESUMEN
BACKGROUND: We evaluated the association between etiology of maternal anemia and iron status throughout infancy. METHODS: Samples from a study designed to examine Praziquantel treatment during pregnancy were used (n = 359). All women were infected with schistosomiasis and randomized to Praziquantel or placebo at 16 ± 2 weeks' gestation. Hemoglobin, serum ferritin (SF), soluble transferrin receptor (sTfR), hepcidin, C-reactive protein, and interleukin-6 were measured in maternal and infant blood. The relationship between both maternal Praziquantel treatment and etiology of anemia and infant iron status was evaluated. RESULTS: Maternal iron-deficiency anemia was associated with increased risk of infant anemia at 6 months of age. Infants of mothers with the lowest levels of circulating hepcidin during gestation, likely a marker for iron deficiency, had higher sTfR:SF levels and lower hemoglobin levels, particularly at 12 months of age. Maternal non-iron-deficiency anemia (NIDA) did not impact infant anemia risk or iron status. Maternal treatment for schistosomiasis had no effect on infant hematologic status. CONCLUSIONS: Maternal iron deficiency anemia was associated with an increased risk for anemia or iron deficiency during late infancy. We did not observe an association between maternal NIDA and increased risk for iron deficiency during infancy.
Asunto(s)
Anemia/diagnóstico , Anemia/genética , Hierro/sangre , Complicaciones Hematológicas del Embarazo , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Esquistosomiasis/tratamiento farmacológico , Antihelmínticos/efectos adversos , Antihelmínticos/farmacología , Antígenos CD/sangre , Proteína C-Reactiva/análisis , Femenino , Ferritinas/sangre , Hemoglobinas/análisis , Hepcidinas/sangre , Humanos , Recién Nacido , Enfermedades del Recién Nacido , Interleucina-6/sangre , Deficiencias de Hierro , Masculino , Exposición Materna , Filipinas , Praziquantel/efectos adversos , Praziquantel/farmacología , Embarazo , Resultado del Embarazo , Receptores de Transferrina/sangre , Esquistosomiasis/complicacionesRESUMEN
BACKGROUND: In holoendemic areas, children suffer the most from Plasmodium falciparum malaria, yet newborns and young infants express a relative resistance to both infection and severe malarial disease (SM). This relative resistance has been ascribed to maternally-derived anti-parasite immunoglobulin G; however, the targets of these protective antibodies remain elusive. METHODS: We enrolled 647 newborns at birth from a malaria-holoendemic region of Tanzania. We collected cord blood, measured antibodies to Plasmodium falciparum Schizont Egress Antigen-1 (PfSEA-1), and related these antibodies to the risk of severe malaria in the first year of life. In addition, we vaccinated female mice with PbSEA-1, mated them, and challenged their pups with P. berghei ANKA parasites to assess the impact of maternal PbSEA-1 vaccination on newborns' resistance to malaria. RESULTS: Children with high cord-blood anti-PfSEA-1 antibody levels had 51.4% fewer cases of SM compared to individuals with lower anti-PfSEA-1 levels over 12 months of follow-up (P = .03). In 3 trials, pups born to PbSEA-1-vaccinated dams had significantly lower parasitemia and longer survival following a P. berghei challenge compared to pups born to control dams. CONCLUSIONS: We demonstrate that maternally-derived, cord-blood anti-PfSEA-1 antibodies predict decreased risk of SM in infants and vaccination of mice with PbSEA-1 prior to pregnancy protects their offspring from lethal P. berghei challenge. These results identify, for the first time, a parasite-specific target of maternal antibodies that protect infants from SM and suggest that vaccination of pregnant women with PfSEA-1 may afford a survival advantage to their offspring.
Asunto(s)
Anticuerpos Antiprotozoarios/sangre , Antígenos de Protozoos/inmunología , Sangre Fetal/inmunología , Inmunidad Materno-Adquirida , Malaria Falciparum/prevención & control , Proteínas Protozoarias/inmunología , Índice de Severidad de la Enfermedad , Animales , Antígenos de Protozoos/administración & dosificación , Estudios de Cohortes , Resistencia a la Enfermedad , Femenino , Humanos , Inmunoglobulina G/sangre , Lactante , Recién Nacido , Malaria Falciparum/inmunología , Ratones , Ratones Endogámicos BALB C , Parasitemia/inmunología , Parasitemia/prevención & control , Plasmodium berghei/inmunología , Plasmodium falciparum , Proteínas Protozoarias/administración & dosificación , Tanzanía , VacunaciónRESUMEN
Low- and middle-income countries (LMICs) carry a high burden of infectious diseases associated with impaired gut integrity, leading to microbial translocation. Pregnancies in this setting are at high risk of fetal growth restriction (FGR). We examined the association among specific risk factors for impaired gut integrity (schistosomiasis, hookworm infection, and alcohol consumption), blood endotoxin levels, and FGR. Endotoxins, lipopolysaccharide-binding proteins (LBPs), and cytokines were measured in blood from women at 32 weeks gestation, the maternal-fetal interface (MFI) at delivery, and cord blood at delivery. Resolution of schistosomiasis had no impact on endotoxin levels; however, maternal hookworm infection and alcohol consumption were associated with modest increases in endotoxin at the MFI. Cytokines responses within the maternal peripheral blood and blood from the MFI were positively associated with endotoxins, but many cord blood cytokines were negatively associated with endotoxins. Newborns with FGR also had higher levels of endotoxins at the MFI. Risk factors for microbial translocation may lead to increased levels of endotoxins at the MFI, which may contribute to poor growth in utero.