RESUMO
BACKGROUND: Benznidazole is an effective drug in the trypanocidal treatment of acute and chronic indeterminate Chagas' disease (CD). However, adverse drug reactions (ADR) are common and frequently cause patients to discontinue treatment. OBJECTIVES: We hypothesized that antioxidant supplementation could mitigate benznidazole-induced toxicity. METHODS: We co-supplemented an adult traveller with chronic indeterminate CD who experienced benznidazole ADR with ascorbic acid (AA), 1000â mg/day. We measured selected serum biomarkers of oxidative stress [total antioxidant status (TAS), total oxidative status (TOS), nuclear factor erythroid 2-related factor 2 (Nrf2), malondialdehyde (MDA), extracellular glutathione peroxidase (GPX3), catalase (CAT) and total superoxide dismutase (T-SOD)] at timepoints before and throughout benznidazole treatment and after AA co-supplementation. RESULTS: AA co-supplementation effectively mitigated benznidazole-induced ADR during the aetiological treatment of chronic indeterminate CD. The kinetics of serum biomarkers of oxidative stress suggested significantly decreased oxidative insult in our patient. CONCLUSIONS: We hypothesize that the key pathophysiological mechanism of benznidazole-associated toxicity is oxidative stress, rather than hypersensitivity. AA co-supplementation may improve adherence to benznidazole treatment of chronic indeterminate (or acute) CD. Oxidative stress biomarkers have the potential to guide the clinical management of CD. Prospective studies are needed to establish the benefit of antioxidant co-supplementation to benznidazole treatment of CD in reducing benznidazole toxicity, parasite clearance and the prevention of end-organ damage.
Assuntos
Doença de Chagas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Nitroimidazóis , Adulto , Antioxidantes/uso terapêutico , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Biomarcadores , Doença de Chagas/tratamento farmacológico , Suplementos Nutricionais , Humanos , Nitroimidazóis/efeitos adversos , Estresse OxidativoRESUMO
Chagas disease is a neglected disease caused by Trypanosoma cruzi parasites. Most diagnosis is based on serological tests, but the lack of a gold standard test complicates the measurement of test performance. To overcome this limitation, we used samples from a cohort of well-characterized T. cruzi-infected women to evaluate the reactivity of two rapid diagnostic tests and one enzyme-linked immunosorbent assay (ELISA). Our cohort was derived from a previous study on congenital transmission of T. cruzi and consisted of 481 blood/plasma samples from Argentina (n = 149), Honduras (n = 228), and Mexico (n = 104), with at least one positive T. cruzi PCR. Reactivity of the three tests ranged from 70.5% for the Wiener ELISA to 81.0% for the T-Detect and 90.4% for the Stat-Pak rapid tests. Test reactivity varied significantly among countries and was highest in Argentina and lowest in Mexico. When considering at least two reactive serological tests to confirm seropositivity, over 12% of T. cruzi infection cases from Argentina were missed by serological tests, over 21% in Honduras, and an alarming 72% in Mexico. Differences in test performance among countries were not due to differences in parasitemia, but differences in antibody levels against ELISA antigens were observed. Geographic differences in T. cruzi parasite strains as well as genetic differences among human populations both may contribute to the discrepancies in serological testing. Improvements in serological diagnostics for T. cruzi infections are critically needed to ensure an optimum identification of cases.
Assuntos
Doença de Chagas , Trypanosoma cruzi , Anticorpos Antiprotozoários , Doença de Chagas/diagnóstico , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Testes SorológicosRESUMO
BACKGROUND: Trypanosoma cruzi has been divided into Discrete Typing Units I and non-I (II-VI). T. cruzi I is predominant in Mexico and Central America, while non-I is predominant in most of South America, including Argentina. Little is known about congenital transmission of T. cruzi I. The specific aim of this study is to determine the rate of congenital transmission of T. cruzi I compared to non-I. METHODS/DESIGN: We are conducting a prospective study to enroll at delivery, 10,000 women in Argentina, 7,500 women in Honduras, and 13,000 women in Mexico. We are measuring transmitted maternal T. cruzi antibodies by performing two rapid tests in cord blood (Stat-Pak, Chembio, Medford, New York, and Trypanosoma Detect, InBios, Seattle, Washington). If at least one of the results is positive, we are identifying infants who are congenitally infected by performing parasitological examinations on cord blood and at 4-8 weeks, and serological follow-up at 10 months. Serological confirmation by ELISA (Wiener, Rosario, Argentina) is performed in cord and maternal blood, and at 10 months. We also are performing T. cruzi standard PCR, real-time quantitative PCR and genotyping on maternal venous blood and on cord blood, and serological examinations on siblings. Data are managed by a Data Center in Montevideo, Uruguay. Data are entered online at the sites in an OpenClinica data management system, and digital pictures of data forms are sent to the Data Center for quality control. Weekly reports allow for rapid feedback to the sites.
Assuntos
Anticorpos Antiprotozoários/sangue , Doença de Chagas/transmissão , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Trypanosoma cruzi/imunologia , Adulto , Argentina , Doença de Chagas/congênito , Doença de Chagas/diagnóstico , Doença de Chagas/prevenção & controle , Feminino , Sangue Fetal/imunologia , Honduras , Humanos , Lactente , Recém-Nascido , México , Gravidez , Complicações Parasitárias na Gravidez/sangue , Complicações Parasitárias na Gravidez/diagnóstico , Estudos Prospectivos , Trypanosoma cruzi/genéticaRESUMO
We previously identified the recombinant (r) macrophage (M) infectivity (I) potentiator (P) of the protozoan parasite Trypanosoma cruzi (Tc) (rTcMIP) as an immuno-stimulatory protein that induces the release of IFN-γ, CCL2 and CCL3 by human cord blood cells. These cytokines and chemokines are important to direct a type 1 adaptive immune response. rTcMIP also increased the Ab response and favored the production of the Th1-related isotype IgG2a in mouse models of neonatal vaccination, indicating that rTcMIP could be used as a vaccine adjuvant to enhance T and B cell responses. In the present study, we used cord and adult blood cells, and isolated NK cells and human monocytes to investigate the pathways and to decipher the mechanism of action of the recombinant rTcMIP. We found that rTcMIP engaged TLR1/2 and TLR4 independently of CD14 and activated the MyD88, but not the TRIF, pathway to induce IFN-γ production by IL-15-primed NK cells, and TNF-α secretion by monocytes and myeloid dendritic cells. Our results also indicated that TNF-α boosted IFN-γ expression. Though cord blood cells displayed lower responses than adult cells, our results allow to consider rTcMIP as a potential pro-type 1 adjuvant that might be associated to vaccines administered in early life or later.
Assuntos
Receptor 2 Toll-Like , Trypanosoma cruzi , Animais , Camundongos , Recém-Nascido , Humanos , Adulto , Receptor 4 Toll-Like , Fator de Necrose Tumoral alfa , Macrófagos , Interferon gama , Células Matadoras NaturaisRESUMO
Activated monocytes/macrophages that produce inflammatory cytokines and nitric oxide are crucial for controlling Trypanosoma cruzi infection. We previously showed that uninfected newborns from T. cruzi infected mothers (M+B- newborns) were sensitized to produce higher levels of inflammatory cytokines than newborns from uninfected mothers (M-B- newborns), suggesting that their monocytes were more activated. Thus, we wondered whether these cells might help limit congenital infection. We investigated this possibility by studying the activation status of M+B- cord blood monocytes and their ability to control T. cruzi in vitro infection. We showed that M+B- monocytes have an upregulated capacity to produce the inflammatory cytokine TNF-α and a better ability to control T. cruzi infection than M-B- monocytes. Our study also showed that T. cruzi-specific Abs transferred from the mother play a dual role by favoring trypomastigote entry into M+B- monocytes and inhibiting intracellular amastigote multiplication. These results support the possibility that some M+B- fetuses may eliminate the parasite transmitted in utero from their mothers, thus being uninfected at birth.
RESUMO
The genetic diversity of Echinococcus multilocularis (E. multilocularis) specimens isolated from patients with alveolar echinococcosis (AE), is a major field of investigation to correlate with sources of infection, clinical manifestations and prognosis of the disease. Molecular markers able to distinguish samples are commonly used worldwide, including the EmsB microsatellite. Here, we report the use of the EmsB microsatellite polymorphism data mining for the retrospective typing of Belgian specimens of E. multilocularis infecting humans. A total of 18 samples from 16 AE patients treated between 2006 and 2021 were analyzed through the EmsB polymorphism. Classification of specimens was performed through a dendrogram construction in order to compare the similarity among Belgian samples, some human referenced specimens on the EWET database (EmsB Website for the Echinococcus Typing) and previously published EmsB profiles from red foxes circulating in/near Belgium. According to a comparison with human European specimens previously genotyped in profiles, the 18 Belgian ones were classified into three EmsB profiles. Four specimens could not be assigned to an already known profile but some are near to EWET referenced samples. This study also highlights that some specimens share the same EmsB profile with profiles characterized in red foxes from north Belgium, the Netherlands, Luxembourg and French department near to the Belgian border. Furthermore, Belgian specimens present a genetic diversity and include one profile that don't share similarities with the ones referenced in the EWET database. However, at this geographical scale, there is no clear correlation between EmsB profiles and geographical location. Further studies including additional clinical samples and isolates from foxes and rodents of south Belgium are necessary to better understand the spatial and temporal circumstances of human infections but also a potential correlation between EmsB profiles and parasite virulence.
Assuntos
Echinococcus multilocularis , Animais , Humanos , Bélgica/epidemiologia , Echinococcus multilocularis/genética , Raposas/parasitologia , Estudos Retrospectivos , Variação Genética , Repetições de MicrossatélitesRESUMO
This work identifies the protein "macrophage infectivity potentiator" of Trypanosoma cruzi trypomastigotes, as supporting a new property, namely a pro-type 1 immunostimulatory activity on neonatal cells. In its recombinant form (rTcMIP), this protein triggers the secretion of the chemokines CCL2 and CCL3 by human umbilical cord blood cells from healthy newborns, after 24h in vitro culture. Further stimulation for 72h results in secretion of IFN-γ, provided cultures are supplemented with IL-2 and IL-18. rTcMIP activity is totally abolished by protease treatment and is not associated with its peptidyl-prolyl cis-trans isomerase enzymatic activity. The ability of rTcMIP to act as adjuvant was studied in vivo in neonatal mouse immunization models, using acellular diphtheria-tetanus-pertussis-vaccine (DTPa) or ovalbumin, and compared to the classical alum adjuvant. As compared to the latter, rTcMIP increases the IgG antibody response towards several antigens meanwhile skewing antibody production towards the Th-1 dependent IgG2a isotype. The amplitude of the rTcMIP adjuvant effect varied depending on the antigen and the co-presence of alum. rTcMIP did by contrast not increase the IgE response to OVA combined with alum. The discovery of the rTcMIP immunostimulatory effect on neonatal cells opens new possibilities for potential use as pro-type 1 adjuvant for neonatal vaccines. This, in turn, may facilitate the development of more efficient vaccines that can be given at birth, reducing infection associated morbidity and mortality which are the highest in the first weeks after birth.
Assuntos
Trypanosoma cruzi , Vacinas , Humanos , Camundongos , Recém-Nascido , Animais , Adjuvantes Imunológicos/farmacologia , Antígenos , Imunoglobulina G , MacrófagosRESUMO
We previously reported that Trypanosoma cruzi, the agent of Chagas disease, induces in congenitally infected fetuses a strong, adult-like parasite-specific CD8(+) T cell response producing IFN-γ (Hermann et al. in Blood 100:2153-2158, 2002). This suggests that the parasite is able to overcome the immaturity of neonatal antigen presenting cells, an issue which has not been previously addressed. We therefore investigated in vitro the ability of T. cruzi to activate cord blood DCs and compared its effect to that on adult cells. We show that T. cruzi induces phenotypic maturation of cord blood CD11c(+) myeloid DCs (mDCs), by enhancing surface expression of CD40, CD80, and CD83, and that parasite-specific IgG purified from cord blood of neonates born to T. cruzi-infected mothers amplify such expression. CD83, considered as the best marker of mature DCs, reaches higher level on cord blood than on adult mDCs. Allo-stimulation experiments showed that T. cruzi-activated cord blood mononuclear cells enriched in DCs (eDCs) stimulate proliferation of cord blood and adult CD3(+) T cells to a similar extent. Of note, T. cruzi-activated eDCs from cord blood trigger more potent proliferation of CD8(+) than CD8(-) (mainly CD4(+)) adult T cells, a feature not observed with adult eDCs. T cell proliferation is associated with IFN-γ release and down-regulation of IL-13 production. These data show that T. cruzi potently activates human cord blood mDCs and endows eDCs to trigger CD8(+) T cell proliferation and favor type 1 immune response. Interestingly, maternal antibodies can strengthen the development of mature DCs that might contribute to overcome the immunological immaturity associated with early life.
Assuntos
Anticorpos Antiprotozoários/imunologia , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Células Dendríticas/imunologia , Sangue Fetal/imunologia , Interferon gama/metabolismo , Trypanosoma cruzi/imunologia , Adulto , Antígenos CD/biossíntese , Antígeno B7-1/biossíntese , Antígenos CD40/biossíntese , Feminino , Expressão Gênica , Humanos , Imunoglobulinas/biossíntese , Recém-Nascido , Interleucina-13/biossíntese , Glicoproteínas de Membrana/biossíntese , Antígeno CD83RESUMO
We recently showed that T. cruzi parasites enhance expression of co-stimulatory surface molecules on cord blood myeloid dendritic cells (mDCs). This study aims to gain insight into the role of live parasites and intracellular infection in mDC activation using CSFE-labelled parasites. First, we observed that only a low proportion of mDCs was infected by T. cruzi after overnight culture of whole blood samples and trypomastigotes, as compared with monocytes and granulocytes. Cord blood mDCs were also less infected than their adult counterpart. Second, expression levels of HLA-DR and co-stimulatory molecules CD80, CD83 and CD86 were similar on infected and uninfected mDCs. Parasite lysate also triggered mDCs phenotypic maturation of both cord and adult blood cells, though in a lower extent than live parasites. These results strongly support a central role for extracellular trypomastigotes in activation of mDCs when parasites are incubated with whole blood cells. However, viability of trypomastigotes was not absolutely required for mDC activation.
Assuntos
Células Dendríticas , Células Mieloides , Trypanosoma cruzi/imunologia , Trypanosoma cruzi/patogenicidade , Adulto , Antígenos CD/metabolismo , Doença de Chagas/imunologia , Doença de Chagas/parasitologia , Células Dendríticas/imunologia , Células Dendríticas/virologia , Sangue Fetal/citologia , Antígenos HLA-DR/metabolismo , Humanos , Recém-Nascido , Células Mieloides/imunologia , Células Mieloides/virologiaRESUMO
BACKGROUND: Trichinellosis is a parasitic infection caused by nematodes of the genus Trichinella, and its principal mode of transmission is the consumption of raw or undercooked contaminated meat. Cardiac involvement in trichinellosis is unusual, yet it represents the most frequent cause of death. Here, we report a case in which Trichinella spiralis-associated myocarditis simulated a myocardial infarction. CASE PRESENTATION: A 35-year-old African man with no previous medical history was admitted to the emergency department for acute substernal discomfort at rest described as a pressure with no radiation. The electrocardiogram performed upon admission showed non-specific alterations of repolarization. Blood biology revealed high levels of troponin T and predominant eosinophilic leukocytosis. A transthoracic echocardiography was carried out and found a significant left ventricular concentric hypertrophy with a preserved ejection fraction. The septal and inferior walls, as well as the endocardium were hyperechogenic. The patient was hospitalized for eosinophilic myocarditis. The cause of hypereosinophilia was investigated, and a Trichinella spiralis serology came back strongly positive. A diagnosis of Trichinella spiralis associated-myocarditis was made.The patient was treated with albendazole-prednisolone dual therapy with favorable clinical and biological outcomes. CONCLUSION: The clinical suspicion of trichinellosis is based on suggestive epidemiology associated with the typical clinical presentation and the presence of eosinophilia. Eosinophilic myocarditis is a severe complication of trichinellosis which can result in death due to rhythm disorders. Chest pain, increase in troponins, and electrocardiographic abnormalities are all elements that can mimic a myocardial infarction and mislead clinicians.Abbreviations: ANCA: Anti-Neutrophil Cytoplasmic Antibodies; ANA: Anti-Nuclear Antibodies; ECDC: European Centre for Disease Prevention and Control; ECG: Electrocardiogram; ELISA: Enzyme-Linked ImmunoSorbent Assay; EMF: Endomyocardial Fibrosis; ES: Excretory-Secretory; ICT: International Commission on Trichinellosis; MRI: Magnetic Resonance Imaging.
Assuntos
Infarto do Miocárdio , Miocardite , Trichinella spiralis , Triquinelose , Adulto , Animais , Anticorpos Anti-Helmínticos , Antígenos de Helmintos , Ensaio de Imunoadsorção Enzimática , Proteínas de Helminto , Humanos , Masculino , Miocardite/diagnóstico , Triquinelose/diagnósticoRESUMO
Aims: To assess the epigenetic effects of in utero exposure to maternal Trypanosoma cruzi infection. Methods: We performed an epigenome-wide association study to compare the DNA methylation patterns of umbilical cord blood cells from uninfected babies from chagasic and uninfected mothers. DNA methylation was measured using Infinium EPIC arrays. Results: We identified a differential DNA methylation signature of fetal exposure to maternal T. cruzi infection, in the absence of parasite transmission, with 12 differentially methylated sites in B cells and CD4+ T cells, including eight protein-coding genes. Conclusion: These genes participate in hematopoietic cell differentiation and the immune response and may be involved in immune disorders. They also have been associated with several developmental disorders and syndromes.
Maternal infection with Trypanosoma cruzi, the parasite that causes Chagas disease, may influence fetal development, even in the absence of parasite transmission. Thus we investigated how exposure to maternal infection might lead to changes in gene expression in the infant, by examining changes in DNA methylation in the umbilical cord blood. We found that exposure to maternal infection alters DNA methylation of at least 12 sites, including eight genes. Expression of these genes may be altered, which may affect blood cell function, the immune response and newborn development later in life. Further studies should monitor newborns from infected mothers to better assess their health and possible longer term effects.
Assuntos
Doença de Chagas , Sangue Fetal , Doença de Chagas/genética , Doença de Chagas/metabolismo , Metilação de DNA , Epigênese Genética , Epigenômica , Feminino , Sangue Fetal/metabolismo , Humanos , Lactente , Recém-Nascido , Exposição Materna , Linfócitos TRESUMO
The newborns of women infected with the parasite Trypanosoma cruzi (the agent of Chagas disease) can be infected either before birth (congenitally), or after birth (as e.g., by vector route). Congenital Chagas disease can induce high levels of neonatal morbidity and mortality. Parasite-infected pregnant women transmit antibodies to their fetus. Antibodies, by opsonizing parasites, can promote phagocytosis and killing of T. cruzi by cells expressing FcγR, on the mandatory condition that such cells are sufficiently activated in an inflammatory context. Antibody-dependent enhancement (ADE) is a mechanism well described in viral infections, by which antibodies enhance entry of infectious agents into host cells by exploiting the phagocytic FcγR pathway. Previously reported Chagas disease studies highlighted a severe reduction of the maternal-fetal/neonatal inflammatory context in parasite-transmitting pregnant women and their congenitally infected newborns. Otherwise, experimental observations brought to light ADE of T. cruzi infection (involving FcγR) in mouse pups displaying maternally transferred antibodies, out of an inflammatory context. Herein, based on such data, we discuss the previously unconsidered possibility of a role of ADE in the trans-placental parasite transmission, and/or the development of severe and mortal clinical forms of congenital/neonatal Chagas disease in newborns of T. cruzi-infected mothers.
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Anticorpos Facilitadores , Doença de Chagas/imunologia , Transmissão Vertical de Doenças Infecciosas , Placenta/parasitologia , Trypanosoma cruzi/imunologia , Animais , Doença de Chagas/congênito , Doença de Chagas/parasitologia , Feminino , Humanos , Recém-Nascido , Camundongos , Placenta/imunologia , Gravidez , Complicações Parasitárias na Gravidez/imunologia , Gestantes , Trypanosoma cruzi/parasitologiaRESUMO
BACKGROUND: IgE characterizes the humoral response of allergic sensitization but less is known about what modulates its function and why some patients present clinical symptoms for a given IgE level and others do not. An IgE response also occurs during helminth diseases, independently of allergic symptoms. This response could be a model of non-functional IgE. OBJECTIVE: To study the IgE response against environmental allergens induced during natural helminth infection. METHODS: In 28 non allergic subjects from the periphery of Ho Chi Minh city with (H+, n = 18) and without helminth infection (H-, n = 10), we measured IgE and IgG4 against several components of Dermatophagoïdes pteronyssinus (Dpt) and Ascaris (a marker of immunization against nematodes), and determined the IgE component sensitization profile using microarray ISAC biochips. The functional ability of IgE to induce degranulation of cultured mast cells was evaluated in the presence of Dpt. RESULTS: Non allergic H+ subjects exhibited higher levels of IgE against Dpt compared to H- subjects. Dpt IgE were not functional in vitro and did not recognize usual Dpt major allergens. IgE recognized other component allergens that belong to different protein families, and most were glycosylated. Depletion of IgE recognizing carbohydrate cross-reactive determinant (CCD) did not induce a reduction in Dpt IgE. The Dpt IgG4 were not significantly different. CONCLUSION: Helminth infections induced IgE against allergens such as Dpt and molecular components that belong to different sources as well as against CCD (such as ß-1,2-xylose and/or âº-1,3-fucose substituted N-glycans). Dpt IgE were not able to induce degranulation of mast cells and were not explained by sensitization to usual major allergens or N-glycans.
Assuntos
Alérgenos/imunologia , Dermatophagoides pteronyssinus/imunologia , Imunoglobulina E/imunologia , Infecções por Nematoides/imunologia , Adolescente , Adulto , Idoso , Ancylostomatoidea/imunologia , Animais , Antígenos de Dermatophagoides/imunologia , Ascaris/imunologia , Estudos de Casos e Controles , Células Cultivadas , Reações Cruzadas , Feminino , Voluntários Saudáveis , Humanos , Imunoglobulina E/sangue , Masculino , Mastócitos , Pessoa de Meia-Idade , Infecções por Nematoides/sangue , Infecções por Nematoides/parasitologia , Cultura Primária de Células , Vietnã , Adulto JovemRESUMO
BACKGROUND: Like other helminths, hookworms (HW) induce a regulatory immune response able to modulate and dampen reactivity of the host to antigens. No data about the evolution of the immune response after treatment are available. We aim to phenotype the regulatory immune response during natural HW infection and its evolution after treatment. METHODOLOGY: Twenty hookworm infected (HW+) and 14 non-infected subjects HW-from endemic area in the periphery of Ho Chi Minh City were included. Blood and feces samples were obtained before, 2 and 4 weeks after treatment with Albendazole 400mg. Additional samples were obtained at 3 and 12 months in the HW+ group. Hematological parameters, Treg (CD4+CD25hiFoxP3hi) and surface molecules (CD39, CD62L, ICOS, PD-1, CD45RA) were measured as well as inflammatory and lymphocytes differentiation cytokines such as IL-1ß, IL-6, IFNγ, IL-4, IL-17, IL-10, IL-2 and TGFß. RESULTS: HW+ subjects showed higher Treg, TregICOS+, Treg PD1-, TregCD62L+ and CD45RA+FoxP3lo resting Treg (rTreg). CD45RA-FoxP3lo non-suppressive Treg cells were also increased. No preferential Th1/Th2 orientation was observed, nor difference for IL-10 between two groups. After treatment, Treg, TregICOS+, TregCD62L+, Treg PD1- and rTreg decreased while IL-4 and IL-6 cytokines increased. CONCLUSION: During HW infection, Treg are increased and characterized by a heterogeneous population: a highly suppressive as well as a non-suppressive T cells phenotype. After treatment, Treg with immune-suppressive phenotype exhibited a decrease parallel to an inflammatory Th2 response.
Assuntos
Albendazol/administração & dosagem , Ancylostomatoidea/imunologia , Anti-Helmínticos/administração & dosagem , Infecções por Uncinaria/tratamento farmacológico , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Adulto , Albendazol/farmacologia , Animais , Anti-Helmínticos/farmacologia , Sangue/parasitologia , Estudos de Casos e Controles , Citocinas/metabolismo , Fezes/parasitologia , Regulação da Expressão Gênica/efeitos dos fármacos , Infecções por Uncinaria/imunologia , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
Major histocompatibility complex (MHC) class I-specific inhibitory natural killer receptors (iNKRs) are expressed by subsets of T cells but the mechanisms inducing their expression are poorly understood, particularly for killer-cell immunoglobulin-like receptors (KIRs). The iNKRs are virtually absent from the surface of cord blood T cells but we found that KIR expression could be induced upon interleukin-2 stimulation in vitro. In addition, KIR expression was enhanced after treatment with 5-aza-2'-deoxycytidine, suggesting a role for DNA methylation. In vivo induction of KIR expression on cord blood T cells was also observed during a human congenital infection with Trypanosoma cruzi which triggers activation of fetal CD8(+) T cells. These KIR(+) T cells had an effector and effector/memory phenotype suggesting that KIR expression was consecutive to the antigenic stimulation; however, KIR was not preferentially found on parasite-specific CD8(+) T cells secreting interferon-gamma upon in vitro restimulation with live T. cruzi. These findings show that KIR expression is likely regulated by epigenetic mechanisms that occur during the maturation process of cord blood T cells. Our data provide a molecular basis for the appearance of KIRs on T cells with age and they have implications for T-cell homeostasis and the regulation of T-cell-mediated immune responses.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Doença de Chagas/congênito , Doença de Chagas/imunologia , Doenças do Recém-Nascido/imunologia , Receptores KIR/metabolismo , Trypanosoma cruzi/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Antígenos CD/metabolismo , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Complexo CD3/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Metilases de Modificação do DNA/antagonistas & inibidores , Decitabina , Inibidores Enzimáticos/farmacologia , Feminino , Sangue Fetal/citologia , Sangue Fetal/imunologia , Humanos , Imunofenotipagem , Recém-Nascido , Interleucina-2/farmacologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Gravidez , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Receptores KIR2DL1/metabolismo , Receptores KIR2DL2/metabolismo , Receptores KIR2DL3/metabolismo , Receptores KIR3DL1/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Congenital Chagas disease acquired special importance in Chile after the certification of the control of Triatoma infestans and transmission by blood donors affected with Trypanosoma cruzi. In order to establish adequate protocols for intervention and control in infected mother-neonate pairs in endemic zones of Chagas disease, we present partial results (2005-2008) of a pilot project which is being carried out in the Province of Choapa, IV Region, Chile, whose objectives are: determine the current prevalence of the disease in pregnant women, estimate the incidence of vertical transmission of T. cruzi to newborns, determine the lineages of the parasite present in mothers who do and do not transmit the disease, determine the prevalence of Chagas disease in maternal grandmothers of neonates and study placental histopathology. Preliminary results indicated that in this study period, 3.7% of the women who gave birth in the Province have Chagas disease and 2.5% of their newborns were infected. The most frequent T. cruzi genotypes found in mothers studied during pregnancy were TCI and TCIId, either alone or in mixed infections. A high percentage (74.3%) of the grandmothers studied was infected with the parasite. In 29 placentas from mothers with Chagas disease we observed edema, necrosis, fibrinoid deposits and slight lymphoplasmocyte infiltration. In three placentas we found erythroblastosis and in one of them amastigote forms of T. cruzi; this was one of the cases of congenital infection. The evaluation of the diagnostic and control protocols generated will allow us to determine if it has been possible to modify the natural history of vertical transmission of T. cruzi in Chile.
Assuntos
Doença de Chagas/transmissão , Doenças Endêmicas , Transmissão Vertical de Doenças Infecciosas/estatística & dados numéricos , Trypanosoma cruzi/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Chagas/congênito , Doença de Chagas/epidemiologia , Chile/epidemiologia , Feminino , Genótipo , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Pessoa de Meia-Idade , Placenta/parasitologia , Placenta/patologia , Gravidez , PrevalênciaRESUMO
Chagas disease (CD), caused by the protozoan parasite Trypanosoma cruzi, is considered a neglected tropical disease by the World Health Organization. Congenital transmission of CD is an increasingly relevant public health problem. It progressively becomes the main transmission route over others and can occur in both endemic and non-endemic countries. Though most congenitally infected newborns are asymptomatic at birth, they display higher frequencies of prematurity, low birth weight, and lower Apgar scores compared to uninfected ones, and some suffer from severe symptoms. If not diagnosed and treated, infected newborns are at risk of developing disabling and life-threatening chronic pathologies later in life. The success or failure of congenital transmission depends on interactions between the parasite, the placenta, the mother, and the fetus. We review and discuss here the current knowledge about these parameters, including parasite virulence factors such as exovesicles, placental tropism, potential placental defense mechanisms, the placental transcriptome of infected women, gene polymorphism, and the maternal and fetal/neonatal immune responses, that might modulate the risk of T. cruzi congenital transmission.
RESUMO
INTRODUCTION: The microscopic examination of microhematocrit tubes (mHCT) has been proposed as the gold standard for acute and congenital Chagas disease diagnosis. We compared different mHCT methodologies detecting T. cruzi parasites in the blood. METHODS: The rotating method, water mount, and immersion oil methods were compared for their suitability, sensitivity, and specificity. RESULTS: The rotating method was easier, faster, and more sensitive than the others with 100% specificity. CONCLUSIONS: The rotating method is feasible for laboratory technicians with standard training in microscopic techniques and is recommended for the diagnosis of acute Chagas disease in primary health care facilities.
Assuntos
Tubo Capilar , Centrifugação/métodos , Doença de Chagas/diagnóstico , Hematócrito/métodos , Parasitemia/diagnóstico , Trypanosoma cruzi/isolamento & purificação , Animais , Doença de Chagas/sangue , Doença de Chagas/parasitologia , Serviços de Laboratório Clínico , Humanos , Parasitemia/parasitologia , Sensibilidade e EspecificidadeRESUMO
Trypanosoma cruzi, the causative agent of Chagas disease, exhibits a high genetic variability and has been classified into six discrete typing units (DTUs) named TcI through TcVI. This genetic diversity is believed to be associated with clinical characteristics and outcomes, but evidence supporting such associations has been limited. Herein, we performed a phylogenetic analysis of T. cruzi sequences of the mini-exon intergenic region obtained from a large cohort of pregnant women and newborns from Argentina, Honduras, and Mexico, to assess parasite genetic diversity and possible associations with congenital transmission. Analysis of 105 samples (including five paired samples) from maternal and umbilical cord blood indicated that T. cruzi DTU distribution was similar among pregnant women and newborns from these three countries, with a high frequency of TcII-TcV-TcVI DTUs, including mixed infections with TcI. However, phylogenetic analysis revealed that although the same parasite haplotypes circulated in these three countries, they were present at different frequencies, leading to significant geographic differences. Of importance, a strong association was observed between parasite haplotypes and congenital infection of newborns. Thus, the identification of parasite haplotypes in pregnant women, but not of parasite DTUs, may help predict congenital transmission of T. cruzi.
Assuntos
Doença de Chagas/parasitologia , Filogenia , Complicações Parasitárias na Gravidez/parasitologia , Trypanosoma cruzi/genética , Argentina , Doença de Chagas/transmissão , Éxons , Feminino , Técnicas de Genotipagem , Haplótipos , Honduras , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas , México , Reação em Cadeia da Polimerase , GravidezRESUMO
Compared with South America, there is a lack of epidemiologic studies about the risk of congenital transmission of Trypanosoma cruzi in Central America and Mexico. It has been suggested that T. cruzi genotypes might differ by region and that congenital transmission might vary according to the parasite's genotype. Our objective was to compare T. cruzi congenital transmission rates in three countries. We performed an observational prospective study in 2011-2014 enrolling women at delivery in one hospital in Argentina, two hospitals in Honduras, and two hospitals in Mexico. Congenital T. cruzi infection was defined as the presence of one or more of the following criteria: presence of parasites in cord blood (direct parasitological microscopic examination) with positive polymerase chain reaction (PCR) in cord blood, presence of parasites in infant's blood at 4-8 weeks (direct parasitological microscopic examination), and persistence of T. cruzi-specific antibodies at 10 months, as measured by at least two tests. Among 28,145 enrolled women, 347 had at least one antibody rapid test positive in cord blood and a positive enzyme-linked immunosorbent assay in maternal blood. PCR in maternal blood was positive in 73.2% of the cases, and genotyping identified a majority of non-TcI in the three countries. We found no (0.0%; 95% confidence interval [CI]: 0.0, 2.0) confirmed congenital case in Honduras. Congenital transmission was 6.6% (95% CI: 3.1, 12.2) in Argentina and 6.3% (95% CI: 0.8, 20.8) in Mexico. Trypanosoma cruzi non-TcI predominated and risks of congenital transmission were similar in Argentina and Mexico.