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Eritrocitos , Malaria Vivax , Plasmodium vivax , Formación de Roseta , Humanos , Eritrocitos/parasitología , Eritrocitos/patología , Femenino , Persona de Mediana Edad , Malaria Vivax/diagnóstico , Malaria Vivax/tratamiento farmacológico , Malaria Vivax/parasitología , Malaria Vivax/patología , Plasmodium vivax/aislamiento & purificación , RecurrenciaRESUMEN
This study investigated the role of genetic variant rs8177374 in MAL/TIRAP gene in mediating the cytokine levels of IFN-γ, TNF-α, IL-10, and TGF-ß in malaria patients due to Plasmodium falciparum or P. vivax infection. The study included human blood samples collected from patients with malaria (n = 228) and healthy controls (n = 226). P. falciparum and P. vivax groups were established based on the causative species of Plasmodium. Malaria samples were divided into mild and severe malaria groups based on the symptoms that appeared in the patients, according to the WHO criteria. In a previous study, we genotyped rs8177374 via allele specific PCR strategy. In this study, cytokine levels were estimated in the blood plasma of rs8177374 genotype samples via Sandwich Enzyme Linked Immunosorbent Assay kits. Increased IFN-γ and TNF-α levels in presence of CC genotype indicates the role of CC genotype in both severe and mild malaria groups. Enhanced IL-10 levels in the CT genotype and mild malaria groups suggest a role of CT genotype and IL-10 in the mild clinical outcomes of malaria. The rs8177374 polymorphism in MAL/TIRAP plays an important role in malaria pathogenesis.
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Malaria Vivax , Malaria , Humanos , Citocinas/genética , Interferón gamma/genética , Interleucina-10/genética , Malaria Vivax/genética , Malaria Vivax/patología , Factor 88 de Diferenciación Mieloide/genética , Polimorfismo Genético , Factor de Crecimiento Transformador beta/genética , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Cerebral malaria is the most serious manifestation of severe falciparum malaria. Sequestration of infected red blood cells and microvascular dysfunction are key contributing processes. Whether these processes occur in early stage disease prior to clinical manifestations is unknown. To help localize and understand these processes during the early stages of infection, we performed 18-F fluorodeoxyglucose positron emission tomography/magnetic resonance imaging in volunteers with Plasmodium falciparum induced blood stage malaria (IBSM) infection, and compared results to individuals with P. vivax infection, in whom coma is rare. Seven healthy, malaria-naïve participants underwent imaging at baseline, and at early symptom onset a median 9 days following inoculation (n = 4 P. falciparum, n = 3 P. vivax). Participants with P. falciparum infection demonstrated marked lability in radiotracer uptake across all regions of the brain, exceeding expected normal variation (within subject coefficient of variation (wCV): 14.4%) compared to the relatively stable uptake in participants with P. vivax infection (wCV: 3.5%). No consistent imaging changes suggestive of microvascular dysfunction were observed in either group. Neuroimaging in early IBSM studies is safe and technically feasible, with preliminary results suggesting that differences in brain tropism between P. falciparum and P. vivax may occur very early in infection.
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Malaria Cerebral , Malaria Falciparum , Malaria Vivax , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Humanos , Imagen por Resonancia Magnética , Malaria Cerebral/diagnóstico por imagen , Malaria Falciparum/diagnóstico por imagen , Malaria Falciparum/patología , Malaria Vivax/patología , Plasmodium falciparum , Plasmodium vivax , Tomografía de Emisión de Positrones , Estudios ProspectivosRESUMEN
Plasmodium vivax is the major cause of human malaria in the Americas. How P. vivax infection can lead to poor clinical outcomes, despite low peripheral parasitaemia, remains a matter of intense debate. Estimation of total P. vivax biomass based on circulating markers indicates existence of a predominant parasite population outside of circulation. In this study, we investigate associations between both peripheral and total parasite biomass and host response in vivax malaria. We analysed parasite and host signatures in a cohort of uncomplicated vivax malaria patients from Manaus, Brazil, combining clinical and parasite parameters, multiplexed analysis of host responses, and ex vivo assays. Patterns of clinical features, parasite burden, and host signatures measured in plasma across the patient cohort were highly heterogenous. Further data deconvolution revealed two patient clusters, here termed Vivaxlow and Vivaxhigh. These patient subgroups were defined based on differences in total parasite biomass but not peripheral parasitaemia. Overall Vivaxlow patients clustered with healthy donors and Vivaxhigh patients showed more profound alterations in haematological parameters, endothelial cell (EC) activation, and glycocalyx breakdown and levels of cytokines regulating different haematopoiesis pathways compared to Vivaxlow. Vivaxhigh patients presented more severe thrombocytopenia and lymphopenia, along with enrichment of neutrophils in the peripheral blood and increased neutrophil-to-lymphocyte ratio (NLCR). When patients' signatures were combined, high association of total parasite biomass with a subset of markers of EC activation, thrombocytopenia, and lymphopenia severity was observed. Finally, machine learning models defined a combination of host parameters measured in the circulation that could predict the extent of parasite infection outside of circulation. Altogether, our data show that total parasite biomass is a better predictor of perturbations in host homeostasis in P. vivax patients than peripheral parasitaemia. This supports the emerging paradigm of a P. vivax tissue reservoir, particularly in the haematopoietic niche of bone marrow and spleen.
Asunto(s)
Malaria Vivax/parasitología , Parasitemia/parasitología , Plasmodium vivax/fisiología , Adulto , Biomasa , Femenino , Humanos , Malaria Vivax/patología , Malaria Vivax/fisiopatología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Knowledge about malaria associated with pregnancy is scarce in Latin America, and in Colombia, little is known about the magnitude of this infection. A systematic review was conducted to determine the prevalence of malaria associated with pregnancy (MAP) and each of its three forms: gestational (GM), placental (PM), and congenital (CM) tested using thick blood smear (TBS) and PCR. Also to compare the proportion of cases due to Plasmodium falciparum and Plasmodium vivax in Colombia from the year 2000-2020. We searched in Pubmed, Science Direct, EMBASE, EMCare, Cochrane Library, Scielo, Lilacs, Google Scholar, libraries, and repositories of Colombian universities, to obtain data on prevalence of GM, PM and CM with their respective testing method. We performed a meta-analysis with a random-effects model to obtain pooled prevalence of MAP and its three forms categorized by testing methods (TBS and PCR). We used data from 14 studies (out of 258 screened) contributing 7932, 2506 women for GM and PM respectively, also data on 1143 umbilical cord blood samples, and 899 peripheral blood of neonates. We found prevalence by TBS as, MAP 4.5% (95%CI = 2.9-6.9), GM 5.8% (95%CI = 3.8-8.7), PM 3.4% (95%CI = 1.7-6.7) and CM 1.3% (95%CI = 0.6-3.0). With PCR the prevalence was, MAP 14.4% (95%CI = 7.6-25.5), GM 16.7% (95%CI = 9.0-28.8), PM 11.0% (95%CI = 4.1-26.3) and CM 16.2% (95%CI = 8.2-29.5). The prevalence of submicroscopic infection was 8.5% (95%CI = 3.4-19.7) in GM, 10.1% (95%CI = 3.5-25.5) in PM and 22.0% (95%CI = 13.2-34.3) in CM. Infections by P. vivax was dominant over P. falciparum when tested with TBS, the PCR test gave similar proportions of P. falciparum and P. vivax. This meta-analysis has demonstrated high prevalence of MAP in Colombia, and highlights the urgent need to increase attention of researchers, research funding institutions, government agencies, and health authorities to study and intervene MAP, that has currently been under investigated.
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Malaria Falciparum , Malaria Vivax , Plasmodium falciparum/metabolismo , Plasmodium vivax/metabolismo , Complicaciones Parasitarias del Embarazo , Colombia , Femenino , Humanos , Malaria Falciparum/sangre , Malaria Falciparum/diagnóstico , Malaria Falciparum/epidemiología , Malaria Falciparum/patología , Malaria Vivax/sangre , Malaria Vivax/diagnóstico , Malaria Vivax/epidemiología , Malaria Vivax/patología , Embarazo , Complicaciones Parasitarias del Embarazo/sangre , Complicaciones Parasitarias del Embarazo/diagnóstico , Complicaciones Parasitarias del Embarazo/epidemiología , Complicaciones Parasitarias del Embarazo/patologíaRESUMEN
BACKGROUND: Plasmodium vivax has been proposed to infect and replicate in the human spleen and bone marrow. Compared to Plasmodium falciparum, which is known to undergo microvascular tissue sequestration, little is known about the behavior of P. vivax outside of the circulating compartment. This may be due in part to difficulties in studying parasite location and activity in life. METHODS AND FINDINGS: To identify organ-specific changes during the early stages of P. vivax infection, we performed 18-F fluorodeoxyglucose (FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) at baseline and just prior to onset of clinical illness in P. vivax experimentally induced blood-stage malaria (IBSM) and compared findings to P. falciparum IBSM. Seven healthy, malaria-naive participants were enrolled from 3 IBSM trials: NCT02867059, ACTRN12616000174482, and ACTRN12619001085167. Imaging took place between 2016 and 2019 at the Herston Imaging Research Facility, Australia. Postinoculation imaging was performed after a median of 9 days in both species (n = 3 P. vivax; n = 4 P. falciparum). All participants were aged between 19 and 23 years, and 6/7 were male. Splenic volume (P. vivax: +28.8% [confidence interval (CI) +10.3% to +57.3%], P. falciparum: +22.9 [CI -15.3% to +61.1%]) and radiotracer uptake (P. vivax: +15.5% [CI -0.7% to +31.7%], P. falciparum: +5.5% [CI +1.4% to +9.6%]) increased following infection with each species, but more so in P. vivax infection (volume: p = 0.72, radiotracer uptake: p = 0.036). There was no change in FDG uptake in the bone marrow (P. vivax: +4.6% [CI -15.9% to +25.0%], P. falciparum: +3.2% [CI -3.2% to +9.6%]) or liver (P. vivax: +6.2% [CI -8.7% to +21.1%], P. falciparum: -1.4% [CI -4.6% to +1.8%]) following infection with either species. In participants with P. vivax, hemoglobin, hematocrit, and platelet count decreased from baseline at the time of postinoculation imaging. Decrements in hemoglobin and hematocrit were significantly greater in participants with P. vivax infection compared to P. falciparum. The main limitations of this study are the small sample size and the inability of this tracer to differentiate between host and parasite metabolic activity. CONCLUSIONS: PET/MRI indicated greater splenic tropism and metabolic activity in early P. vivax infection compared to P. falciparum, supporting the hypothesis of splenic accumulation of P. vivax very early in infection. The absence of uptake in the bone marrow and liver suggests that, at least in early infection, these tissues do not harbor a large parasite biomass or do not provoke a prominent metabolic response. PET/MRI is a safe and noninvasive method to evaluate infection-associated organ changes in morphology and glucose metabolism.
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Médula Ósea/parasitología , Glucosa/metabolismo , Hígado/parasitología , Malaria Falciparum/parasitología , Malaria Vivax/parasitología , Bazo/parasitología , Médula Ósea/metabolismo , Médula Ósea/patología , Femenino , Humanos , Hígado/metabolismo , Hígado/patología , Imagen por Resonancia Magnética , Malaria Falciparum/patología , Malaria Falciparum/fisiopatología , Malaria Vivax/patología , Malaria Vivax/fisiopatología , Masculino , Plasmodium falciparum , Plasmodium vivax , Tomografía de Emisión de Positrones , Estudios Prospectivos , Queensland , Columna Vertebral/metabolismo , Columna Vertebral/parasitología , Columna Vertebral/patología , Bazo/metabolismo , Bazo/patología , Adulto JovenRESUMEN
BACKGROUND: Malaria in Brazil represents one of the highest percentages of Latin America cases, where approximately 84% of infections are attributed to Plasmodium (P.) vivax. Despite the high incidence, many aspects of gestational malaria resulting from P. vivax infections remain poorly studied. As such, we aimed to evaluate the consequences of P. vivax infections during gestation on the health of mothers and their neonates in an endemic area of the Amazon. METHODS AND FINDINGS: We have conducted an observational cohort study in Brazilian Amazon between January 2013 and April 2015. 600 pregnant women were enrolled and followed until delivery. After applying exclusion criteria, 329 mother-child pairs were included in the analysis. Clinical data regarding maternal infection, newborn's anthropometric measures, placental histopathological characteristics, and angiogenic and inflammatory factors were evaluated. The presence of plasma IgG against the P. vivax (Pv) MSP119 protein was used as marker of exposure and possible associations with pregnancy outcomes were analyzed. Multivariate logistic regression analysis revealed that P. vivax infections during the first trimester of pregnancy are associated with adverse gestational outcomes such as premature birth (adjusted odds ratio [aOR] 8.12, 95% confidence interval [95%CI] 2.69-24.54, p < 0.0001) and reduced head circumference (aOR 3.58, 95%CI 1.29-9.97, p = 0.01). Histopathology analysis showed marked differences between placentas from P. vivax-infected and non-infected pregnant women, especially regarding placental monocytes infiltrate. Placental levels of vasomodulatory factors such as angiopoietin-2 (ANG-2) and complement proteins such as C5a were also altered at delivery. Plasma levels of anti-PvMSP119 IgG in infected pregnant women were shown to be a reliable exposure marker; yet, with no association with improved pregnancy outcomes. CONCLUSIONS: This study indicates that P. vivax malaria during the first trimester of pregnancy represents a higher likelihood of subsequent poor pregnancy outcomes associated with marked placental histologic modification and angiogenic/inflammatory imbalance. Additionally, our findings support the idea that antibodies against PvMSP119 are not protective against poor pregnancy outcomes induced by P. vivax infections.
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Malaria Vivax/patología , Placenta/patología , Plasmodium vivax/patogenicidad , Complicaciones Infecciosas del Embarazo/patología , Resultado del Embarazo , Adolescente , Adulto , Antígenos de Protozoos/inmunología , Brasil , Femenino , Humanos , Inmunoglobulina G/sangre , Recién Nacido , Modelos Logísticos , Malaria Falciparum/epidemiología , Malaria Vivax/diagnóstico , Malaria Vivax/inmunología , Masculino , Análisis Multivariante , Plasmodium vivax/inmunología , Embarazo , Complicaciones Infecciosas del Embarazo/diagnóstico , Primer Trimestre del Embarazo , Nacimiento Prematuro/etiología , Estudios Prospectivos , Adulto JovenRESUMEN
O Plasmodium vivax é a espécie mais comum de parasita causador da malária humana encontrada fora da África, com maior endemicidade na Ásia, América Central e do Sul e Oceania. Embora o Plasmodium falciparum cause a maioria do número de mortes, o P. vivax pode levar à malária grave e resultar em morbimortalidade significativa. O desenvolvimento de uma vacina protetora será um passo importante para a eliminação da malária. Recentemente, uma formulação contendo as três variantes alélicas da proteína circumsporozoíta de P. vivax (PvCSP - All epitopes) induziu proteção parcial em camundongos após desafio com esporozoíto híbrido Plasmodium berghei (Pb), no qual as repetições centrais do PbCSP foram substituídas por repetições PvCSP-VK210 (esporozoítos Pb/Pv). No presente estudo, a proteína quimérica PvCSP contendo as variantes alélicas (VK210, VK247 e P. vivax-like) fusionadas com a proteína de nucleocapsídeo do vírus da caxumba (formando partículas semelhantes a nucleocapsídeos ou do inglês, NLP - Núcleo Like Particles) na ausência (NLP-CSPR) ou na presença do domínio C-terminal (CT) conservado da PvCSP (NLP-CSPCT). Para a realização do estudo selecionamos os adjuvantes Poly (I:C), um RNA sintético de dupla fita, agonista do receptor Toll do tipo 3 (TLR3) ou o adjuvante Montanide ISA 720, uma emulação óleo em agua. Para obter uma forte resposta imune, a levedura Pichia pastoris foi usada para expressar as proteínas recombinantes na forma de NLPs. Camundongos foram imunizados com cada uma das proteínas recombinantes em combinação com os adjuvantes citados. Embora ambas as NLPs tenham sido capazes de gerar uma forte resposta imune, com altos níveis de títulos e longevidade, apenas a formulação contendo a proteína NLP-CSPCT na presença do adjuvante Poly (I:C) foi selecionada para ser explorada em experimentos futuros. Esta proteína em combinação com o adjuvante Poly (I:C) induziu alta frequência de células secretoras de anticorpos específicas para o antígeno homólogo nos dias 5 e 30, no baço e na medula óssea, respectivamente. Altos títulos de IgG contra as 3 variantes de PvCSP foram detectados nos soros. Posteriormente camundongos imunizados com NLP-CSPCT foram desafiados com esporozoítos Pb/Pv e a parasitemia no 5º dia demonstrou proteção estéril em 30% dos camundongos desafiados. Portanto, a formulação vacinal gerada neste estudo tem potencial para ser explorada no desenvolvimento de uma vacina universal contra a malária causada por P. vivax
Plasmodium vivax is the most common species of human malaria parasite found outside Africa, with high endemicity in Asia, Central and South America, and Oceania. Although Plasmodium falciparum causes the majority of deaths, P. vivax can lead to severe malaria and result in significant morbidity and mortality. The development of a protective vaccine will be a major step toward malaria elimination. Recently, a formulation containing the three allelic variants of the P. vivax circumsporozoite protein (PvCSP--All epitopes) showed partial protection in mice after a challenge with the hybrid Plasmodium berghei (Pb) sporozoite, in which the PbCSP central repeats were replaced by the VK210 PvCSP repeats (Pb/Pv sporozoite). In the present study, the chimeric PvCSP allelic variants (VK210, VK247, and P. vivax-like) were fused with the mumps virus nucleocapsid protein (assembling into nucleo like particles - NLP) in the absence (NLP-CSPR) or presence of the conserved C-terminal (CT) domain of PvCSP (NLP-CSPCT). To carry out the study, we selected the adjuvants Poly (I:C), a synthetic double-stranded RNA, Toll-like receptor 3 (TLR3) agonist or Montanide ISA 720 adjuvant, an oil-water emulation. To elicit stronger immune response, Pichia pastoris yeast was used to produce the NLPs. Mice were immunized with each recombinant protein in combination with above. Although both NLPs were able to generate stronger immune response, with high antibodies titer levels and longevity, formulation containing NLP-CSPCT in the presence of Poly (I:C) was selected to be explored in future experiments. NLP-CSPCT with Poly (I:C) adjuvant presented a high frequency of antigen-specific antibody-secreting cells (ASCs) on days 5 and 30, respectively, in the spleen and bone marrow. Moreover, high IgG titers against all PvCSP variants were detected in the sera. Later, immunized mice with NLP-CSPCT were challenged with Pb/Pv sporozoites. Sterile protection was observed in 30% of the challenged mice. Therefore, this vaccine formulation use has the potential to be a good candidate for the development of a universal vaccine against P. vivax malaria.
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Animales , Femenino , Ratones , Plasmodium vivax/clasificación , Vacunas de Partículas Similares a Virus/análisis , ARN Bicatenario , Malaria Vivax/patología , Vacunas contra la Malaria , Receptor Toll-Like 3 , Malaria/patología , Células Productoras de Anticuerpos/clasificación , Antígenos/efectos adversosRESUMEN
Management of severe malaria remains a critical global challenge. In this study, using a multiplexed quantitative proteomics pipeline we systematically investigated the plasma proteome alterations in non-severe and severe malaria patients. We identified a few parasite proteins in severe malaria patients, which could be promising from a diagnostic perspective. Further, from host proteome analysis we observed substantial modulations in many crucial physiological pathways, including lipid metabolism, cytokine signaling, complement, and coagulation cascades in severe malaria. We propose that severe manifestations of malaria are possibly underpinned by modulations of the host physiology and defense machinery, which is evidently reflected in the plasma proteome alterations. Importantly, we identified multiple blood markers that can effectively define different complications of severe falciparum malaria, including cerebral syndromes and severe anemia. The ability of our identified blood markers to distinguish different severe complications of malaria may aid in developing new clinical tests for monitoring malaria severity.
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Malaria Falciparum/diagnóstico , Malaria Falciparum/patología , Proteómica/métodos , Anemia/diagnóstico , Anemia/patología , Biomarcadores/sangre , Dengue/diagnóstico , Dengue/metabolismo , Dengue/patología , Humanos , Malaria Falciparum/metabolismo , Malaria Vivax/sangre , Malaria Vivax/metabolismo , Malaria Vivax/patologíaRESUMEN
BACKGROUND: Plasmodium vivax, once considered benign species, is recently being recognised to be causing severe malaria like Plasmodium falciparum. In the present study, the authors report the trends in malaria severity in P. vivax among patients from a Delhi government hospital. The aim of the study was to understand the disease severity and the burden of severe vivax malaria. METHODS: A hospital based study was carried out from June 2017 to December 2018 at a tertiary care centre from Delhi, India. Patients were tested for malaria using peripheral blood smear (PBS) and/or rapid malaria antigen test (RMAT). The severe and non-severe vivax malaria categorization was done as per the WHO guidelines. Sociodemographic, clinic and paraclinical data were collected from patients and their medical records. RESULTS: Of the 205 patients, 177 (86.3%) had P. vivax infection, 22 (10.7%) had P. falciparum infection and six (2.9%) had mixed infection with both the species. Out of 177 P. vivax cases included in this study one or more manifestations of severe malaria was found in 58 cases (32.7%). Severe anaemia (56.9%), jaundice (15%) and significant bleeding (15%) were the most common complications reported in most of patients, along with thrombocytopenia. CONCLUSIONS: In this study, it is evident that vivax malaria is emerging as the new severe disease in malaria patients, a significant shift in the paradigm of P. vivax pathogenesis. The spectrum of complications and alterations in the laboratory parameters in P. vivax clinical cases also indicate the recent shift in the disease severity.
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Malaria Vivax/patología , Adolescente , Adulto , Sangre/parasitología , Niño , Preescolar , Femenino , Humanos , India/epidemiología , Malaria Vivax/complicaciones , Malaria Vivax/epidemiología , Malaria Vivax/parasitología , Masculino , Persona de Mediana Edad , Plasmodium vivax/fisiología , Índice de Severidad de la Enfermedad , Centros de Atención Terciaria/estadística & datos numéricos , Adulto JovenRESUMEN
BACKGROUND: Thrombocytopenia in malaria involves platelet destruction and consumption; however, the cellular response underlying this phenomenon has still not been elucidated. OBJECTIVE: To find associations between platelet indices and unbalanced Th1/Th2/Th17 cytokines as a response to thrombocytopenia in Plasmodium vivax infected (Pv-MAL) patients. METHODS: Platelet counts and quantification of Th1/Th2/Th17 cytokine levels were compared in 77 patients with uncomplicated P. vivax malaria and 37 healthy donors from the same area (endemic control group - ENCG). FINDINGS: Thrombocytopenia was the main manifestation in 55 patients, but was not associated with parasitaemia. The Pv-MAL patients showed increases in the mean platelet volume (MPV), which may be consistent with larger or megaplatelets. Contrary to the findings regarding the endemic control group, MPV and platelet distribution width (PDW) did not show an inverse correlation, due the increase in the heterogeneity of platelet width. In addition, the Pv-MAL patients presented increased IL-1ß and reduced IL-12p70 and IL-2 serum concentrations. Furthermore, the reduction of these cytokines was associated with PDW values. MAIN CONCLUSIONS: Our data demonstrate that an increase in MPV and the association between reductions of IL-2 and IL-12 and PDW values may be an immune response to thrombocytopenia in uncomplicated P. vivax malaria.
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Subgrupos Linfocitarios/inmunología , Malaria Vivax/inmunología , Malaria Vivax/patología , Plasmodium vivax/inmunología , Trombocitopenia/sangre , Trombocitopenia/patología , Humanos , Interleucina-12/sangre , Interleucina-2/sangre , Malaria Vivax/sangre , Malaria Vivax/parasitología , Trombocitopenia/parasitologíaRESUMEN
Autoantibodies play an important role in the destruction of non-infected red blood cells (nRBCs) during malaria. However, the relationship between this clearance and ABO blood groups is yet to be fully enlightened, especially for Plasmodium vivax infections. Here we show that anti-RBC IgG and IgM are increased in anemic patients with acute vivax malaria. Furthermore, both antibodies are able to decrease the deformability of nRBCs, but only IgG can induce in vitro erythrophagocytosis. Such effects are enhanced in type O erythrocytes, suggesting that individuals from this blood group infected with P. vivax malaria may be more susceptible to develop anemia.
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Sistema del Grupo Sanguíneo ABO/inmunología , Anemia/inmunología , Autoanticuerpos/inmunología , Eritrocitos/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Malaria Vivax/inmunología , Anemia/etiología , Anemia/patología , Membrana Celular/patología , Susceptibilidad a Enfermedades , Eritrocitos/patología , Humanos , Malaria Vivax/complicaciones , Malaria Vivax/patología , Fagocitosis , Plasmodium vivaxRESUMEN
BACKGROUND Thrombocytopenia in malaria involves platelet destruction and consumption; however, the cellular response underlying this phenomenon has still not been elucidated. OBJECTIVE To find associations between platelet indices and unbalanced Th1/Th2/Th17 cytokines as a response to thrombocytopenia in Plasmodium vivax infected (Pv-MAL) patients. METHODS Platelet counts and quantification of Th1/Th2/Th17 cytokine levels were compared in 77 patients with uncomplicated P. vivax malaria and 37 healthy donors from the same area (endemic control group - ENCG). FINDINGS Thrombocytopenia was the main manifestation in 55 patients, but was not associated with parasitaemia. The Pv-MAL patients showed increases in the mean platelet volume (MPV), which may be consistent with larger or megaplatelets. Contrary to the findings regarding the endemic control group, MPV and platelet distribution width (PDW) did not show an inverse correlation, due the increase in the heterogeneity of platelet width. In addition, the Pv-MAL patients presented increased IL-1β and reduced IL-12p70 and IL-2 serum concentrations. Furthermore, the reduction of these cytokines was associated with PDW values. MAIN CONCLUSIONS Our data demonstrate that an increase in MPV and the association between reductions of IL-2 and IL-12 and PDW values may be an immune response to thrombocytopenia in uncomplicated P. vivax malaria.
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Humanos , Plasmodium vivax/inmunología , Trombocitopenia/patología , Trombocitopenia/sangre , Subgrupos Linfocitarios/inmunología , Malaria Vivax/inmunología , Malaria Vivax/patología , Trombocitopenia/parasitología , Interleucina-2/sangre , Malaria Vivax/parasitología , Malaria Vivax/sangre , Interleucina-12/sangreRESUMEN
BACKGROUND: Plasmodium vivax and Hepatitis B virus (HBV) are globally outspread in similar geographic regions. The concurrence of both infections and its association with some degree of protection against symptomatic and/or severe vivax malaria has been already described. Nevertheless, data on how host response to both pathogens undermines the natural progression of the malarial infection are scarce. Here, a large cohort of vivax malaria and HBV patients is retrospectively analyzed in an attempt to depict how inflammatory characteristics could be potentially related to the protection to severe malaria in coinfection. METHODS: A retrospective analysis of a databank containing 601 individuals from the Brazilian Amazon, including 179 symptomatic P. vivax monoinfected patients, 145 individuals with asymptomatic P. vivax monoinfection, 28 P. vivax-HBV coinfected patients, 29 HBV monoinfected subjects and 165 healthy controls, was performed. Data on plasma levels of multiple chemokines, cytokines, acute phase proteins, hepatic enzymes, bilirubin and creatinine were analyzed to describe and compare biochemical profiles associated to each type of infection. RESULTS: Coinfected individuals predominantly presented asymptomatic malaria, referred increased number of previous malaria episodes than symptomatic vivax-monoinfected patients, and were predominantly younger than asymptomatic vivax-monoinfected individuals. Coinfection was hallmarked by substantially elevated concentrations of interleukin (IL)-10 and heightened levels of C-C motif chemokine ligand (CCL)2. Correlation matrices showed that coinfected individuals presented a distinct biomarker profile when compared to asymptomatic or symptomatic P. vivax patients, or HBV-monoinfected individuals. Parasitemia could distinguish coinfected from symptomatic or asymptomatic P. vivax-monoinfected patients. HBV viremia was associated to distinct inflammatory profiles in HBV-monoinfected and coinfected patients. CONCLUSION: The findings demonstrate a distinct inflammatory profile in coinfected patients, with characteristics associated with immune responses to both pathogens. These host responses to P. vivax and HBV, in conjunction, could be potentially associated, if not mainly responsible, for the protection against symptomatic vivax malaria.
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Coinfección/patología , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/patología , Factores Inmunológicos/sangre , Malaria Vivax/complicaciones , Malaria Vivax/patología , Adulto , Análisis Químico de la Sangre , Brasil , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
Malaria pathogenesis is caused by the replication of Plasmodium parasites within the red blood cells (RBCs) of the vertebrate host. This selective pressure has favored the evolution of protective polymorphisms in erythrocyte proteins, a subset of which serve as cognate receptors for parasite invasion ligands. Recently, the generation of RBCs from immortalized hematopoietic stem cells (HSCs) has offered a more tractable system for genetic manipulation and long-term in vitro culture, enabling elucidation of the functional determinants of host susceptibility in vitro. Here we report the generation of an immortalized erythroid progenitor cell line (EJ cells) from as few as 100 000 peripheral blood mononuclear cells. It offers a robust method for the creation of customized model systems from small volumes of peripheral blood. The EJ cell differentiation mirrored erythropoiesis of primary HSCs, yielding orthochromatic erythroblasts and enucleated RBCs after eight days (ejRBCs). The ejRBCs supported invasion by both P. vivax and P. falciparum. To demonstrate the genetic tractability of this system, we used CRISPR/Cas9 to disrupt the Duffy Antigen/Receptor for Chemokines (DARC) gene, which encodes the canonical receptor of P. vivax in humans. Invasion of P. vivax into this DARC-knockout cell line was strongly inhibited providing direct genetic evidence that P. vivax requires DARC for RBC invasion. Further, genetic complementation of DARC restored P. vivax invasion. Taken together, the peripheral blood immortalization method presented here offers the capacity to generate biologically representative model systems for studies of blood-stage malaria invasion from the peripheral blood of donors harboring unique genetic backgrounds, or rare polymorphisms.
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Células Precursoras Eritroides , Malaria Falciparum , Malaria Vivax , Modelos Biológicos , Células Madre de Sangre Periférica , Plasmodium falciparum/metabolismo , Plasmodium vivax/metabolismo , Línea Celular Transformada , Células Precursoras Eritroides/metabolismo , Células Precursoras Eritroides/parasitología , Células Precursoras Eritroides/fisiología , Humanos , Malaria Falciparum/metabolismo , Malaria Falciparum/patología , Malaria Vivax/metabolismo , Malaria Vivax/patología , Células Madre de Sangre Periférica/metabolismo , Células Madre de Sangre Periférica/parasitología , Células Madre de Sangre Periférica/patologíaRESUMEN
BACKGROUND: There has been a marked increase in the reporting of confirmed vivax malaria cases in certain geographical areas. This study investigated cases of severe vivax malaria in the Republic of Korea. METHODS: We retrospectively reviewed the medical records of adult patients diagnosed with vivax malaria in the Republic of Korea during the period 2000 to 2016. Diagnosis was made using the World Health Organization criteria, with the exception of parasite density. RESULTS: Among 1366 malaria cases, 255 (18.7%) were classified as severe vivax malaria, and 46 (3.4%) required intensive care. None of patients died of malaria. Patients with severe vivax malaria were older and had more comorbidity. The enrollment periods were classified into three groups, 2000 to 2005 (506 cases), 2006 to 2010 (696 cases), and 2011 to 2016 (304 cases). Malaria cases decreased from 2011 to 2016, but severe malaria cases increased significantly over time (14.3%, 20.1%, and 22.8%, p = 0.003). Common severe manifestations were shock (45.6%) and jaundice (43.1%). CONCLUSIONS: Cases of severe malaria increased, and shock and jaundice were the predominant findings of severe vivax malaria in the Republic of Korea.
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Malaria Vivax/epidemiología , Adulto , Femenino , Humanos , Malaria Vivax/patología , Masculino , Persona de Mediana Edad , República de Corea/epidemiología , Estudios RetrospectivosRESUMEN
The association of hematological parameters especially platelet parameters with disease severity in malaria is poorly understood. We aimed to characterize the platelet parameters across Plasmodium falciparum and Plasmodium vivax malaria stratified by severity and to elucidate the potential role of platelet parameters to predict disease severity. Individuals > 18 years, of either gender with microscopically proven symptomatic malaria were prospectively enrolled between October 2014 and August 2016 in a tertiary center in Manipal, India. Severity of malaria was defined as per the WHO definition. Among 159 patients, 32 (20.1%) had severe malaria. 116 (73%) had infection with P. vivax, 37 (23%) P. falciparum and 6 mixed infection. Thrombocytopenia was seen in 32 (86.4%) of P. falciparum and 105 (90.5%) of P. vivax malaria cases. Patients with renal failure (p=0.02), shock (p=0.04) and liver dysfunction (p<0.001) had significantly lower platelet count compared to those who did not. Admission platelet count of 50,000 cell/mm3 had a sensitivity and specificity of 65.6% and 70.6% respectively, to discriminate severe malaria. A plateletcrit of 0.05% had a sensitivity and specificity of 65.6 % and of 70.6% respectively. Thrombocytopenia was seen in 89.3% of malaria cases due to both P. vivax and P. falciparum. Platelet count and plateletcrit could be used as markers of disease severity. P. vivax malaria which has been traditionally regarded as 'benign' can be as sinister and menacing as P. falciparum malaria and hence warrants equal attention. Unnecessary transfusion of platelets should be avoided.
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Plaquetas/patología , Pruebas Diagnósticas de Rutina/métodos , Malaria Falciparum/patología , Malaria Vivax/patología , Recuento de Plaquetas , Índice de Severidad de la Enfermedad , Adulto , Femenino , Humanos , India , Malaria Falciparum/diagnóstico , Malaria Vivax/diagnóstico , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sensibilidad y EspecificidadRESUMEN
Plasmodium vivax invasion of reticulocytes relies on distinct receptor-ligand interactions between the parasite and host erythrocytes. Engagement of the highly polymorphic domain II of the P. vivax Duffy-binding protein (DBPII) with the erythrocyte's Duffy Ag receptor for chemokines (DARC) is essential. Some P. vivax-exposed individuals acquired Abs to DBPII that block DBPII-DARC interaction and inhibit P. vivax reticulocyte invasion, and Ab levels correlate with protection against P. vivax malaria. To better understand the functional characteristics and fine specificity of protective human Abs to DBPII, we sorted single DBPII-specific IgG+ memory B cells from three individuals with high blocking activity to DBPII. We identified 12 DBPII-specific human mAbs from distinct lineages that blocked DBPII-DARC binding. All mAbs were P. vivax strain transcending and targeted known binding motifs of DBPII with DARC. Eleven mAbs competed with each other for binding, indicating recognition of the same or overlapping epitopes. Naturally acquired blocking Abs to DBPII from individuals with high levels residing in different P. vivax-endemic areas worldwide competed with mAbs, suggesting broadly shared recognition sites. We also found that mAbs inhibited P. vivax entry into reticulocytes in vitro. These findings suggest that IgG+ memory B cell activity in individuals with P. vivax strain-transcending Abs to DBPII display a limited clonal response with inhibitory blocking directed against a distinct region of the molecule.
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Anticuerpos Bloqueadores/inmunología , Anticuerpos Monoclonales/inmunología , Especificidad de Anticuerpos , Linfocitos B/inmunología , Memoria Inmunológica , Malaria Vivax/inmunología , Plasmodium vivax/inmunología , Antígenos de Protozoos/inmunología , Linfocitos B/patología , Femenino , Humanos , Malaria Vivax/patología , Malaria Vivax/prevención & control , Masculino , Proteínas Protozoarias/inmunología , Receptores de Superficie Celular/inmunologíaRESUMEN
BACKGROUND: Recent reports highlight malaria as a frequent diagnosis in migrants who originate from Eritrea. A descriptive analysis of GeoSentinel cases of malaria in Eritrean migrants was done together with a literature review to elucidate key attributes of malaria in this group with a focus on possible areas of acquisition of malaria and treatment challenges. RESULTS: A total of 146 cases were identified from the GeoSentinel database from 1999 through September 2017, with a marked increase in 2014 and 2015. All patients originated from Eritrea and the main reporting GeoSentinel sites were in Norway, Switzerland, Sweden, Israel and Germany. The majority of patients (young adult males) were diagnosed with malaria following arrival in the host country. All patients had a possible exposure in Eritrea, but may have been exposed in documented transit countries including Ethiopia, Sudan and possibly Libya in detention centres. Most infections were due to Plasmodium vivax (84.2%), followed by Plasmodium falciparum (8.2%). Two patients were pregnant, and both had P. vivax malaria. Some 31% of the migrants reported having had malaria while in transit. The median time to onset of malaria symptoms post arrival in the host country was 39 days. Some 66% of patients were hospitalized and nine patients had severe malaria (according to WHO criteria), including five due to P. vivax. CONCLUSIONS: The 146 cases of mainly late onset, sometimes severe, P. vivax malaria in Eritrean migrants described in this multi-site, global analysis reflect the findings of single-centre analyses identified in the literature search. Host countries receiving asylum-seekers from Eritrea need to be prepared for large surges in vivax and, to a lesser extent, falciparum malaria, and need to be aware and prepared for glucose-6-phosphate dehydrogenase deficiency testing and primaquine treatment, which is difficult to procure and mainly unlicensed in Europe. There is an urgent need to explore the molecular epidemiology of P. vivax in Eritrean asylum-seekers, to investigate the area of acquisition of P. vivax along common transit routes and to determine whether there has been re-introduction of malaria in areas, such as Libya, where malaria is considered eliminated, but where capable vectors and Plasmodium co-circulate.