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1.
Nat Microbiol ; 6(9): 1163-1174, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34400833

RESUMO

Periodic fever is a characteristic clinical feature of human malaria, but how parasites survive febrile episodes is not known. Although the genomes of Plasmodium species encode a full set of chaperones, they lack the conserved eukaryotic transcription factor HSF1, which activates the expression of chaperones following heat shock. Here, we show that PfAP2-HS, a transcription factor in the ApiAP2 family, regulates the protective heat-shock response in Plasmodium falciparum. PfAP2-HS activates the transcription of hsp70-1 and hsp90 at elevated temperatures. The main binding site of PfAP2-HS in the entire genome coincides with a tandem G-box DNA motif in the hsp70-1 promoter. Engineered parasites lacking PfAP2-HS have reduced heat-shock survival and severe growth defects at 37 °C but not at 35 °C. Parasites lacking PfAP2-HS also have increased sensitivity to imbalances in protein homeostasis (proteostasis) produced by artemisinin, the frontline antimalarial drug, or the proteasome inhibitor epoxomicin. We propose that PfAP2-HS contributes to the maintenance of proteostasis under basal conditions and upregulates specific chaperone-encoding genes at febrile temperatures to protect the parasite against protein damage.


Assuntos
Febre/parasitologia , Malária Falciparum/parasitologia , Plasmodium falciparum/fisiologia , Proteínas de Protozoários/metabolismo , Fatores de Transcrição/metabolismo , Antimaláricos/farmacologia , Artemisininas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Resposta ao Choque Térmico , Temperatura Alta , Humanos , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Plasmodium falciparum/crescimento & desenvolvimento , Proteostase/efeitos dos fármacos , Proteínas de Protozoários/genética , Fatores de Transcrição/genética
2.
Nat Commun ; 12(1): 4806, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376675

RESUMO

The malaria parasite Plasmodium falciparum replicates inside erythrocytes in the blood of infected humans. During each replication cycle, a small proportion of parasites commits to sexual development and differentiates into gametocytes, which are essential for parasite transmission via the mosquito vector. Detailed molecular investigation of gametocyte biology and transmission has been hampered by difficulties in generating large numbers of these highly specialised cells. Here, we engineer P. falciparum NF54 inducible gametocyte producer (iGP) lines for the routine mass production of synchronous gametocytes via conditional overexpression of the sexual commitment factor GDV1. NF54/iGP lines consistently achieve sexual commitment rates of 75% and produce viable gametocytes that are transmissible by mosquitoes. We also demonstrate that further genetic engineering of NF54/iGP parasites is a valuable tool for the targeted exploration of gametocyte biology. In summary, we believe the iGP approach developed here will greatly expedite basic and applied malaria transmission stage research.


Assuntos
Sistemas CRISPR-Cas , Malária Falciparum/sangue , Plasmodium falciparum/genética , Esporos de Protozoários/genética , Animais , Anopheles/parasitologia , Células Cultivadas , Eritrócitos/parasitologia , Hepatócitos/citologia , Hepatócitos/parasitologia , Interações Hospedeiro-Parasita , Humanos , Malária Falciparum/parasitologia , Malária Falciparum/transmissão , Microscopia de Fluorescência , Mosquitos Vetores/parasitologia , Plasmodium falciparum/fisiologia , Esporos de Protozoários/fisiologia , Esporozoítos/genética , Esporozoítos/fisiologia
3.
Nat Commun ; 12(1): 4851, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381047

RESUMO

Pathogens are thought to use host molecular cues to control when to initiate life-cycle transitions, but these signals are mostly unknown, particularly for the parasitic disease malaria caused by Plasmodium falciparum. The chemokine CXCL10 is present at high levels in fatal cases of cerebral malaria patients, but is reduced in patients who survive and do not have complications. Here we show a Pf 'decision-sensing-system' controlled by CXCL10 concentration. High CXCL10 expression prompts P. falciparum to initiate a survival strategy via growth acceleration. Remarkably, P. falciparum inhibits CXCL10 synthesis in monocytes by disrupting the association of host ribosomes with CXCL10 transcripts. The underlying inhibition cascade involves RNA cargo delivery into monocytes that triggers RIG-I, which leads to HUR1 binding to an AU-rich domain of the CXCL10 3'UTR. These data indicate that when the parasite can no longer keep CXCL10 at low levels, it can exploit the chemokine as a cue to shift tactics and escape.


Assuntos
Quimiocina CXCL10/metabolismo , Malária Falciparum/parasitologia , Plasmodium falciparum/fisiologia , Regiões 3' não Traduzidas , Quimiocina CXCL10/genética , Proteína DEAD-box 58/metabolismo , Proteína Semelhante a ELAV 1/metabolismo , Vesículas Extracelulares/metabolismo , Interações Hospedeiro-Parasita , Humanos , Estágios do Ciclo de Vida , Malária Falciparum/imunologia , Monócitos/metabolismo , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/metabolismo , Biossíntese de Proteínas , RNA de Protozoário/metabolismo , Receptores Imunológicos/metabolismo , Ribossomos/metabolismo , Células THP-1
4.
Nat Commun ; 12(1): 4226, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244481

RESUMO

RIFIN, a large family of Plasmodium variant surface antigens, plays a crucial role in malaria pathogenesis by mediating immune suppression through activation of inhibitory receptors such as LAIR1, and antibodies with LAIR1 inserts have been identified that bind infected erythrocytes through RIFIN. However, details of RIFIN-mediated LAIR1 recognition and receptor activation have been unclear. Here, we use negative-stain EM to define the architecture of LAIR1-inserted antibodies and determine crystal structures of RIFIN-variable 2 (V2) domain in complex with a LAIR1 domain. These structures reveal the LAIR1-binding region of RIFIN to be hydrophobic and membrane-distal, to exhibit extensive structural diversity, and to interact with RIFIN-V2 in a one-to-one fashion. Through structural and sequence analysis of various LAIR1 constructs, we identify essential elements of RIFIN-binding on LAIR1. Furthermore, a structure-derived LAIR1-binding sequence signature ascertained >20 LAIR1-binding RIFINs, including some from P. falciparum field strains and Plasmodium species infecting gorillas and chimpanzees.


Assuntos
Antígenos de Protozoários/ultraestrutura , Malária Falciparum/imunologia , Proteínas de Membrana/ultraestrutura , Plasmodium falciparum/imunologia , Proteínas de Protozoários/ultraestrutura , Receptores Imunológicos/ultraestrutura , Anticorpos Antiprotozoários/genética , Anticorpos Antiprotozoários/metabolismo , Variação Antigênica/genética , Antígenos de Protozoários/imunologia , Antígenos de Protozoários/metabolismo , Cristalografia por Raios X , Humanos , Malária Falciparum/parasitologia , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Mutação , Plasmodium falciparum/metabolismo , Domínios Proteicos/genética , Proteínas de Protozoários/imunologia , Proteínas de Protozoários/metabolismo , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo
5.
Molecules ; 26(13)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34279413

RESUMO

Malaria i a serious health problem caused by Plasmodium spp. that can be treated by an anti-folate pyrimethamine (PYR) drug. Deferiprone (DFP) is an oral iron chelator used for the treatment of iron overload and has been recognized for its potential anti-malarial activity. Deferiprone-resveratrol hybrids (DFP-RVT) have been synthesized to present therapeutic efficacy at a level which is superior to DFP. We have focused on determining the lipophilicity, toxicity and inhibitory effects on P. falciparum growth and the iron-chelating activity of labile iron pools (LIPs) by DFP-RVT. According to our findings, DFP-RVT was more lipophilic than DFP (p < 0.05) and nontoxic to blood mononuclear cells. Potency for the inhibition of P. falciparum was PYR > DFP-RVT > DFP in the 3D7 strain (IC50 = 0.05, 16.82 and 47.67 µM, respectively) and DFP-RVT > DFP > PYR in the K1 strain (IC50 = 13.38, 42.02 and 105.61 µM, respectively). The combined treatment of DFP-RVT with PYR additionally enhanced the PYR activity in both strains. DFP-RVT dose-dependently lowered LIP levels in PRBCs and was observed to be more effective than DFP at equal concentrations. Thus, the DFP-RVT hybrid should be considered a candidate as an adjuvant anti-malarial drug through the deprivation of cellular iron.


Assuntos
Antimaláricos/farmacologia , Deferiprona/farmacologia , Eritrócitos/efeitos dos fármacos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Resveratrol/farmacologia , Antioxidantes/farmacologia , Eritrócitos/parasitologia , Humanos , Quelantes de Ferro/farmacologia , Malária Falciparum/parasitologia
6.
Molecules ; 26(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34279438

RESUMO

Molecular hybridization is a drug discovery strategy that involves the rational design of new chemical entities by the fusion (usually via a covalent linker) of two or more drugs, both active compounds and/or pharmacophoric units recognized and derived from known bioactive molecules. The expected outcome of this chemical modification is to produce a new hybrid compound with improved affinity and efficacy compared to the parent drugs. Additionally, this strategy can result in compounds presenting modified selectivity profiles, different and/or dual modes of action, reduced undesired side effects and ultimately lead to new therapies. In this study, molecular hybridization was used to generate new molecular hybrids which were tested against the chloroquine sensitive (NF54) strain of P. falciparum. To prepare the new molecular hybrids, the quinoline nucleus, one of the privileged scaffolds, was coupled with various chalcone derivatives via an appropriate linker to produce a total of twenty-two molecular hybrids in 11%-96% yield. The synthesized compounds displayed good antiplasmodial activity with IC50 values ranging at 0.10-4.45 µM.


Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Chalconas/química , Descoberta de Drogas , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Quinolinas/química , Humanos , Malária Falciparum/parasitologia , Relação Estrutura-Atividade
7.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205228

RESUMO

BACKGROUND: Artemether-lumefantrine is a highly effective artemisinin-based combination therapy that was adopted in Mali as first-line treatment for uncomplicated Plasmodium falciparum malaria. This study was designed to measure the efficacy of artemether-lumefantrine and to assess the selection of the P. falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multi-drug resistance 1 (pfmdr1) genotypes that have been associated with drug resistance. METHODS: A 28-day follow-up efficacy trial of artemether-lumefantrine was conducted in patients aged 6 months and older suffering from uncomplicated falciparum malaria in four different Malian areas during the 2009 malaria transmission season. The polymorphic genetic markers MSP2, MSP1, and Ca1 were used to distinguish between recrudescence and reinfection. Reinfection and recrudescence were then grouped as recurrent infections and analyzed together by PCR-restriction fragment length polymorphism (RFLP) to identify candidate markers for artemether-lumefantrine tolerance in the P. falciparum chloroquine resistance transporter (pfcrt) gene and the P. falciparum multi-drug resistance 1 (pfmdr1) gene. RESULTS: Clinical outcomes in 326 patients (96.7%) were analyzed and the 28-day uncorrected adequate clinical and parasitological response (ACPR) rate was 73.9%. The total PCR-corrected 28-day ACPR was 97.2%. The pfcrt 76T and pfmdr1 86Y population prevalence decreased from 49.3% and 11.0% at baseline (n = 337) to 38.8% and 0% in patients with recurrent infection (n = 85); p = 0.001), respectively. CONCLUSION: Parasite populations exposed to artemether-lumefantrine in this study were selected toward chloroquine-sensitivity and showed a promising trend that may warrant future targeted reintroduction of chloroquine or/and amodiaquine.


Assuntos
Combinação Arteméter e Lumefantrina/administração & dosagem , Malária Falciparum/tratamento farmacológico , Proteínas de Membrana Transportadoras/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Protozoários/genética , Alelos , Combinação Arteméter e Lumefantrina/efeitos adversos , Artemisininas/administração & dosagem , Artemisininas/efeitos adversos , Criança , Pré-Escolar , Cloroquina/administração & dosagem , Cloroquina/efeitos adversos , Resistência a Medicamentos/genética , Feminino , Humanos , Malária Falciparum/genética , Malária Falciparum/parasitologia , Malária Falciparum/patologia , Masculino , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/patogenicidade
8.
Nat Commun ; 12(1): 4563, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315897

RESUMO

The emergence and spread of Plasmodium falciparum parasites resistant to front-line antimalarial artemisinin-combination therapies (ACT) threatens to erase the considerable gains against the disease of the last decade. Here, we develop a large-scale phenotypic screening pipeline and use it to carry out a large-scale forward-genetic phenotype screen in P. falciparum to identify genes allowing parasites to survive febrile temperatures. Screening identifies more than 200 P. falciparum mutants with differential responses to increased temperature. These mutants are more likely to be sensitive to artemisinin derivatives as well as to heightened oxidative stress. Major processes critical for P. falciparum tolerance to febrile temperatures and artemisinin include highly essential, conserved pathways associated with protein-folding, heat shock and proteasome-mediated degradation, and unexpectedly, isoprenoid biosynthesis, which originated from the ancestral genome of the parasite's algal endosymbiont-derived plastid, the apicoplast. Apicoplast-targeted genes in general are upregulated in response to heat shock, as are other Plasmodium genes with orthologs in plant and algal genomes. Plasmodium falciparum parasites appear to exploit their innate febrile-response mechanisms to mediate resistance to artemisinin. Both responses depend on endosymbiont-derived genes in the parasite's genome, suggesting a link to the evolutionary origins of Plasmodium parasites in free-living ancestors.


Assuntos
Apicoplastos/metabolismo , Artemisininas/farmacologia , Resistência a Medicamentos , Febre/parasitologia , Malária Falciparum/parasitologia , Parasitos/fisiologia , Animais , Apicoplastos/efeitos dos fármacos , Resistência a Medicamentos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Resposta ao Choque Térmico/efeitos dos fármacos , Mutação/genética , Parasitos/efeitos dos fármacos , Fenótipo , Plasmodium falciparum/genética , Transdução de Sinais/efeitos dos fármacos , Temperatura , Terpenos/metabolismo , Transcrição Genética/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos
9.
Nat Commun ; 12(1): 4711, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330920

RESUMO

Following Plasmodium falciparum infection, individuals can remain asymptomatic, present with mild fever in uncomplicated malaria cases, or show one or more severe malaria symptoms. Several studies have investigated associations between parasite transcription and clinical severity, but no broad conclusions have yet been drawn. Here, we apply a series of bioinformatic approaches based on P. falciparum's tightly regulated transcriptional pattern during its ~48-hour intraerythrocytic developmental cycle (IDC) to publicly available transcriptomes of parasites obtained from malaria cases of differing clinical severity across multiple studies. Our analysis shows that within each IDC, the circulation time of infected erythrocytes without sequestering to endothelial cells decreases with increasing parasitaemia or disease severity. Accordingly, we find that the size of circulating infected erythrocytes is inversely related to parasite density and disease severity. We propose that enhanced adhesiveness of infected erythrocytes leads to a rapid increase in parasite burden, promoting higher parasitaemia and increased disease severity.


Assuntos
Perfilação da Expressão Gênica/métodos , Regulação Bacteriana da Expressão Gênica , Malária Falciparum/sangue , Parasitemia/sangue , Plasmodium falciparum/genética , Tempo de Circulação Sanguínea , Eritrócitos/parasitologia , Ontologia Genética , Genes Bacterianos/genética , Humanos , Malária Falciparum/parasitologia , Malária Falciparum/fisiopatologia , Parasitemia/parasitologia , Parasitemia/fisiopatologia , Plasmodium falciparum/fisiologia
10.
Commun Biol ; 4(1): 697, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103669

RESUMO

Biophysical separation promises label-free, less-invasive methods to manipulate the diverse properties of live cells, such as density, magnetic susceptibility, and morphological characteristics. However, some cellular changes are so minute that they are undetectable by current methods. We developed a multiparametric cell-separation approach to profile cells with simultaneously changing density and magnetic susceptibility. We demonstrated this approach with the natural biophysical phenomenon of Plasmodium falciparum infection, which modifies its host erythrocyte by simultaneously decreasing density and increasing magnetic susceptibility. Current approaches have used these properties separately to isolate later-stage infected cells, but not in combination. We present biophysical separation of infected erythrocytes by balancing gravitational and magnetic forces to differentiate infected cell stages, including early stages for the first time, using magnetic levitation. We quantified height distributions of erythrocyte populations-27 ring-stage synchronized samples and 35 uninfected controls-and quantified their unique biophysical signatures. This platform can thus enable multidimensional biophysical measurements on unique cell types.


Assuntos
Separação Celular/métodos , Eritrócitos/patologia , Malária/patologia , Algoritmos , Eritrócitos/parasitologia , Humanos , Processamento de Imagem Assistida por Computador , Malária/parasitologia , Malária Falciparum/parasitologia , Malária Falciparum/patologia , Plasmodium falciparum/isolamento & purificação
11.
Nat Biomed Eng ; 5(6): 571-585, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34112997

RESUMO

In machine learning for image-based medical diagnostics, supervised convolutional neural networks are typically trained with large and expertly annotated datasets obtained using high-resolution imaging systems. Moreover, the network's performance can degrade substantially when applied to a dataset with a different distribution. Here, we show that adversarial learning can be used to develop high-performing networks trained on unannotated medical images of varying image quality. Specifically, we used low-quality images acquired using inexpensive portable optical systems to train networks for the evaluation of human embryos, the quantification of human sperm morphology and the diagnosis of malarial infections in the blood, and show that the networks performed well across different data distributions. We also show that adversarial learning can be used with unlabelled data from unseen domain-shifted datasets to adapt pretrained supervised networks to new distributions, even when data from the original distribution are not available. Adaptive adversarial networks may expand the use of validated neural-network models for the evaluation of data collected from multiple imaging systems of varying quality without compromising the knowledge stored in the network.


Assuntos
Interpretação de Imagem Assistida por Computador/estatística & dados numéricos , Malária Falciparum/diagnóstico por imagem , Redes Neurais de Computação , Espermatozoides/ultraestrutura , Aprendizado de Máquina Supervisionado , Conjuntos de Dados como Assunto , Embrião de Mamíferos/diagnóstico por imagem , Embrião de Mamíferos/ultraestrutura , Feminino , Histocitoquímica/métodos , Humanos , Malária Falciparum/parasitologia , Masculino , Microscopia/métodos , Plasmodium falciparum/ultraestrutura , Imagem com Lapso de Tempo/métodos , Imagem com Lapso de Tempo/estatística & dados numéricos
12.
Mol Biochem Parasitol ; 244: 111385, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34062177

RESUMO

The sexual blood stages of the human malaria parasite Plasmodium falciparum undergo a remarkable transformation from a roughly spherical shape to an elongated crescent or "falciform" morphology from which the species gets its name. In this review, the molecular events that drive this spectacular shape change are discussed and some questions that remain regarding the mechanistic underpinnings are posed. We speculate on the role of the shape changes in promoting sequestration and release of the developing gametocyte, thereby facilitating parasite survival in the host and underpinning transmission to the mosquito vector.


Assuntos
Culicidae/parasitologia , Gametogênese , Insetos Vetores/parasitologia , Estágios do Ciclo de Vida/genética , Malária Falciparum/parasitologia , Plasmodium falciparum/crescimento & desenvolvimento , Animais , Fenômenos Biomecânicos , Eritrócitos/parasitologia , Feminino , Hepatócitos/parasitologia , Interações Hospedeiro-Parasita/genética , Humanos , Malária Falciparum/transmissão , Masculino , Microtúbulos/parasitologia , Microtúbulos/ultraestrutura , Plasmodium falciparum/citologia , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Reprodução Assexuada
13.
Int J Mol Sci ; 22(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068393

RESUMO

The highly complex life cycle of the human malaria parasite, Plasmodium falciparum, is based on an orchestrated and tightly regulated gene expression program. In general, eukaryotic transcription regulation is determined by a combination of sequence-specific transcription factors binding to regulatory DNA elements and the packaging of DNA into chromatin as an additional layer. The accessibility of regulatory DNA elements is controlled by the nucleosome occupancy and changes of their positions by an active process called nucleosome remodeling. These epigenetic mechanisms are poorly explored in P. falciparum. The parasite genome is characterized by an extraordinarily high AT-content and the distinct architecture of functional elements, and chromatin-related proteins also exhibit high sequence divergence compared to other eukaryotes. Together with the distinct biochemical properties of nucleosomes, these features suggest substantial differences in chromatin-dependent regulation. Here, we highlight the peculiarities of epigenetic mechanisms in P. falciparum, addressing chromatin structure and dynamics with respect to their impact on transcriptional control. We focus on the specialized chromatin remodeling enzymes and discuss their essential function in P. falciparum gene regulation.


Assuntos
Montagem e Desmontagem da Cromatina , Epigênese Genética , Regulação da Expressão Gênica , Malária Falciparum/parasitologia , Plasmodium falciparum/genética , Transcrição Genética , Animais , Humanos , Estágios do Ciclo de Vida
14.
BMC Infect Dis ; 21(1): 507, 2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059017

RESUMO

BACKGROUND: Hematological abnormalities are common features in falciparum malaria but vary among different populations across countries. Therefore, we compared hematological indices and abnormalities between Plasmodium falciparum-infected patients and malaria-negative subjects in Kosti city of the White Nile State, Sudan. METHODS: A comparative, cross-sectional study was conducted at the Clinical Laboratory Unit of Kosti Teaching Hospital from June to December 2018. A total of 392 participants (192 P. falciparum-infected patients and 200 malaria-negative subjects) were recruited in the study. Hematological indices of hemoglobin (Hb), red blood cells (RBCs), white blood cells (WBCs) and platelets were measured, and their median values were statistically compared. RESULTS: The majority of P. falciparum-infected patients (67.6%) showed a low-level parasitemia. The median values of Hb concentration, RBC count, mean corpuscular volume (MCV), mean corpuscular Hb (MCH) and mean corpuscular Hb concentration (MCHC) were significantly lower in P. falciparum-infected patients, while the median red cell distribution width (RDW) was significantly higher in the patients compared to malaria-negative subjects. Anemia, low MCV, low MCH, low MCHC and high RDW were significantly associated with falciparum malaria, but parasitemia level was not significantly associated with anemia severity. The median total WBC count was non-significantly higher in P. falciparum-infected patients, with neutropenia being significantly associated with falciparum malaria. The median platelet count was significantly lower in P. falciparum-infected patients, with thrombocytopenia being significantly associated with falciparum malaria. CONCLUSIONS: Falciparum malaria among patients in Kosti city of the White Nile State, Sudan is predominantly of low-level parasitemia. It is significantly associated with anemia, low MCV, low MCH, low MCHC, high RDW, thrombocytopenia and neutropenia. However, parasitemia level is not a significant predictor of anemia severity. On the other hand, leucopenia is not useful to predict falciparum malaria. Further large-scale studies in community and healthcare settings and inclusion of patients with complicated or severe malaria and those with high parasite densities are recommended.


Assuntos
Malária Falciparum/sangue , Adolescente , Adulto , Anemia/sangue , Anemia/parasitologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Testes Hematológicos , Humanos , Lactente , Leucopenia/sangue , Leucopenia/parasitologia , Malária Falciparum/parasitologia , Masculino , Pessoa de Meia-Idade , Parasitemia/sangue , Parasitemia/parasitologia , Plasmodium falciparum , Trombocitopenia/sangue , Trombocitopenia/parasitologia , Adulto Jovem
15.
Parasitol Int ; 83: 102374, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33957296

RESUMO

Vietnam achieved outstanding success against malaria in the last few decades. The mortality and morbidity of malaria in Vietnam have decreased remarkably in recent years, but malaria is still a major public health concern in the country, particularly in the Central Highlands region. In this study, molecular analyses of malaria parasites in the Central Highlands were performed to understand the population structure and genetic diversity of the parasites circulating in the region. Plasmodium falciparum (68.7%) and P. vivax (27.4%) along with mixed infections with P. falciparum/P. vivax (3.9%) were detected in 230 blood samples from patients with malaria. Allele-specific nested-polymerase chain reaction (PCR) or PCR-restriction fragment length polymorphism (PCR-RFLP) analyses of pfmsp-1, pfama-1, pvcsp, and pvmsp-1 revealed complex genetic makeup in P. falciparum and P. vivax populations of Vietnam. Substantial multiplicity of infection (MOI) was also identified, suggesting significant genetic diversity and polymorphism of P. falciparum and P. vivax populations in the Central Highlands of Vietnam. These results provide fundamental insight into the current patterns of dispersion and genetic nature of malaria parasites as well as for the development of malaria elimination strategies in the endemic region.


Assuntos
Malária Falciparum/epidemiologia , Malária Vivax/epidemiologia , Plasmodium falciparum/isolamento & purificação , Plasmodium vivax/isolamento & purificação , Adulto , Monitoramento Epidemiológico , Feminino , Variação Genética , Humanos , Malária Falciparum/parasitologia , Malária Vivax/parasitologia , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/genética , Plasmodium vivax/genética , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Prevalência , Proteínas de Protozoários/análise , Vietnã/epidemiologia , Adulto Jovem
16.
PLoS Med ; 18(5): e1003567, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34038421

RESUMO

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.


Assuntos
Medula Óssea/parasitologia , Glucose/metabolismo , Fígado/parasitologia , Malária Falciparum/parasitologia , Malária Vivax/parasitologia , Baço/parasitologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Feminino , Humanos , Fígado/metabolismo , Fígado/patologia , Imageamento por Ressonância Magnética , Malária Falciparum/patologia , Malária Falciparum/fisiopatologia , Malária Vivax/patologia , Malária Vivax/fisiopatologia , Masculino , Plasmodium falciparum , Plasmodium vivax , Tomografia por Emissão de Pósitrons , Estudos Prospectivos , Queensland , Coluna Vertebral/metabolismo , Coluna Vertebral/parasitologia , Coluna Vertebral/patologia , Baço/metabolismo , Baço/patologia , Adulto Jovem
17.
Trends Parasitol ; 37(8): 709-721, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34001441

RESUMO

Strategies to counteract or prevent emerging drug resistance are crucial for the design of next-generation antimalarials. In the past, resistant parasites were generally identified following treatment failures in patients, and compounds would have to be abandoned late in development. An early understanding of how candidate therapeutics lose efficacy as parasites evolve resistance is important to facilitate drug design and improve resistance detection and monitoring up to the postregistration phase. We describe a new strategy to assess resistance to antimalarial compounds as early as possible in preclinical development by leveraging tools to define the Plasmodium falciparum resistome, predict potential resistance risks of clinical failure for candidate therapeutics, and inform decisions to guide antimalarial drug development.


Assuntos
Antimaláricos/farmacologia , Resistência a Medicamentos , Plasmodium falciparum/efeitos dos fármacos , Malária Falciparum/parasitologia , Medição de Risco
18.
Malar J ; 20(1): 218, 2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980241

RESUMO

BACKGROUND: Malaria control and elimination strategies are based on levels of transmission that are usually determined by data collected from health facilities. In endemic areas, asymptomatic Plasmodium infection is thought to represent the majority of infections, though they are not diagnosed nor treated. Therefore, there might be an underestimation of the malaria reservoir, resulting in inadequate control strategies. In addition, these untreated asymptomatic Plasmodium infections maintain transmission, making it difficult or impossible to reach malaria elimination goals. Thus, the aim of this study was to determine the prevalence of asymptomatic Plasmodium infections in southeastern Senegal. METHODS: A cross sectional study was conducted among asymptomatic individuals (N = 122) living in the village of Andiel located in Bandafassi, Kédougou, which consisted of about 200 inhabitants during the malaria transmission season in late October 2019. For each individual without malaria-related symptoms and who consented to participate, a rapid diagnostic test (RDT) was performed in the field. Results were confirmed in the laboratory with photo-induced electron transfer (PET-PCR). RESULTS: Malaria prevalence was 70.3% by PET-PCR and 41.8% by RDT. During the same period, the health post of the area reported 49. 1% test positivity rate by RDT. The majority of the infected study population, 92.9%, was infected with a single species and 7.1% had two or three species of Plasmodium. Plasmodium falciparum was predominant and represented 90.2% of the infections, while 6.5% were due to Plasmodium ovale and 3.3% to Plasmodium malariae. 59.4% of children targeted for SMC (zero to ten years old) were infected. CONCLUSION: In southeastern Senegal, where the transmission is the highest, malaria control strategies should address asymptomatic Plasmodium infections at the community level. The results suggest that this area could be eligible for mass drug administration. Moreover, non-falciparum species could be more common and its prevalence should be determined countrywide.


Assuntos
Infecções Assintomáticas/epidemiologia , Malária/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Malária/parasitologia , Malária Falciparum/epidemiologia , Malária Falciparum/parasitologia , Malária Vivax/epidemiologia , Malária Vivax/parasitologia , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/isolamento & purificação , Plasmodium malariae/isolamento & purificação , Plasmodium ovale/isolamento & purificação , Plasmodium vivax/isolamento & purificação , Prevalência , Senegal/epidemiologia , Adulto Jovem
19.
Malar J ; 20(1): 236, 2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34039364

RESUMO

BACKGROUND: Malaria remains a public health burden especially in Nigeria. To develop new malaria control and elimination strategies or refine existing ones, understanding parasite population diversity and transmission patterns is crucial. METHODS: In this study, characterization of the parasite diversity and structure of Plasmodium falciparum isolates from 633 dried blood spot samples in Nigeria was carried out using 12 microsatellite loci of P. falciparum. These microsatellite loci were amplified via semi-nested polymerase chain reaction (PCR) and fragments were analysed using population genetic tools. RESULTS: Estimates of parasite genetic diversity, such as mean number of different alleles (13.52), effective alleles (7.13), allelic richness (11.15) and expected heterozygosity (0.804), were high. Overall linkage disequilibrium was weak (0.006, P < 0.001). Parasite population structure was low (Fst: 0.008-0.105, AMOVA: 0.039). CONCLUSION: The high level of parasite genetic diversity and low population structuring in this study suggests that parasite populations circulating in Nigeria are homogenous. However, higher resolution methods, such as the 24 SNP barcode and whole genome sequencing, may capture more specific parasite genetic signatures circulating in the country. The results obtained can be used as a baseline for parasite genetic diversity and structure, aiding in the formulation of appropriate therapeutic and control strategies in Nigeria.


Assuntos
Variação Genética , Malária Falciparum/parasitologia , Repetições de Microssatélites , Plasmodium falciparum/genética , Criança , Pré-Escolar , Teste em Amostras de Sangue Seco , Feminino , Humanos , Lactente , Desequilíbrio de Ligação , Masculino , Nigéria
20.
Nat Commun ; 12(1): 3196, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34045457

RESUMO

Malaria parasites have a complex life cycle featuring diverse developmental strategies, each uniquely adapted to navigate specific host environments. Here we use single-cell transcriptomics to illuminate gene usage across the transmission cycle of the most virulent agent of human malaria - Plasmodium falciparum. We reveal developmental trajectories associated with the colonization of the mosquito midgut and salivary glands and elucidate the transcriptional signatures of each transmissible stage. Additionally, we identify both conserved and non-conserved gene usage between human and rodent parasites, which point to both essential mechanisms in malaria transmission and species-specific adaptations potentially linked to host tropism. Together, the data presented here, which are made freely available via an interactive website, provide a fine-grained atlas that enables intensive investigation of the P. falciparum transcriptional journey. As well as providing insights into gene function across the transmission cycle, the atlas opens the door for identification of drug and vaccine targets to stop malaria transmission and thereby prevent disease.


Assuntos
Anopheles/parasitologia , Estágios do Ciclo de Vida/genética , Malária Falciparum/transmissão , Mosquitos Vetores/parasitologia , Plasmodium falciparum/genética , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Feminino , Interações Hospedeiro-Parasita/genética , Humanos , Estágios do Ciclo de Vida/efeitos dos fármacos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Masculino , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/patogenicidade , RNA-Seq , Análise de Célula Única , Especificidade da Espécie , Transcriptoma/efeitos dos fármacos
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