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1.
Nature ; 582(7810): 104-108, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32427965

RESUMO

Malaria caused by Plasmodium falciparum remains the leading single-agent cause of mortality in children1, yet the promise of an effective vaccine has not been fulfilled. Here, using our previously described differential screening method to analyse the proteome of blood-stage P. falciparum parasites2, we identify P. falciparum glutamic-acid-rich protein (PfGARP) as a parasite antigen that is recognized by antibodies in the plasma of children who are relatively resistant-but not those who are susceptible-to malaria caused by P. falciparum. PfGARP is a parasite antigen of 80 kDa that is expressed on the exofacial surface of erythrocytes infected by early-to-late-trophozoite-stage parasites. We demonstrate that antibodies against PfGARP kill trophozoite-infected erythrocytes in culture by inducing programmed cell death in the parasites, and that vaccinating non-human primates with PfGARP partially protects against a challenge with P. falciparum. Furthermore, our longitudinal cohort studies showed that, compared to individuals who had naturally occurring anti-PfGARP antibodies, Tanzanian children without anti-PfGARP antibodies had a 2.5-fold-higher risk of severe malaria and Kenyan adolescents and adults without these antibodies had a twofold-higher parasite density. By killing trophozoite-infected erythrocytes, PfGARP could synergize with other vaccines that target parasite invasion of hepatocytes or the invasion of and egress from erythrocytes.


Assuntos
Apoptose/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Malária Falciparum/imunologia , Malária Falciparum/prevenção & controle , Parasitos/imunologia , Plasmodium falciparum/citologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Adolescente , Adulto , Animais , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/química , Antígenos de Protozoários/imunologia , Aotidae/imunologia , Aotidae/parasitologia , Caspases/metabolismo , Criança , Estudos de Coortes , DNA de Protozoário/química , DNA de Protozoário/metabolismo , Ativação Enzimática , Eritrócitos/parasitologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/química , Quênia , Vacinas Antimaláricas/imunologia , Malária Falciparum/parasitologia , Masculino , Camundongos , Parasitos/citologia , Parasitos/crescimento & desenvolvimento , Plasmodium falciparum/crescimento & desenvolvimento , Proteínas de Protozoários/química , Tanzânia , Trofozoítos/citologia , Trofozoítos/crescimento & desenvolvimento , Trofozoítos/imunologia , Vacúolos/imunologia
2.
J Infect Dis ; 221(6): 956-962, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-31616928

RESUMO

Spreading antimalarial resistance threatens effective treatment of malaria, an infectious disease caused by Plasmodium parasites. We identified a compound, BCH070, that inhibits asexual growth of multiple antimalarial-resistant strains of Plasmodium falciparum (half maximal inhibitory concentration [IC50] = 1-2 µM), suggesting that BCH070 acts via a novel mechanism of action. BCH070 preferentially kills early ring-form trophozoites, and, importantly, equally inhibits ring-stage survival of wild-type and artemisinin-resistant parasites harboring the PfKelch13:C580Y mutation. Metabolomic analysis demonstrates that BCH070 likely targets multiple pathways in the parasite. BCH070 is a promising lead compound for development of new antimalarial combination therapy that retains activity against artemisinin-resistant parasites.


Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/administração & dosagem , Antimaláricos/química , Células Cultivadas , Resistência a Medicamentos , Fibroblastos/parasitologia , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Trypanosoma cruzi/efeitos dos fármacos
3.
Clin Infect Dis ; 68(10): 1718-1724, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30165569

RESUMO

BACKGROUND: In holoendemic areas, children suffer the most from Plasmodium falciparum malaria, yet newborns and young infants express a relative resistance to both infection and severe malarial disease (SM). This relative resistance has been ascribed to maternally-derived anti-parasite immunoglobulin G; however, the targets of these protective antibodies remain elusive. METHODS: We enrolled 647 newborns at birth from a malaria-holoendemic region of Tanzania. We collected cord blood, measured antibodies to Plasmodium falciparum Schizont Egress Antigen-1 (PfSEA-1), and related these antibodies to the risk of severe malaria in the first year of life. In addition, we vaccinated female mice with PbSEA-1, mated them, and challenged their pups with P. berghei ANKA parasites to assess the impact of maternal PbSEA-1 vaccination on newborns' resistance to malaria. RESULTS: Children with high cord-blood anti-PfSEA-1 antibody levels had 51.4% fewer cases of SM compared to individuals with lower anti-PfSEA-1 levels over 12 months of follow-up (P = .03). In 3 trials, pups born to PbSEA-1-vaccinated dams had significantly lower parasitemia and longer survival following a P. berghei challenge compared to pups born to control dams. CONCLUSIONS: We demonstrate that maternally-derived, cord-blood anti-PfSEA-1 antibodies predict decreased risk of SM in infants and vaccination of mice with PbSEA-1 prior to pregnancy protects their offspring from lethal P. berghei challenge. These results identify, for the first time, a parasite-specific target of maternal antibodies that protect infants from SM and suggest that vaccination of pregnant women with PfSEA-1 may afford a survival advantage to their offspring.


Assuntos
Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/imunologia , Sangue Fetal/imunologia , Imunidade Materno-Adquirida , Malária Falciparum/prevenção & controle , Proteínas de Protozoários/imunologia , Índice de Gravidade de Doença , Animais , Antígenos de Protozoários/administração & dosagem , Estudos de Coortes , Resistência à Doença , Feminino , Humanos , Imunoglobulina G/sangue , Lactente , Recém-Nascido , Malária Falciparum/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Parasitemia/imunologia , Parasitemia/prevenção & controle , Plasmodium berghei/imunologia , Plasmodium falciparum , Proteínas de Protozoários/administração & dosagem , Tanzânia , Vacinação
4.
Antimicrob Agents Chemother ; 57(1): 425-35, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23129054

RESUMO

Malaria is a deadly infectious disease in many tropical and subtropical countries. Previous efforts to eradicate malaria have failed, largely due to the emergence of drug-resistant parasites, insecticide-resistant mosquitoes and, in particular, the lack of drugs or vaccines to block parasite transmission. ATP-binding cassette (ABC) transporters are known to play a role in drug transport, metabolism, and resistance in many organisms, including malaria parasites. To investigate whether a Plasmodium falciparum ABC transporter (Pf14_0244 or PfABCG2) modulates parasite susceptibility to chemical compounds or plays a role in drug resistance, we disrupted the gene encoding PfABCG2, screened the recombinant and the wild-type 3D7 parasites against a library containing 2,816 drugs approved for human or animal use, and identified an antihistamine (ketotifen) that became less active against the PfABCG2-disrupted parasite in culture. In addition to some activity against asexual stages and gametocytes, ketotifen was highly potent in blocking oocyst development of P. falciparum and the rodent parasite Plasmodium yoelii in mosquitoes. Tests of structurally related tricyclic compounds identified additional compounds with similar activities in inhibiting transmission. Additionally, ketotifen appeared to have some activity against relapse of Plasmodium cynomolgi infection in rhesus monkeys. Further clinical evaluation of ketotifen and related compounds, including synthetic new derivatives, in blocking malaria transmission may provide new weapons for the current effort of malaria eradication.


Assuntos
Antimaláricos/farmacologia , Cetotifeno/farmacologia , Malária Falciparum/prevenção & controle , Malária/prevenção & controle , Oocistos/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Plasmodium yoelii/efeitos dos fármacos , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Antialérgicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Reposicionamento de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Cetotifeno/análogos & derivados , Macaca mulatta , Malária/metabolismo , Malária/parasitologia , Malária/transmissão , Malária Falciparum/metabolismo , Malária Falciparum/parasitologia , Malária Falciparum/transmissão , Camundongos , Oocistos/crescimento & desenvolvimento , Plasmodium cynomolgi/efeitos dos fármacos , Plasmodium cynomolgi/crescimento & desenvolvimento , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium yoelii/crescimento & desenvolvimento , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
5.
J Exp Med ; 218(9)2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34342640

RESUMO

We previously identified a Plasmodium falciparum (Pf) protein of unknown function encoded by a single-copy gene, PF3D7_1134300, as a target of antibodies in plasma of Tanzanian children in a whole-proteome differential screen. Here we characterize this protein as a blood-stage antigen that localizes to the surface membranes of both parasitized erythrocytes and merozoites, hence its designation as Pf erythrocyte membrane and merozoite antigen 1 (PfEMMA1). Mouse anti-PfEMMA1 antisera and affinity-purified human anti-PfEMMA1 antibodies inhibited growth of P. falciparum strains by up to 68% in growth inhibition assays. Following challenge with uniformly fatal Plasmodium berghei (Pb) ANKA, up to 40% of mice immunized with recombinant PbEMMA1 self-cured, and median survival of lethally infected mice was up to 2.6-fold longer than controls (21 vs. 8 d, P = 0.005). Furthermore, high levels of naturally acquired human anti-PfEMMA1 antibodies were associated with a 46% decrease in parasitemia over 2.5 yr of follow-up of Tanzanian children. Together, these findings suggest that antibodies to PfEMMA1 mediate protection against malaria.


Assuntos
Antígenos de Protozoários/metabolismo , Membrana Eritrocítica/parasitologia , Malária Falciparum/parasitologia , Merozoítos/metabolismo , Plasmodium falciparum/fisiologia , Proteínas de Protozoários/genética , Animais , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/genética , Antígenos de Protozoários/imunologia , Pré-Escolar , Feminino , Interações Hospedeiro-Parasita/fisiologia , Humanos , Lactente , Vacinas Antimaláricas/genética , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Malária Falciparum/mortalidade , Merozoítos/imunologia , Camundongos Endogâmicos BALB C , Plasmodium falciparum/imunologia , Plasmodium falciparum/patogenicidade , Polimorfismo de Nucleotídeo Único , Proteínas de Protozoários/química , Proteínas de Protozoários/imunologia , Proteínas de Protozoários/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Tanzânia
6.
Science ; 344(6186): 871-7, 2014 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-24855263

RESUMO

Novel vaccines are urgently needed to reduce the burden of severe malaria. Using a differential whole-proteome screening method, we identified Plasmodium falciparum schizont egress antigen-1 (PfSEA-1), a 244-kilodalton parasite antigen expressed in schizont-infected red blood cells (RBCs). Antibodies to PfSEA-1 decreased parasite replication by arresting schizont rupture, and conditional disruption of PfSEA-1 resulted in a profound parasite replication defect. Vaccination of mice with recombinant Plasmodium berghei PbSEA-1 significantly reduced parasitemia and delayed mortality after lethal challenge with the Plasmodium berghei strain ANKA. Tanzanian children with antibodies to recombinant PfSEA-1A (rPfSEA-1A) did not experience severe malaria, and Kenyan adolescents and adults with antibodies to rPfSEA-1A had significantly lower parasite densities than individuals without these antibodies. By blocking schizont egress, PfSEA-1 may synergize with other vaccines targeting hepatocyte and RBC invasion.


Assuntos
Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Eritrócitos/parasitologia , Vacinas Antimaláricas/imunologia , Malária Falciparum/prevenção & controle , Plasmodium falciparum/crescimento & desenvolvimento , Proteínas de Protozoários/imunologia , Esquizontes/crescimento & desenvolvimento , Adolescente , Adulto , Animais , Anticorpos Antiprotozoários/sangue , Criança , Hepatócitos/imunologia , Hepatócitos/parasitologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Quênia , Malária/prevenção & controle , Camundongos , Plasmodium berghei/imunologia , Plasmodium falciparum/imunologia , Proteínas Recombinantes/imunologia , Adulto Jovem
7.
Mol Cell Probes ; 21(5-6): 355-62, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17560074

RESUMO

A single step novel multiplex polymerase chain reaction (PCR) has been developed for simultaneous detection of human filarial parasites, Brugia malayi and Wuchereria bancrofti, from blood samples and mosquitoes. The primers used were novel and have been tested with the parasite DNA amplifying 188bp (BM) and 129bp (WB) DNA fragments, specific to B. malayi and W. bancrofti, respectively, in a single reaction. The specificity of the PCR product was confirmed by DNA sequencing and slot blot hybridization assay. The test was found highly sensitive for both B. malayi and W. bancrofti by detecting the parasitaemia up to the level of one microfilaria per reaction. The assay was further evaluated on 98 blood samples and 144 mosquito samples collected from filarial endemic areas. The PCR was found to be more efficient in comparison to microscopy by detecting 8% and 5% more filarial parasites in field-collected blood and mosquito samples, respectively. This novel PCR that offers scope for simultaneous detection of both the parasites may be used as a diagnostic tool for the detection of filariasis in population and can be adopted for rapid surveillance and monitoring of mosquitoes for use in the effective control of filariasis.


Assuntos
Brugia Malayi/genética , Brugia Malayi/isolamento & purificação , Reação em Cadeia da Polimerase/métodos , Wuchereria bancrofti/genética , Wuchereria bancrofti/isolamento & purificação , Animais , Sequência de Bases , Culicidae/parasitologia , DNA de Helmintos/análise , DNA de Helmintos/genética , Humanos , Dados de Sequência Molecular , Parasitos/genética , Parasitos/isolamento & purificação
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