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1.
Front Immunol ; 12: 565625, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679730

RESUMO

Sub-Saharan Africa has generally experienced few cases and deaths of coronavirus disease 2019 (COVID-19). In addition to other potential explanations for the few cases and deaths of COVID-19 such as the population socio-demographics, early lockdown measures and the possibility of under reporting, we hypothesize in this mini review that individuals with a recent history of malaria infection may be protected against infection or severe form of COVID-19. Given that both the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Plasmodium falciparum (P. falciparum) merozoites bind to the cluster of differentiation 147 (CD147) immunoglobulin, we hypothesize that the immunological memory against P. falciparum merozoites primes SARS-CoV-2 infected cells for early phagocytosis, hence protecting individuals with a recent P. falciparum infection against COVID-19 infection or severity. This mini review therefore discusses the potential biological link between P. falciparum infection and COVID-19 infection or severity and further highlights the importance of CD147 immunoglobulin as an entry point for both SARS-CoV-2 and P. falciparum into host cells.


Assuntos
Basigina/imunologia , Memória Imunológica , Malária Falciparum , Plasmodium falciparum/imunologia , /imunologia , África ao Sul do Saara/epidemiologia , /imunologia , Humanos , Malária Falciparum/epidemiologia , Malária Falciparum/imunologia , Merozoítos/imunologia , Índice de Gravidade de Doença
2.
Malar J ; 20(1): 124, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33653360

RESUMO

BACKGROUND: Thrombospondin-related adhesive protein (TRAP) is a transmembrane protein that plays a crucial role during the invasion of Plasmodium falciparum into liver cells. As a potential malaria vaccine candidate, the genetic diversity and natural selection of PfTRAP was assessed and the global PfTRAP polymorphism pattern was described. METHODS: 153 blood spot samples from Bioko malaria patients were collected during 2016-2018 and the target TRAP gene was amplified. Together with the sequences from database, nucleotide diversity and natural selection analysis, and the structural prediction were preformed using bioinformatical tools. RESULTS: A total of 119 Bioko PfTRAP sequences were amplified successfully. On Bioko Island, PfTRAP shows its high degree of genetic diversity and heterogeneity, with π value for 0.01046 and Hd for 0.99. The value of dN-dS (6.2231, p < 0.05) hinted at natural selection of PfTRAP on Bioko Island. Globally, the African PfTRAPs showed more diverse than the Asian ones, and significant genetic differentiation was discovered by the fixation index between African and Asian countries (Fst > 0.15, p < 0.05). 667 Asian isolates clustered in 136 haplotypes and 739 African isolates clustered in 528 haplotypes by network analysis. The mutations I116T, L221I, Y128F, G228V and P299S were predicted as probably damaging by PolyPhen online service, while mutations L49V, R285G, R285S, P299S and K421N would lead to a significant increase of free energy difference (ΔΔG > 1) indicated a destabilization of protein structure. CONCLUSIONS: Evidences in the present investigation supported that PfTRAP gene from Bioko Island and other malaria endemic countries is highly polymorphic (especially at T cell epitopes), which provided the genetic information background for developing an PfTRAP-based universal effective vaccine. Moreover, some mutations have been shown to be detrimental to the protein structure or function and deserve further study and continuous monitoring.


Assuntos
Malária Falciparum/parasitologia , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Epitopos , Guiné Equatorial/epidemiologia , Frequência do Gene , Variação Genética , Haplótipos , Humanos , Vacinas Antimaláricas , Malária Falciparum/epidemiologia , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Polimorfismo Genético , Proteínas de Protozoários/química , Proteínas de Protozoários/imunologia , Seleção Genética
3.
Molecules ; 26(4)2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672753

RESUMO

The cell wall of Mycobacterium tuberculosis (Mtb) has a unique structural organisation, comprising a high lipid content mixed with polysaccharides. This makes cell wall a formidable barrier impermeable to hydrophilic agents. In addition, during host infection, Mtb resides in macrophages within avascular necrotic granulomas and cavities, which shield the bacterium from the action of most antibiotics. To overcome these protective barriers, a new class of anti-TB agents exhibiting lipophilic character have been recommended by various reports in literature. Herein, a series of lipophilic heterocyclic quinolone compounds was synthesised and evaluated in vitro against pMSp12::GFP strain of Mtb, two protozoan parasites (Plasmodium falciparum and Trypanosoma brucei brucei) and against ESKAPE pathogens. The resultant compounds exhibited varied anti-Mtb activity with MIC90 values in the range of 0.24-31 µM. Cross-screening against P. falciparum and T.b. brucei, identified several compounds with antiprotozoal activities in the range of 0.4-20 µM. Compounds were generally inactive against ESKAPE pathogens, with only compounds 8c, 8g and 13 exhibiting moderate to poor activity against S. aureus and A. baumannii.


Assuntos
Antibacterianos/farmacologia , Antiprotozoários/farmacologia , Quinolonas/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Quinolonas/síntese química , Quinolonas/química , Staphylococcus aureus/efeitos dos fármacos , Trypanosoma brucei brucei/efeitos dos fármacos
4.
Nat Commun ; 12(1): 1892, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33767187

RESUMO

Plasmodium falciparum, the causative agent of malaria, moves by an atypical process called gliding motility. Actomyosin interactions are central to gliding motility. However, the details of these interactions remained elusive until now. Here, we report an atomic structure of the divergent Plasmodium falciparum actomyosin system determined by electron cryomicroscopy at the end of the powerstroke (Rigor state). The structure provides insights into the detailed interactions that are required for the parasite to produce the force and motion required for infectivity. Remarkably, the footprint of the myosin motor on filamentous actin is conserved with respect to higher eukaryotes, despite important variability in the Plasmodium falciparum myosin and actin elements that make up the interface. Comparison with other actomyosin complexes reveals a conserved core interface common to all actomyosin complexes, with an ancillary interface involved in defining the spatial positioning of the motor on actin filaments.


Assuntos
Citoesqueleto de Actina/metabolismo , Actomiosina/metabolismo , Movimento Celular/fisiologia , Plasmodium falciparum/fisiologia , Plasmodium falciparum/ultraestrutura , Actinas/metabolismo , Microscopia Crioeletrônica , Malária Falciparum/parasitologia , Miosinas/metabolismo , Conformação Proteica , Proteínas de Protozoários/metabolismo
5.
Nat Commun ; 12(1): 1555, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33692343

RESUMO

A counterargument to the importance of climate change for malaria transmission has been that regions where an effect of warmer temperatures is expected, have experienced a marked decrease in seasonal epidemic size since the turn of the new century. This decline has been observed in the densely populated highlands of East Africa at the center of the earlier debate on causes of the pronounced increase in epidemic size from the 1970s to the 1990s. The turnaround of the incidence trend around 2000 is documented here with an extensive temporal record for malaria cases for both Plasmodium falciparum and Plasmodium vivax in an Ethiopian highland. With statistical analyses and a process-based transmission model, we show that this decline was driven by the transient slowdown in global warming and associated changes in climate variability, especially ENSO. Decadal changes in temperature and concurrent climate variability facilitated rather than opposed the effect of interventions.


Assuntos
Malária/epidemiologia , África Oriental/epidemiologia , Aquecimento Global , Humanos , Incidência , Malária Falciparum/epidemiologia , Plasmodium falciparum/patogenicidade , Plasmodium vivax/patogenicidade , Temperatura
6.
Nat Commun ; 12(1): 1792, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33741926

RESUMO

In both sickle cell disease and malaria, red blood cells (RBCs) are phagocytosed in the spleen, but receptor-ligand pairs mediating uptake have not been identified. Here, we report that patches of high mannose N-glycans (Man5-9GlcNAc2), expressed on diseased or oxidized RBC surfaces, bind the mannose receptor (CD206) on phagocytes to mediate clearance. We find that extravascular hemolysis in sickle cell disease correlates with high mannose glycan levels on RBCs. Furthermore, Plasmodium falciparum-infected RBCs expose surface mannose N-glycans, which occur at significantly higher levels on infected RBCs from sickle cell trait subjects compared to those lacking hemoglobin S. The glycans are associated with high molecular weight complexes and protease-resistant, lower molecular weight fragments containing spectrin. Recognition of surface N-linked high mannose glycans as a response to cellular stress is a molecular mechanism common to both the pathogenesis of sickle cell disease and resistance to severe malaria in sickle cell trait.


Assuntos
Anemia Falciforme/metabolismo , Eritrócitos/metabolismo , Manose/metabolismo , Fagócitos/metabolismo , Polissacarídeos/metabolismo , Membrana Eritrocítica/metabolismo , Membrana Eritrocítica/parasitologia , Eritrócitos/parasitologia , Citometria de Fluxo/métodos , Hemólise , Humanos , Ligantes , Malária Falciparum/metabolismo , Malária Falciparum/parasitologia , Glicoproteínas de Membrana/metabolismo , Fagocitose , Plasmodium falciparum/fisiologia , Ligação Proteica , Receptores Imunológicos/metabolismo
7.
Nat Commun ; 12(1): 1750, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33741942

RESUMO

Malaria elimination requires tools that interrupt parasite transmission. Here, we characterize B cell receptor responses among Malian adults vaccinated against the first domain of the cysteine-rich 230 kDa gamete surface protein Pfs230, a key protein in sexual stage development of P. falciparum parasites. Among nine Pfs230 human monoclonal antibodies (mAbs) that we generated, one potently blocks transmission to mosquitoes in a complement-dependent manner and reacts to the gamete surface; the other eight show only low or no blocking activity. The structure of the transmission-blocking mAb in complex with vaccine antigen reveals a large discontinuous conformational epitope, specific to domain 1 of Pfs230 and comprising six structural elements in the protein. The epitope is conserved, suggesting the transmission-blocking mAb is broadly functional. This study provides a rational basis to improve malaria vaccines and develop therapeutic antibodies for malaria elimination.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Antiprotozoários/farmacologia , Epitopos/imunologia , Células Germinativas/imunologia , Malária Falciparum/prevenção & controle , Plasmodium falciparum/efeitos dos fármacos , Adulto , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/química , Antígenos de Protozoários/imunologia , Sítios de Ligação , Células Cultivadas , Epitopos/química , Interações Hospedeiro-Parasita/efeitos dos fármacos , Interações Hospedeiro-Parasita/imunologia , Humanos , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/imunologia , Malária Falciparum/parasitologia , Malária Falciparum/transmissão , Mosquitos Vetores/parasitologia , Plasmodium falciparum/imunologia , Plasmodium falciparum/fisiologia , Conformação Proteica , Proteínas de Protozoários/química , Proteínas de Protozoários/imunologia
8.
Nat Commun ; 12(1): 1742, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33741975

RESUMO

A highly protective vaccine will greatly facilitate achieving and sustaining malaria elimination. Understanding mechanisms of antibody-mediated immunity is crucial for developing vaccines with high efficacy. Here, we identify key roles in humoral immunity for Fcγ-receptor (FcγR) interactions and opsonic phagocytosis of sporozoites. We identify a major role for neutrophils in mediating phagocytic clearance of sporozoites in peripheral blood, whereas monocytes contribute a minor role. Antibodies also promote natural killer cell activity. Mechanistically, antibody interactions with FcγRIII appear essential, with FcγRIIa also required for maximum activity. All regions of the circumsporozoite protein are targets of functional antibodies against sporozoites, and N-terminal antibodies have more activity in some assays. Functional antibodies are slowly acquired following natural exposure to malaria, being present among some exposed adults, but uncommon among children. Our findings reveal targets and mechanisms of immunity that could be exploited in vaccine design to maximize efficacy.


Assuntos
Imunidade Humoral , Malária/imunologia , Malária/prevenção & controle , Receptores de IgG/imunologia , Esporozoítos/imunologia , Adulto , Idoso , Anticorpos Antiprotozoários/imunologia , Criança , Feminino , Humanos , Quênia , Vacinas Antimaláricas/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Neutrófilos/imunologia , Fagocitose/imunologia , Plasmodium falciparum/imunologia , Receptores de IgG/metabolismo , Células THP-1 , Adulto Jovem
9.
Artigo em Inglês | MEDLINE | ID: mdl-33533814

RESUMO

Malaria represents a serious public health problem, presenting with high rates of incidence, morbidity and mortality in tropical and subtropical regions of the world. According to the World Health Organization, in 2018 there were 228 million cases and 405 thousand deaths caused by this disease in the world, affecting mainly children and pregnant women in Africa. Despite the programs carried out to control this disease, drug resistance and invertebrate vector resistance to insecticides have generated difficulties. An efficient vaccine against malaria would be a strategy with a high impact on the eradication and control of this disease. Researches aimed at developing vaccines have focused on antigens of high importance for the survival of the parasite such as the Circumsporozoite Surface Protein, involved in the pre-erythrocytic cycle during parasites invasion in hepatocytes. Currently, RTS'S is the most promising vaccine for malaria and was constructed using CSP; its performance was evaluated using two types of adjuvants: AS01 and AS02. The purpose of this review was to provide a bibliographic survey of historical researches that led to the development of RTS'S and its performance analysis over the decade. The search for new adjuvants to be associated with this antigen seems to be a way to obtain higher percentages of protection for a future malaria vaccine.


Assuntos
Vacinas Antimaláricas/uso terapêutico , Malária/prevenção & controle , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Proteínas de Protozoários , Humanos , Malária/parasitologia , Vacinas Antimaláricas/administração & dosagem , Proteínas de Membrana
10.
Nat Commun ; 12(1): 1063, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594061

RESUMO

The most advanced P. falciparum circumsporozoite protein-based malaria vaccine, RTS,S/AS01 (RTS,S), confers partial protection but with antibody titers that wane relatively rapidly, highlighting the need to elicit more potent and durable antibody responses. Here, we elucidate crystal structures, binding affinities and kinetics, and in vivo protection of eight anti-NANP antibodies derived from an RTS,S phase 2a trial and encoded by three different heavy-chain germline genes. The structures reinforce the importance of homotypic Fab-Fab interactions in protective antibodies and the overwhelmingly dominant preference for a germline-encoded aromatic residue for recognition of the NANP motif. In this study, antibody apparent affinity correlates best with protection in an in vivo mouse model, with the more potent antibodies also recognizing epitopes with repeating secondary structural motifs of type I ß- and Asn pseudo 310 turns; such insights can be incorporated into design of more effective immunogens and antibodies for passive immunization.


Assuntos
Anticorpos Antiprotozoários/imunologia , Malária Falciparum/imunologia , Malária Falciparum/prevenção & controle , Plasmodium falciparum/imunologia , Sequências Repetitivas de Aminoácidos , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Afinidade de Anticorpos/imunologia , Cristalografia por Raios X , Epitopos/química , Epitopos/imunologia , Fragmentos Fab das Imunoglobulinas/química , Fragmentos Fab das Imunoglobulinas/imunologia , Cinética , Camundongos Endogâmicos C57BL , Modelos Moleculares , Parasitos/imunologia , Peptídeos/química , Peptídeos/metabolismo , Ligação Proteica
11.
J Leukoc Biol ; 109(1): 77-90, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33617048

RESUMO

B cells play a central role in antiviral and antiparasitic immunity, not only as producers of antibodies, but also as APCs and mediators of inflammation. In this study, we used 16-color flow cytometry analysis to investigate the frequency, differentiation, and activation status of peripheral B cells of patients with SARS-CoV-2 infection or acute Plasmodium falciparum malaria compared with the healthy individuals. As a main result, we observed an increase of the frequency of (CD27-, CD21-) atypical memory B cells and (CD19+, CD27+, CD38+) plasmablasts in malaria and COVID-19 patients. Additionally, CD86, PD-1, CXCR3, and CD39 expression was up-regulated, whereas CD73 was down-regulated on plasmablasts of COVID-19 and malaria patients compared with the bulk B cell population. In particular, there was a more pronounced loss of CD73+ B cells in malaria. The frequency of plasmablasts positively correlated with serum levels of CRP, IL-6, and LDH of COVID-19 patients. In the longitudinal course of COVID-19, a rapid normalization of the frequency of atypical memory B cells was observed. The role and function of plasmablasts and atypical memory B cells in COVID-19 and other acute infections remain to be further investigated. The role of B cells as either "driver or passenger" of hyperinflammation during COVID-19 needs to be clarified.


Assuntos
/imunologia , Memória Imunológica , Malária Falciparum/imunologia , Plasmócitos/imunologia , Plasmodium falciparum/imunologia , /imunologia , Adulto , Idoso , Antígenos CD/imunologia , Feminino , Humanos , Malária Falciparum/patologia , Masculino , Pessoa de Meia-Idade , Plasmócitos/patologia
12.
BMC Complement Med Ther ; 21(1): 71, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33607987

RESUMO

BACKGROUND: In previous studies, Cassia spectabilis DC leaf has shown a good antiplasmodial activity. Therefore, this study is a follow-up study of the extract of leaf of C. spectabilis DC on its in vitro and in vivo antiplasmodial activity and mechanism as an antimalarial. METHODS: The extract was fractionated, sub-fractionated and isolated to obtain the purified compound. In vitro antiplasmodial activity test against Plasmodium falciparum to find out the active compound. In vivo test against P. berghei ANKA-infected mice was conducted to determine prophylactic activity and antiplasmodial activity either alone or in combination with artesunate. The inhibition of heme detoxification test as one of the antimalarial mechanisms was carried out using the Basilico method. RESULTS: The results showed that active antimalarial compound isolated from C. spectabilis DC leaf had a structural pattern that was identical to (-)-7-hydroxycassine. Prophylactic test of 90% ethanolic extract of C. spectabilis DC leaf alone against P. berghei ANKA-infected mice obtained the highest percentage inhibition was 68.61%, while positive control (doxycycline 13 mg/kg) was 73.54%. In combination with artesunate, 150 mg/kg three times a day of C. spectabilis DC (D0-D2) + artesunate (D2) was better than the standard combination of amodiaquine + artesunate where the inhibition percentages were 99.18 and 92.88%, respectively. The IC50 of the extract for the inhibitory activity of heme detoxification was 0.375 mg/ml which was better than chloroquine diphosphate (0.682 mg/ml). CONCLUSION: C. spectabilis DC leaf possessed potent antiplasmodial activity and may offer a potential agent for effective and affordable antimalarial phytomedicine.


Assuntos
Antimaláricos/farmacologia , Cassia/química , Heme/metabolismo , Malária/parasitologia , Extratos Vegetais/farmacologia , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/isolamento & purificação , Antimaláricos/uso terapêutico , Artesunato/uso terapêutico , Cloroquina/análogos & derivados , Cloroquina/farmacologia , Cetonas , Malária/tratamento farmacológico , Masculino , Camundongos Endogâmicos BALB C , Fitoterapia , Piperidinas , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Plasmodium berghei/metabolismo , Plasmodium falciparum/metabolismo
13.
Nat Commun ; 12(1): 909, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568678

RESUMO

Malaria control may be enhanced by targeting reservoirs of Plasmodium falciparum transmission. One putative reservoir is asymptomatic malaria infections and the scale of their contribution to transmission in natural settings is not known. We assess the contribution of asymptomatic malaria to onward transmission using a 14-month longitudinal cohort of 239 participants in a high transmission site in Western Kenya. We identify P. falciparum in asymptomatically- and symptomatically-infected participants and naturally-fed mosquitoes from their households, genotype all parasites using deep sequencing of the parasite genes pfama1 and pfcsp, and use haplotypes to infer participant-to-mosquito transmission through a probabilistic model. In 1,242 infections (1,039 in people and 203 in mosquitoes), we observe 229 (pfcsp) and 348 (pfama1) unique parasite haplotypes. Using these to link human and mosquito infections, compared with symptomatic infections, asymptomatic infections more than double the odds of transmission to a mosquito among people with both infection types (Odds Ratio: 2.56; 95% Confidence Interval (CI): 1.36-4.81) and among all participants (OR 2.66; 95% CI: 2.05-3.47). Overall, 94.6% (95% CI: 93.1-95.8%) of mosquito infections likely resulted from asymptomatic infections. In high transmission areas, asymptomatic infections are the major contributor to mosquito infections and may be targeted as a component of transmission reduction.


Assuntos
Anopheles/parasitologia , Malária Falciparum/parasitologia , Malária Falciparum/transmissão , Mosquitos Vetores/parasitologia , Plasmodium falciparum/genética , Adulto , Animais , Anopheles/fisiologia , Infecções Assintomáticas/epidemiologia , Estudos de Coortes , Feminino , Genótipo , Humanos , Quênia/epidemiologia , Estudos Longitudinais , Malária Falciparum/epidemiologia , Masculino , Mosquitos Vetores/fisiologia , Plasmodium falciparum/classificação , Plasmodium falciparum/isolamento & purificação
14.
Life Sci ; 270: 119158, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33545200

RESUMO

AIMS: Malaria is a serious health threat in tropical countries. The causative parasite of Malaria tropica, the severe form, is the protozoan Plasmodium falciparum. In humans, it infects red blood cells, compromising blood flow and tissue perfusion. This study aims to identify potential biomarkers and RNA networks in leukocyte transcriptomes from patients suffering from Malaria tropica. MATERIALS AND METHODS: We identified differentially regulated mRNAs and microRNAs in peripheral blood leukocytes of healthy donors and Malaria patients. Genes whose expression changes were not attributable to changes in leukocyte composition were used for bioinformatics analysis and network construction. Using a previously published cohort of community-acquired pneumonia (CAP) patients, we established discriminating transcriptomic features versus Malaria. We aimed to establish differences between the patient groups by principal component (PCA) and receiving operator characteristic (ROC) analyses and in silico cell type deconvolution. KEY FINDINGS: We found 870 genes that were significantly differentially expressed between healthy donors and Malaria patients. E2F1, BIRC5 and CCNB1 were identified to be primarily responsible for PCA separation of these two groups. We searched for biological function and found that cell cycle processes were strongly activated. By in silico cell type deconvolution, we attribute this to an expansion of γδ T cells. Additional discrimination between CAP and Malaria yielded 445 differentially expressed genes, among which immune proteasome transcripts PSMB8, PSMB9 and PSMB10 were significantly induced in Malaria. SIGNIFICANCE: We identified transcripts from patient leukocytes that differentiate between healthy, Malaria and CAP, and indicate a biological context with potential pathophysiological relevance.


Assuntos
Malária/genética , Adulto , Biomarcadores/sangue , Biologia Computacional , Feminino , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Humanos , Malária/parasitologia , Masculino , MicroRNAs/sangue , MicroRNAs/genética , Pessoa de Meia-Idade , Plasmodium falciparum/genética , Plasmodium falciparum/patogenicidade , RNA Mensageiro/sangue , RNA Mensageiro/genética , Transcriptoma/genética
15.
Nat Commun ; 12(1): 1172, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608523

RESUMO

Mature red blood cells (RBCs) lack internal organelles and canonical defense mechanisms, making them both a fascinating host cell, in general, and an intriguing choice for the deadly malaria parasite Plasmodium falciparum (Pf), in particular. Pf, while growing inside its natural host, the human RBC, secretes multipurpose extracellular vesicles (EVs), yet their influence on this essential host cell remains unknown. Here we demonstrate that Pf parasites, cultured in fresh human donor blood, secrete within such EVs assembled and functional 20S proteasome complexes (EV-20S). The EV-20S proteasomes modulate the mechanical properties of naïve human RBCs by remodeling their cytoskeletal network. Furthermore, we identify four degradation targets of the secreted 20S proteasome, the phosphorylated cytoskeletal proteins ß-adducin, ankyrin-1, dematin and Epb4.1. Overall, our findings reveal a previously unknown 20S proteasome secretion mechanism employed by the human malaria parasite, which primes RBCs for parasite invasion by altering membrane stiffness, to facilitate malaria parasite growth.


Assuntos
Transporte Biológico/fisiologia , Eritrócitos/metabolismo , Interações Hospedeiro-Parasita/fisiologia , Malária Falciparum/metabolismo , Plasmodium falciparum/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Citoesqueleto/metabolismo , Eritrócitos/citologia , Eritrócitos/parasitologia , Humanos , Malária Falciparum/parasitologia , Proteínas de Membrana/metabolismo , Fosforilação , Plasmodium falciparum/crescimento & desenvolvimento , Proteômica
16.
Artigo em Inglês | MEDLINE | ID: mdl-33530386

RESUMO

Aims: This study examines the dynamics of malaria as influenced by meteorological factors in French Guiana from 2005 to 2019. It explores spatial hotspots of malaria transmission and aims to determine the factors associated with variation of hotspots with time. Methods: Data for individual malaria cases came from the surveillance system of the Delocalized Centers for Prevention and Care (CDPS) (n = 17) from 2005-2019. Meteorological data was acquired from the NASA Goddard Earth Sciences Data and Information Services Center (GES DISC) database. The Box-Jenkins autoregressive integrated moving average (ARIMA) model tested stationarity of the time series, and the impact of meteorological indices (issued from principal component analysis-PCA) on malaria incidence was determined with a general additive model. Hotspot characterization was performed using spatial scan statistics. Results: The current sample includes 7050 eligible Plasmodium vivax (n = 4111) and Plasmodium falciparum (n = 2939) cases from health centers across French Guiana. The first and second PCA-derived meteorological components (maximum/minimum temperature/minimum humidity and maximum humidity, respectively) were significantly negatively correlated with total malaria incidence with a lag of one week and 10 days, respectively. Overall malaria incidence decreased across the time series until 2017 when incidence began to trend upwards. Hotspot characterization revealed a few health centers that exhibited spatial stability across the entire time series: Saint Georges de l'Oyapock and Antecume Pata for P. falciparum, and Saint Georges de l'Oyapock, Antecume Pata, Régina and Camopi for P. vivax. Conclusions: This study highlighted changing malaria incidence in French Guiana and the influences of meteorological factors on transmission. Many health centers showed spatial stability in transmission, albeit not temporal. Knowledge of the areas of high transmission as well as how and why transmission has changed over time can inform strategies to reduce the transmission of malaria in French Guiana. Hotspots should be further investigated to understand other influences on local transmission, which will help to facilitate elimination.


Assuntos
Malária Falciparum , Malária Vivax , Guiana Francesa/epidemiologia , Humanos , Malária Falciparum/epidemiologia , Malária Vivax/epidemiologia , Plasmodium falciparum , Plasmodium vivax
17.
Nat Commun ; 12(1): 269, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431834

RESUMO

Chemical matter is needed to target the divergent biology associated with the different life cycle stages of Plasmodium. Here, we report the parallel de novo screening of the Medicines for Malaria Venture (MMV) Pandemic Response Box against Plasmodium asexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. Unique chemotypes were identified with both multistage activity or stage-specific activity, including structurally diverse gametocyte-targeted compounds with potent transmission-blocking activity, such as the JmjC inhibitor ML324 and the antitubercular clinical candidate SQ109. Mechanistic investigations prove that ML324 prevents histone demethylation, resulting in aberrant gene expression and death in gametocytes. Moreover, the selection of parasites resistant to SQ109 implicates the druggable V-type H+-ATPase for the reduced sensitivity. Our data therefore provides an expansive dataset of compounds that could be redirected for antimalarial development and also point towards proteins that can be targeted in multiple parasite life cycle stages.


Assuntos
Antimaláricos/uso terapêutico , Descoberta de Drogas , Malária/tratamento farmacológico , Malária/transmissão , Pandemias , Aedes/parasitologia , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Análise por Conglomerados , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Concentração Inibidora 50 , Estágios do Ciclo de Vida/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/parasitologia , Malária/epidemiologia , Masculino , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento
18.
Nat Commun ; 12(1): 530, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33483501

RESUMO

The emergence and spread of artemisinin resistance, driven by mutations in Plasmodium falciparum K13, has compromised antimalarial efficacy and threatens the global malaria elimination campaign. By applying systems-based quantitative transcriptomics, proteomics, and metabolomics to a panel of isogenic K13 mutant or wild-type P. falciparum lines, we provide evidence that K13 mutations alter multiple aspects of the parasite's intra-erythrocytic developmental program. These changes impact cell-cycle periodicity, the unfolded protein response, protein degradation, vesicular trafficking, and mitochondrial metabolism. K13-mediated artemisinin resistance in the Cambodian Cam3.II line was reversed by atovaquone, a mitochondrial electron transport chain inhibitor. These results suggest that mitochondrial processes including damage sensing and anti-oxidant properties might augment the ability of mutant K13 to protect P. falciparum against artemisinin action by helping these parasites undergo temporary quiescence and accelerated growth recovery post drug elimination.


Assuntos
Artemisininas/farmacologia , Resistência a Medicamentos/genética , Eritrócitos/metabolismo , Mutação , Plasmodium falciparum/genética , Antimaláricos/farmacologia , Atovaquona/farmacologia , Pontos de Checagem do Ciclo Celular/genética , Eritrócitos/parasitologia , Perfilação da Expressão Gênica/métodos , Humanos , Metabolômica/métodos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Modelos Genéticos , Plasmodium falciparum/metabolismo , Plasmodium falciparum/fisiologia , Proteômica/métodos , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo
19.
Parasitol Res ; 120(2): 423-434, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33459846

RESUMO

The malaria-causing parasite Plasmodium falciparum is a severe threat to human health across the globe. This parasite alone causes the highest morbidity and mortality than any other species of Plasmodium. The parasites dynamically multiply in the erythrocytes of the vertebrate hosts, a large number of reactive oxygen species that damage biological macromolecules are produced in the cell during parasite growth. To relieve this intense oxidative stress, the parasite employs an NADPH-dependent thioredoxin and glutathione system that acts as an antioxidant and maintains redox status in the parasite. The mutual interaction of both redox proteins is involved in various biological functions and the survival of the erythrocytic stage of the parasite. Since the Plasmodium species is deficient in catalase and classical glutathione peroxidase, so their redox balance relies on a complex set of five peroxiredoxins, differentially positioned in the cytosol, mitochondria, apicoplast, and nucleus with partly overlapping substrate preferences. Moreover, Plasmodium falciparum possesses a set of members belonging to the thioredoxin superfamily, such as three thioredoxins, two thioredoxin-like proteins, one dithiol, three monocysteine glutaredoxins, and one redox-active plasmoredoxin with largely redundant functions. This review paper aims to discuss and encapsulate the biological function and current knowledge of the functional redox network of Plasmodium falciparum.


Assuntos
Malária Falciparum/parasitologia , Peroxirredoxinas/metabolismo , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/metabolismo , Tiorredoxinas/metabolismo , Animais , Antioxidantes/metabolismo , Eritrócitos/metabolismo , Eritrócitos/parasitologia , Humanos , Oxirredução , Estresse Oxidativo , Plasmodium falciparum/crescimento & desenvolvimento , Espécies Reativas de Oxigênio/metabolismo
20.
Anal Chem ; 93(4): 2097-2105, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33464825

RESUMO

In many countries targeting malaria elimination, persistent malaria infections can have parasite loads significantly below the lower limit of detection (LLOD) of standard diagnostic techniques, making them difficult to identify and treat. The most sensitive diagnostic methods involve amplification and detection of Plasmodium DNA by polymerase chain reaction (PCR), which requires expensive thermal cycling equipment and is difficult to deploy in resource-limited settings. Isothermal DNA amplification assays have been developed, but they require complex primer design, resulting in high nonspecific amplification, and show a decrease in sensitivity than PCR methods. Here, we have used a computational approach to design a novel isothermal amplification assay with a simple primer design to amplify P. falciparum DNA with analytical sensitivity comparable to PCR. We have identified short DNA sequences repeated throughout the parasite genome to be used as primers for DNA amplification and demonstrated that these primers can be used, without modification, to isothermally amplify P. falciparum parasite DNA via strand displacement amplification. Our novel assay shows a LLOD of ∼1 parasite/µL within a 30 min amplification time. The assay was demonstrated with clinical samples using patient blood and saliva. We further characterized the assay using direct amplicon next-generation sequencing and modified the assay to work with a visual readout. The technique developed here achieves similar analytical sensitivity to current gold standard PCR assays requiring a fraction of time and resources for PCR. This highly sensitive isothermal assay can be more easily adapted to field settings, making it a potentially useful tool for malaria elimination.


Assuntos
DNA de Protozoário/genética , Malária Falciparum/diagnóstico , Técnicas de Amplificação de Ácido Nucleico/métodos , Plasmodium falciparum/genética , Sequências Repetitivas de Ácido Nucleico/genética , DNA de Protozoário/isolamento & purificação , Humanos , Limite de Detecção , Plasmodium falciparum/isolamento & purificação , Reprodutibilidade dos Testes
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