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1.
Malar J ; 21(1): 230, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35915453

RESUMO

BACKGROUND: The increase in detections of Plasmodium vivax infection in Duffy-negative individuals in Africa has challenged the dogma establishing the unique P. vivax Duffy Binding Protein-Duffy antigen receptor for chemokines (PvDBP-DARC) pathway used by P. vivax merozoites to invade reticulocytes. Information on the impact of Duffy antigen polymorphisms on the epidemiology of P. vivax malaria remains elusive. The objective of this study was to determine the distribution of asexual parasitaemia of P. vivax according to the Duffy antigen polymorphisms in Ethiopia. METHODS: DNA was extracted from dried blood spots (DBS) collected from prospectively recruited 138 P. vivax-infected patients from health centres. The identification and estimation of P. vivax asexual parasitaemia were performed by microscopic examination and quantitative real-time polymerase chain reaction (PCR). Duffy genotyping was conducted by DNA sequencing in a total of 138 P.vivax infected samples. RESULTS: The proportion of Duffy-negatives (FY*BES/FY*BES) in P. vivax infected patients was 2.9% (4/138). Duffy genotype FY*B/FY*BES (48.6%) was the most common, followed by FY*A/FY*BES genotype (25.4%). In one patient, the FY*02 W.01/FY*02 N.01 genotype conferring a weak expression of the Fyb antigen was observed. All P.vivax infected Duffy-negative patients showed low asexual parasitaemia (≤ 110 parasites/µL). The median P. vivax parasitaemia in Duffy-negative patients (53 parasites/µL) was significantly lower than those found in homozygous and heterozygous individuals (P < 0.0001). CONCLUSION: Plasmodium vivax in Duffy-negative patients shows invariably low asexual parasitaemia. This finding suggests that the pathway used by P. vivax to invade Duffy-negative reticulocytes is much less efficient than that used in Duffy-positives. Moreover, the low asexual parasitaemia observed in Duffy-negative individuals could constitute an 'undetected silent reservoir', thus likely delaying the elimination of vivax malaria in Ethiopia.


Assuntos
Malária Vivax , Malária , Sistema do Grupo Sanguíneo Duffy/genética , Etiópia/epidemiologia , Humanos , Parasitemia/epidemiologia , Plasmodium vivax/genética
2.
J Evid Based Integr Med ; 27: 2515690X221116407, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35929106

RESUMO

The current work investigated the chemical profile, antimalarial potential and capacity of hydroethanolic Senna alata extract (SAE) to reverse hematological and biochemical pertubation in Plasmodium berghei infected mice. Results of the phytochemical analysis revealed the presence of alkaloids, flavonoids, phenolics, tannins, terpenoids, saponins, steroids and cardiac glycosides. Total phenolic and flavonoid content was estimated to be 45.29 ± 2.34 mg GAE/g and 25.22 ± 2.26 mg QE/g respectively. In vitro analysis of the extract also confirmed its antioxidant property. Results of the test for prophylaxis of P. berghei indicated that SAE suppressed parasitemia significantly in treated groups in a dose dependent manner when compared with negative control group. Similarly, SAE improved the mean survival time (MST) and packed cell volume (PCV) of infected mice. The test for curative effect showed that SAE significantly suppressed parasitemia to 4.50 ± 1.05% compared to untreated group 29.83 ± 3.49%. Results of liver and kidney functions indices of treated animals indicated that whereas infection with P. berghei caused increase in the levels of AST, ALT, ALP, urea and creatinine, treatment with SAE significantly reversed the perturbation. Similarly, infected mice were dyslipidemic with concomitant increased activity of HMG CoA reductase and decreased activity of antioxidant enzymes with increase in lipid peroxides levels. However, these alterations were significantly reversed by administration of SAE. Results of this study shows that Senna alata possess antimalarial activity and therefore justify the traditional use of plant for the treatment of malaria.


Assuntos
Antimaláricos , Plasmodium berghei , Animais , Antimaláricos/farmacologia , Antioxidantes/farmacologia , Flavonoides/farmacologia , Camundongos , Parasitemia/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Folhas de Planta/química
3.
Sci Rep ; 12(1): 13303, 2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35922467

RESUMO

Controlled human malaria infection (CHMI) using cryopreserved non-attenuated Plasmodium falciparum sporozoites (PfSPZ) offers a unique opportunity to investigate naturally acquired immunity (NAI). By analyzing blood samples from 5 malaria-naïve European and 20 African adults with lifelong exposure to malaria, before, 5, and 11 days after direct venous inoculation (DVI) with SanariaR PfSPZ Challenge, we assessed the immunological patterns associated with control of microscopic and submicroscopic parasitemia. All (5/5) European individuals developed parasitemia as defined by thick blood smear (TBS), but 40% (8/20) of the African individuals controlled their parasitemia, and therefore remained thick blood smear-negative (TBS- Africans). In the TBS- Africans, we observed higher baseline frequencies of CD4+ T cells producing interferon-gamma (IFNγ) that significantly decreased 5 days after PfSPZ DVI. The TBS- Africans, which represent individuals with either very strong and rapid blood-stage immunity or with immunity to liver stages, were stratified into subjects with sub-microscopic parasitemia (TBS-PCR+) or those with possibly sterilizing immunity (TBS-PCR-). Higher frequencies of IFNγ+TNF+CD8+ γδ T cells at baseline, which later decreased within five days after PfSPZ DVI, were associated with those who remained TBS-PCR-. These findings suggest that naturally acquired immunity is characterized by different cell types that show varying strengths of malaria parasite control. While the high frequencies of antigen responsive IFNγ+CD4+ T cells in peripheral blood keep the blood-stage parasites to a sub-microscopic level, it is the IFNγ+TNF+CD8+ γδ T cells that are associated with either immunity to the liver-stage, or rapid elimination of blood-stage parasites.


Assuntos
Vacinas Antimaláricas , Malária Falciparum , Malária , Adulto , Animais , Gabão , Humanos , Interferon gama , Malária Falciparum/parasitologia , Parasitemia/parasitologia , Plasmodium falciparum , Esporozoítos , Voluntários
5.
N Engl J Med ; 387(5): 397-407, 2022 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-35921449

RESUMO

BACKGROUND: New approaches for the prevention and elimination of malaria, a leading cause of illness and death among infants and young children globally, are needed. METHODS: We conducted a phase 1 clinical trial to assess the safety and pharmacokinetics of L9LS, a next-generation antimalarial monoclonal antibody, and its protective efficacy against controlled human malaria infection in healthy adults who had never had malaria or received a vaccine for malaria. The participants received L9LS either intravenously or subcutaneously at a dose of 1 mg, 5 mg, or 20 mg per kilogram of body weight. Within 2 to 6 weeks after the administration of L9LS, both the participants who received L9LS and the control participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying Plasmodium falciparum (3D7 strain). RESULTS: No safety concerns were identified. L9LS had an estimated half-life of 56 days, and it had dose linearity, with the highest mean (±SD) maximum serum concentration (Cmax) of 914.2±146.5 µg per milliliter observed in participants who had received 20 mg per kilogram intravenously and the lowest mean Cmax of 41.5±4.7 µg per milliliter observed in those who had received 1 mg per kilogram intravenously; the mean Cmax was 164.8±31.1 in the participants who had received 5 mg per kilogram intravenously and 68.9±22.3 in those who had received 5 mg per kilogram subcutaneously. A total of 17 L9LS recipients and 6 control participants underwent controlled human malaria infection. Of the 17 participants who received a single dose of L9LS, 15 (88%) were protected after controlled human malaria infection. Parasitemia did not develop in any of the participants who received 5 or 20 mg per kilogram of intravenous L9LS. Parasitemia developed in 1 of 5 participants who received 1 mg per kilogram intravenously, 1 of 5 participants who received 5 mg per kilogram subcutaneously, and all 6 control participants through 21 days after the controlled human malaria infection. Protection conferred by L9LS was seen at serum concentrations as low as 9.2 µg per milliliter. CONCLUSIONS: In this small trial, L9LS administered intravenously or subcutaneously protected recipients against malaria after controlled infection, without evident safety concerns. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 614 ClinicalTrials.gov number, NCT05019729.).


Assuntos
Anticorpos Monoclonais , Malária , Administração Cutânea , Administração Intravenosa , Adulto , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Criança , Pré-Escolar , Humanos , Malária/prevenção & controle , Malária Falciparum/tratamento farmacológico , Malária Falciparum/prevenção & controle , Parasitemia/parasitologia , Plasmodium falciparum
6.
J Trace Elem Med Biol ; 73: 127028, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35797926

RESUMO

BACKGROUND: Malaria is a parasitic disease with the highest morbidity and mortality worldwide. Unfortunately, during the last decades, the causal agent, Plasmodium spp., has developed resistance to chloroquine and artemisinin. For this reason, metallic compounds have been proposed as an optional treatment since they have shown a potential antimalarial effect with diverse action mechanisms in the parasite and the host. OBJECTIVE: To show the possible targets of metallic compounds in Plasmodium spp. CONCLUSION: The metallic compounds are an option attractive to treatment for the malaria, for its low cost and its great activity to reduce parasitemia; however is necessary more studies principally in vivo in order to know the interactions that it can have in an experimental model.


Assuntos
Antimaláricos , Malária , Plasmodium , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Cloroquina/uso terapêutico , Humanos , Malária/tratamento farmacológico , Parasitemia/tratamento farmacológico , Parasitemia/parasitologia
7.
Front Cell Infect Microbiol ; 12: 855119, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35865815

RESUMO

Drug repurposing and combination therapy have been proposed as cost-effective strategies to improve Chagas disease treatment. Miltefosine (MLT), a synthetic alkylphospholipid initially developed for breast cancer and repositioned for leishmaniasis, is a promising candidate against Trypanosoma cruzi infection. This study evaluates the efficacy of MLT as a monodrug and combined with benznidazole (BZ) in both in vitro and in vivo models of infection with T. cruzi (VD strain, DTU TcVI). MLT exhibited in vitro activity on amastigotes and trypomastigotes with values of IC50 = 0.51 µM (0.48 µM; 0,55 µM) and LC50 = 31.17 µM (29.56 µM; 32.87 µM), respectively. Drug interaction was studied with the fixed-ration method. The sum of the fractional inhibitory concentrations (ΣFICs) resulted in ∑FIC= 0.45 for trypomastigotes and ∑FIC= 0.71 for amastigotes, suggesting in vitro synergistic and additive effects, respectively. No cytotoxic effects on host cells were observed. MLT efficacy was also evaluated in a murine model of acute infection alone or combined with BZ. Treatment was well tolerated with few adverse effects, and all treated animals displayed significantly lower mean peak parasitemia and mortality than infected non-treated controls (p<0.05). The in vivo studies showed that MLT led to a dose-dependent parasitostatic effect as monotherapy which could be improved by combining with BZ, preventing parasitemia rebound after a stringent immunosuppression protocol. These results support MLT activity in clinically relevant stages from T. cruzi, and it is the first report of positive interaction with BZ, providing further support for evaluating combined schemes using MLT and exploring synthetic alkylphospholipids as drug candidates.


Assuntos
Doença de Chagas , Tripanossomicidas , Trypanosoma cruzi , Animais , Doença de Chagas/tratamento farmacológico , Camundongos , Nitroimidazóis , Parasitemia/tratamento farmacológico , Fosforilcolina/análogos & derivados , Tripanossomicidas/farmacologia
8.
Nat Commun ; 13(1): 4098, 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35835738

RESUMO

Ring-infected erythrocytes are the predominant asexual stage in the peripheral circulation but are rarely investigated in the context of acquired immunity against Plasmodium falciparum malaria. Here we compare antibody-dependent phagocytosis of ring-infected parasite cultures in samples from a controlled human malaria infection (CHMI) study (NCT02739763). Protected volunteers did not develop clinical symptoms, maintained parasitaemia below a predefined threshold of 500 parasites/µl and were not treated until the end of the study. Antibody-dependent phagocytosis of both ring-infected and uninfected erythrocytes from parasite cultures was strongly correlated with protection. A surface proteomic analysis revealed the presence of merozoite proteins including erythrocyte binding antigen-175 and -140 on ring-infected and uninfected erythrocytes, providing an additional antibody-mediated protective mechanism for their activity beyond invasion-inhibition. Competition phagocytosis assays support the hypothesis that merozoite antigens are the key mediators of this functional activity. Targeting ring-stage parasites may contribute to the control of parasitaemia and prevention of clinical malaria.


Assuntos
Malária Falciparum , Malária , Parasitos , Animais , Anticorpos Antiprotozoários , Antígenos de Protozoários , Eritrócitos/parasitologia , Humanos , Malária Falciparum/parasitologia , Merozoítos , Parasitemia , Fagocitose , Plasmodium falciparum , Proteômica
9.
Front Immunol ; 13: 866120, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35812458

RESUMO

Chagas disease (CD) is a neglected chronic infection caused by the protozoan parasite Trypanosoma cruzi (T. cruzi). A significant portion of infected people develops cardiac or digestive alterations over a lifetime. Since several chronic infections associated with antigen persistence and inflammation have been shown to lead to T cell exhaustion, new therapies targeting co-inhibitory receptors to regain T cell activity are under consideration. This study explored immune therapeutic approaches targeting the inhibitory PD-1/PD-L pathway in an experimental model for CD. Infected PD-L1 knockout mice (PD-L1 KO) showed increased systemic parasitemia in blood although no significant differences in parasite load were observed in different organs. Furthermore, we found no significant differences in the frequency of activated T cells or proinflammatory cytokine production when compared to WT counterparts. PD-L1 deficiency led to the production of IL-10 by CD8+ T cells and an upregulation of Tim-3 and CD244 (2B4). Unexpectedly, the lack of PD-L1 did not contribute to a significantly improved T cell response to infection. Single blockade and combined blockade of PD-1 and Tim-3 using monoclonal antibodies confirmed the results observed in infected. PD-L1 KO mice. Our results describe for the first time that the interruption of the PD-1/PD-L1 axis during acute T. cruzi infection does not necessarily enhance the immune response against this parasite. Its interruption favors increased levels of parasitemia and sustained upregulation of other co-inhibitory receptors as well as the production of regulatory cytokines. These results suggest that the clinical application of immune therapeutic approaches targeting the PD-1/PD-L1 axis in CD might be risky and associated with adverse events. It highlights that more research is urgently needed to better understand the immune regulation of T cells in CD before designing immune therapeutic approaches for a clinical context.


Assuntos
Doença de Chagas , Receptor Celular 2 do Vírus da Hepatite A , Animais , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos , Humanos , Camundongos , Parasitemia , Receptor de Morte Celular Programada 1/metabolismo
10.
Parasit Vectors ; 15(1): 267, 2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35906670

RESUMO

BACKGROUND: Sequencing parasite genomes in the presence of host DNA is challenging. Sequence capture can overcome this problem by using RNA probes that hybridize with the parasite DNA and then are removed from solution, thus isolating the parasite DNA for efficient sequencing. METHODS: Here we describe a set of sequence capture probes designed to target 1035 genes (c. 2.5 Mbp) of the globally distributed avian haemosporidian parasite, Plasmodium relictum. Previous sequence capture studies of avian haemosporidians from the genus Haemoproteus have shown that sequencing success depends on parasitemia, with low-intensity, chronic infections (typical of most infected birds in the wild) often being difficult to sequence. We evaluate the relationship between parasitemia and sequencing success using birds experimentally infected with P. relictum and kept under laboratory conditions. RESULTS: We confirm the dependence of sequencing success on parasitemia. Sequencing success was low for birds with low levels of parasitemia (< 1% infected red blood cells) and high for birds with higher levels of parasitemia. Plasmodium relictum is composed of multiple lineages defined by their mitochondrial DNA haplotype including three that are widespread (SGS1, GRW11, and GRW4); the probes successfully isolated DNA from all three. Furthermore, we used data from 25 genes to describe both among- and within-lineage genetic variation. For example, two samples of SGS1 isolated from different host species differed by 11 substitutions across those 25 genes. CONCLUSIONS: The sequence capture approach we describe will allow for the generation of genomic data that will contribute to our understanding of the population genetic structure and evolutionary history of P. relictum, an extreme host generalist and widespread parasite.


Assuntos
Haemosporida , Malária Aviária , Plasmodium , Animais , Aves , Genômica , Haemosporida/genética , Malária Aviária/parasitologia , Parasitemia/parasitologia , Parasitemia/veterinária
11.
PLoS One ; 17(7): e0271527, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35839244

RESUMO

Decreased platelet count is an early phenomenon in asexual Plasmodium falciparum parasitemia, but its association with acute or long-term functional changes in platelets and coagulation is unknown. Moreover, the impact of gametocytemia on platelets and coagulation remains unclear. We investigated the changes in platelet number and function during early asexual parasitemia, gametocytemia and convalescence in 16 individuals participating in a controlled human malaria infection study, and studied its relationship with changes in total and active von Willebrand factor levels (VWF) and the coagulation system. Platelet activation and reactivity were determined by flow cytometry, and the coagulation system was assessed using different representative assays including antigen assays, activity assays and global functional assays. Platelet count was decreased during asexual blood stage infection but normalized during gametocytemia. Platelet P-selectin expression was slightly increased during asexual parasitemia, gametocytemia and at day 64. In contrast, platelet reactivity to different agonists remained unchanged, except a marked decrease in reactivity to low dose collagen-related peptide-XL. Thrombin generation and antigen assays did not show a clear activation of the coagulation during asexual parasitemia, whereas total and active VWF levels were markedly increased. During gametocytemia and on day 64, the endogenous thrombin potential, thrombin peak and velocity index were increased and prothrombin conversion and plasma prothrombin levels were decreased. We conclude that the decreased platelet count during asexual parasitemia is associated with increased active VWF levels (i.e. endothelial activation), but not platelet hyperreactivity or hypercoagulability, and that the increased platelet clearance in asexual parasitemia could cause spontaneous VWF-platelet complexes formation.


Assuntos
Hemostasia , Malária , Parasitemia , Plaquetas/metabolismo , Hemostasia/fisiologia , Humanos , Malária/complicações , Malária/metabolismo , Parasitemia/complicações , Parasitemia/metabolismo , Protrombina/metabolismo , Trombina/metabolismo , Fator de von Willebrand/metabolismo
12.
Am J Case Rep ; 23: e936326, 2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-35844076

RESUMO

BACKGROUND Babesia species are intraerythrocytic parasitic protozoa that are endemic to the Northeast and north Midwest of the United States. Babesia microti is the most common cause of babesiosis in North America and causes a malaria-like tick-borne parasitosis. Babesia is commonly transmitted through the bite of Ixodes species ticks, often concomitantly with other tick-borne organisms such as Borrelia burgdorferi, Ehrlichia, Rickettsia rickettsii, and Anaplasma phagocytophilum. In the Midwest, Lyme disease is the most common tick-borne illness, and other organisms can sometimes be overlooked. The risk of tick-borne parasitic or bacterial infection is increased in patients after splenectomy. CASE REPORT An 89-year-old man with asplenia and multiple other comorbidities presented to the Emergency Department after a fall at home preceded by 2 to 3 days of fever and loss of appetite and 1 week of generalized weakness. The patient had thrombocytopenia, leukocytosis with neutrophilia, transaminitis, hyperbilirubinemia, and elevated creatine kinase level consistent with tick-borne illness. Laboratory testing revealed Borrelia and Babesia co-infection and other culprits were ruled out via high sensitivity PCR. Owing to the patient's asplenic status, the babesiosis was slow to resolve with appropriate treatment. After an extended 8-week treatment with azithromycin and atovaquone, the patient demonstrated clinical resolution of babesiosis with a negative blood smear. CONCLUSIONS First-line treatment with azithromycin and atovaquone is effective in treating babesiosis even in complicated patients, such as this elderly, asplenic patient. However, in cases such as this, an extended course of a first-line treatment regimen is still appropriate.


Assuntos
Babesia , Babesiose , Idoso , Idoso de 80 Anos ou mais , Atovaquona , Azitromicina , Babesiose/diagnóstico , Babesiose/tratamento farmacológico , Humanos , Masculino , Parasitemia , Confiança , Estados Unidos
13.
Methods Mol Biol ; 2470: 3-10, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35881333

RESUMO

Estimating malaria parasite density is important for patient care and management in rural and urban health centers in endemic areas. Here, we describe methodologically the protocols and methods to identify and enumerate Plasmodium falciparum parasites from infected blood using light microscopy. We provide step-by-step protocols and evaluate any possible drawbacks that may limit the methods and prospects of using light microscopy in diagnosing malaria.


Assuntos
Malária Falciparum , Malária , Parasitos , Animais , Humanos , Malária/diagnóstico , Malária Falciparum/diagnóstico , Malária Falciparum/parasitologia , Microscopia/métodos , Parasitemia/diagnóstico , Parasitemia/parasitologia , Plasmodium falciparum
14.
BMC Ecol Evol ; 22(1): 73, 2022 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-35655150

RESUMO

BACKGROUND: Hosts are often simultaneously infected with several parasite species. These co-infections can lead to within-host interactions of parasites, including mutualism and competition, which may affect both virulence and transmission. Birds are frequently co-infected with different haemosporidian parasites, but very little is known about if and how these parasites interact in natural host populations and what consequences there are for the infected hosts. We therefore set out to study Plasmodium and Haemoproteus parasites in house sparrows Passer domesticus with naturally acquired infections using a protocol where the parasitemia (infection intensity) is quantified by qPCR separately for the two parasites. We analysed infection status (presence/absence of the parasite) and parasitemia of parasites in the blood of both adult and juvenile house sparrows repeatedly over the season. RESULTS: Haemoproteus passeris and Plasmodium relictum were the two dominating parasite species, found in 99% of the analyzed Sanger sequences. All birds were infected with both Plasmodium and Haemoproteus parasites during the study period. Seasonality explained infection status for both parasites in the adults: H. passeris was completely absent in the winter while P. relictum was present all year round. Among adults infected with H. passeris there was a positive effect of P. relictum parasitemia on H. passeris parasitemia and likewise among adults infected with P. relictum there was a positive effect of H. passeris parasitemia on P. relictum parasitemia. No such associations on parasitemia were seen in juvenile house sparrows. CONCLUSIONS: The reciprocal positive relationships in parasitemia between P. relictum and H. passeris in adult house sparrows suggests either mutualistic interactions between these frequently occurring parasites or that there is variation in immune responses among house sparrow individuals, hence some individuals suppress the parasitemia of both parasites whereas other individuals suppress neither. Our detailed screening of haemosporidian parasites over the season shows that co-infections are very frequent in both juvenile and adult house sparrows, and since co-infections often have stronger negative effects on host fitness than the single infection, it is imperative to use screening systems with the ability to detect multiple parasites in ecological studies of host-parasite interactions.


Assuntos
Coinfecção , Haemosporida , Malária Aviária , Parasitos , Plasmodium , Pardais , Animais , Coinfecção/epidemiologia , Humanos , Malária Aviária/epidemiologia , Parasitemia/veterinária , Pardais/parasitologia
15.
J Vector Borne Dis ; 59(1): 45-51, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35708403

RESUMO

BACKGROUND & OBJECTIVES: Malaria affects around 228 million people all over the globe. Malaria causing parasite Plasmodium infection leads to activation of immune responses. The growth of parasite and immune activation requires semi essential amino acids like L-arginine. Malaria infection leads to condition of hyperargininemia and low availability of nitric oxide. However, the effect of L-arginine supplementation in malaria infected mice has not been explored in in-vivo studies. In this study we have compared the effect of oral supplementation of nitric oxide donor, L-arginine and L-citrulline, in malaria infected mice Methods: To examine the effect of oral supplementation of L-arginine and L-citrulline, Plasmodium berghei infected mice were divided in different groups and respective groups were fed with L- arginine and L-citrulline, parasitemia was measured on different days. Mice was sacrificed and immunophenotyping was done on 10 days post infection. RESULTS: our results show that supplementation of L-arginine induces conducive environment for Plasmodium growth due to which the infected mice dies earlier than control wild type infected mice whereas L-citrulline supplementation inhibits parasite growth and mice survives for longer period of time. Flow cytometric analysis shows that supplementation of L-arginine increases cTLA-4 on T cell population, increases Treg cells leading to immunosuppression while supplementation of L-citrulline does not have effect on T cells population and number of Treg cell decrease compared to P. berghei infected mice. INTERPRETATION & CONCLUSION: our results show that L-citrulline can be a better alternative than L-arginine because of lower expression of inhibitory molecules and lower parasitemia as well as increased survival of infected mice.


Assuntos
Citrulina , Malária , Animais , Arginina/metabolismo , Arginina/farmacologia , Citrulina/metabolismo , Citrulina/farmacologia , Humanos , Malária/prevenção & controle , Camundongos , Parasitemia/prevenção & controle , Plasmodium berghei , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia
16.
BMC Med ; 20(1): 190, 2022 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-35672703

RESUMO

BACKGROUND: In Papua (Indonesia), infants with P. falciparum and/or P. vivax malaria are at risk of severe anaemia and death. We hypothesized that in an area of high malaria transmission, intermittent screening and treatment of infants with malaria (ISTi) will reduce morbidity compared to passive case detection (PCDi). METHODS: We conducted a cluster randomised, open label, superiority trial. A total of 21 clusters of village health posts (VHP) were randomised 1:1 to either IST for infants coinciding with 4 routine immunisation visits or PCDi. Healthy term infants born to consenting mothers enrolled into a maternal malaria cluster randomised trial were included in the study and followed for 12 months. Point of care malaria rapid diagnostic tests were used to detect peripheral parasitaemia at 2, 3, 4 and 9 months old in all infants in ISTi clusters and when symptomatic in PCDi clusters. Infants with detected peripheral parasitaemia were treated with dihydroartemisinin-piperaquine. The co-primary outcomes were the incidence rate of clinical malaria in the first year of life and the prevalence of parasitaemia at age 12 months. The incidence rate ratio and prevalence ratio between ISTi and PCDi were estimated using mixed-effects Poisson and log-binomial regression modelling (accounting for clustering at VHP level). RESULTS: Between May 2014 and February 2017, 757 infants were enrolled into the study, 313 into 10 ISTi clusters, and 444 into 11 PCDi clusters. Overall, 132 episodes of parasitaemia were detected, of whom 17 (12.9%) were in symptomatic infants. Over 12 months, the incidence rate (IR) of clinical malaria was 24 [95% CI, 10-50] per 1000 children-years at risk in the ISTi arm and 19 [95% CI, 8,38] per 1000 children-years in the PCDi arm (adjusted incidence rate ratio [aIRR] 1.77 [95% CI, 0.62-5.01]; p = 0.280). The prevalence of parasitaemia at 12 months was 13% (33/254) in the IST clusters and 15% (57/379) in the PCD clusters (adjusted prevalence ratio (aPR) = 0.92 (95% CI, 0.70-1.21), p = 0.55). There was no difference in the risk of anaemia between treatment arms. CONCLUSIONS: In high malaria transmission area outside of Africa, our study suggests that compared to PCDi, ISTi offers no significant benefit in reducing the risk of clinical malaria in infants born to women receiving effective protection from malaria during pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02001428 , registered on 20 Nov 2013.


Assuntos
Anemia , Antimaláricos , Malária Falciparum , Malária Vivax , Malária , Anemia/epidemiologia , Antimaláricos/uso terapêutico , Criança , Feminino , Humanos , Indonésia/epidemiologia , Lactente , Malária/diagnóstico , Malária/epidemiologia , Malária/prevenção & controle , Malária Falciparum/diagnóstico , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Malária Vivax/diagnóstico , Malária Vivax/tratamento farmacológico , Malária Vivax/epidemiologia , Parasitemia/diagnóstico , Parasitemia/epidemiologia , Parasitemia/prevenção & controle , Gravidez , Vacinação
17.
Ticks Tick Borne Dis ; 13(5): 101982, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35716428

RESUMO

This study aimed to morphologically and molecularly detect Hepatozoon procyonis in ring-tailed coatis' (Nasua nasua) blood and associated ticks from central-western Brazil, Campo Grande, Mato Grosso do Sul state and also evaluate the impact of the protozoa in blood parameters and coati´s health. Samplings were performed in a conservation area Parque Estadual do Prosa (PEP) and in a Brazilian Air Force Private Area namely Vila da Base Aérea (VBA), between March 2018 and April 2019. We collected 165 blood samples, 61 from recaptured coatis. Peripheral blood smears were stained with Romanovsky-type stain for H. procyonis parasitemia assessment. DNA extracted from blood samples and ticks (Amblyomma spp.) were submitted to a nested PCR (nPCR) assay based on the 18S rRNA gene for Hepatozoon spp. Out of 104 individuals sampled, 80 (77%) were positive for H. procyonis in at least one capture. Overall, 67/165 (40.6%) blood smears showed H. procyonis gametocytes (PEP: 41/63 - 65%; VBA: 26/102 - 25.5%). Parasitemia based on 500 assessed leucocytes ranged from 1 (0.2%) to 50 (10%) and 1 (0.2%) to 25 (5%), from animals sampled in PEP and VBA, respectively. Fluctuation on the parasitemia was observed during recaptures. nPCR results showed higher positivity when compared to blood smears, i.e. 112/165 (68%) positive blood samples [PEP: 41/63 (65%), VBA: 26/102 (25.5%)]. In total, 63/248 (25.4%) tick DNA samples were positive at nPCR for Hepatozoon sp., including 32/87 (37%) pools (1 to 10 larvae) of Amblyomma larvae, 21/105 (20%) pools (1 to 5 nymphs) of Amblyomma sculptum nymphs, 9/43 (21%) pools (1 to 5 nymphs) of Amblyomma dubitatumnymphs, and 1/12 (8%) A. sculptum adult female. The partial 18S rRNA sequence from one coati's blood sample and one representative of each positive tick species randomly selected from each area for sequencing (1,000 bp) showed 100% identity with sequences of H. procyonis from GenBank previously detected in coatis. Regarding H. procyonis infection, no statistical differences were obtained when comparing males vs. females (p-value 0.67), immature animals vs. adults (p-value 0.31), rainy vs. dry season (p-value 0.51) and sampling location (p-value 0.42). No noticeable alteration in blood parameters or heath status was observed in parasite animals. H. procyonis circulates in a high prevalence in coatis from central-western Brazil. Parasitemia fluctuates among different coatis' recaptures and apparently the infection has no influence in coatis' hematological and clinical parameters.


Assuntos
Apicomplexa , Carnívoros , Eucoccidiida , Procyonidae , Carrapatos , Animais , Apicomplexa/genética , Brasil/epidemiologia , Eucoccidiida/genética , Feminino , Masculino , Parasitemia/epidemiologia , Parasitemia/veterinária , Procyonidae/parasitologia , Carrapatos/parasitologia
18.
Mem Inst Oswaldo Cruz ; 117: e210287, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35730803

RESUMO

BACKGROUND: It has been demonstrated that proteins expressed by liver-stage Plasmodium parasites can inhibit the translocation of transcription factors to the nucleus of different cells. This process would hinder the expression of immune genes, such as the CCL20 chemokine. OBJECTIVE: Since CCR6 is the only cognate receptor for CCL20, we investigated the importance of this chemokine-receptor axis against rodent malaria. METHODS: CCR6-deficient (KO) and wild-type (WT) C57BL/6 mice were challenged with Plasmodium berghei (Pb) NK65 sporozoites or infected red blood cells (iRBCs). Liver parasitic cDNA, parasitemia and serum cytokine concentrations were respectively evaluated through reverse transcription-polymerase chain reaction (RT-PCR), staining thin-blood smears with Giemsa solution, and enzyme-linked immunosorbent assay (ELISA). FINDINGS: Although the sporozoite challenges yielded similar liver parasitic cDNA and parasitemia, KO mice presented a prolonged survival than WT mice. After iRBC challenges, KO mice kept displaying higher survival rates as well as a decreased IL-12 p70 concentration in the serum than WT mice. CONCLUSION: Our data suggest that malaria triggered by PbNK65 liver- or blood-stage forms elicit a pro-inflammatory environment that culminates with a decreased survival of infected C57BL/6 mice.


Assuntos
Malária , Plasmodium berghei , Animais , DNA Complementar , Malária/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Parasitemia/parasitologia , Receptores CCR6
19.
Malar J ; 21(1): 204, 2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35761324

RESUMO

BACKGROUND: Malaria is an infectious disease considered as one of the biggest causes of mortality in endemic areas. This life-threatening disease needs to be quickly diagnosed and treated. The standard diagnostic tools recommended by the World Health Organization are thick blood smears microscopy and immuno-chromatographic rapid diagnostic tests. However, these methods lack sensitivity especially in cases of low parasitaemia and non-falciparum infections. Therefore, the need for more accurate and reliable diagnostic tools, such as real-time polymerase chain reaction based methods which have proven greater sensitivity particularly in the screening of malaria, is prominent. This study was conducted at the French National Malaria Reference Centre to assess sensitivity and specificity of two commercial malaria qPCR kits and two in-house developed qPCRs compared to LAMP. METHODS: 183 blood samples received for expertise at the FNMRC were included in this study and were subjected to four different qPCR methods: the Biosynex Ampliquick® Malaria test, the BioEvolution Plasmodium Typage test, the in-house HRM and the in-house TaqMan qPCRs. The specificity and sensitivity of each method and their confidence intervals were determined with the LAMP-based assay Alethia® Malaria as the reference for malaria diagnosis. The accuracy of species diagnosis of the Ampliquick® Malaria test and the two in-house qPCRs was also evaluated using the BioEvolution Plasmodium Typage test as the reference method for species identification. RESULTS: The main results showed that when compared to LAMP, a test with excellent diagnostic performances, the two in-house developed qPCRs were the most sensitive (sensitivity at 100% for the in-house TaqMan qPCR and 98.1% for the in-house HRM qPCR), followed by the two commercial kits: the Biosynex Ampliquick® Malaria test (sensitivity at 97.2%) and the BioEvolution Plasmodium Typage (sensitivity at 95.4%). Additionally, with the in-house qPCRs we were able to confirm a Plasmodium falciparum infection in microscopically negative samples that were not detected by commercial qPCR kits. This demonstrates that the var genes of P. falciparum used in these in-house qPCRs are more reliable targets than the 18S sRNA commonly used in most of the developed qPCR methods for malaria diagnosis. CONCLUSION: Overall, these results accentuate the role molecular methods could play in the screening of malaria. This may represent a helpful tool for other laboratories looking to implement molecular diagnosis methods in their routine analysis, which could be essential for the detection and treatment of malaria carriers and even for the eradication of this disease.


Assuntos
Malária Falciparum , Malária , Plasmodium , Humanos , Laboratórios , Malária/diagnóstico , Malária Falciparum/diagnóstico , Malária Falciparum/epidemiologia , Técnicas de Amplificação de Ácido Nucleico/métodos , Parasitemia/diagnóstico , Plasmodium/genética , Plasmodium falciparum/genética , Reação em Cadeia da Polimerase em Tempo Real , Sensibilidade e Especificidade
20.
Trends Parasitol ; 38(8): 660-672, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35680541

RESUMO

Currently recommended methods of assessing the efficacy of uncomplicated falciparum malaria treatment work less well in high-transmission than in low-transmission settings. There is also uncertainty how to assess intermittent preventive therapies and seasonal malaria chemoprevention (SMC), and Plasmodium vivax radical cure. A pharmacometric antimalarial resistance monitoring (PARM) approach is proposed specifically for evaluating slowly eliminated antimalarial drugs in areas of high transmission. In PARM antimalarial drug concentrations at recurrent parasitaemia are measured to identify outliers (i.e., recurrent parasitaemias in the presence of normally suppressive drug concentrations) and to evaluate changes over time. PARM requires characterization of pharmacometric profiles but should be simpler and more sensitive than current molecular genotyping-based methodologies. PARM does not require parasite genotyping and can be applied to the assessment of both prevention and treatment.


Assuntos
Antimaláricos , Malária Falciparum , Malária Vivax , Malária , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Resistência a Medicamentos/genética , Humanos , Malária/prevenção & controle , Malária Falciparum/tratamento farmacológico , Malária Falciparum/prevenção & controle , Malária Vivax/tratamento farmacológico , Malária Vivax/prevenção & controle , Parasitemia/tratamento farmacológico , Plasmodium falciparum/genética , Plasmodium vivax/genética
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