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Plasmodium vivax readiness to transmit: implication for malaria eradication.

ABSTRACT: BACKGROUND:The lack of a continuous long-term in vitro culture system for Plasmodium vivax severely limits our knowledge of pathophysiology of the most widespread malaria parasite. To gain direct understanding of P. vivax human infections, we used Next Generation Sequencing data mining to unravel parasite in vivo expression profiles for P. vivax, and P. falciparum as comparison. RESULTS:We performed cloud and local computing to extract parasite transcriptomes from publicly available raw data of human blood samples. We developed a Poisson Modelling (PM) method to confidently identify parasite derived transcripts in mixed RNAseq signals of infected host tissues. We successfully retrieved and reconstructed parasite transcriptomes from infected patient blood as early as the first blood stage cycle; and the same methodology did not recover any significant signal from controls. Surprisingly, these first generation blood parasites already show strong signature of transmission, which indicates the commitment from asexual-to-sexual stages. Further, we place the results within the context of P. vivax's complex life cycle, by developing mathematical models for P. vivax and P. falciparum and using sensitivity analysis assess the relative epidemiological impact of possible early stage transmission. CONCLUSION:The study uncovers the earliest onset of P. vivax blood pathogenesis and highlights the challenges of P. vivax eradication programs.

SUBMITTER: Adapa SR

PROVIDER: S-EPMC6330404 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Plasmodium vivax readiness to transmit: implication for malaria eradication.

Adapa Swamy Rakesh SR Taylor Rachel A RA Wang Chengqi C Thomson-Luque Richard R Johnson Leah R LR Jiang Rays H Y RHY

BMC systems biology 20190111 1

<h4>Background</h4>The lack of a continuous long-term in vitro culture system for Plasmodium vivax severely limits our knowledge of pathophysiology of the most widespread malaria parasite. To gain direct understanding of P. vivax human infections, we used Next Generation Sequencing data mining to unravel parasite in vivo expression profiles for P. vivax, and P. falciparum as comparison.<h4>Results</h4>We performed cloud and local computing to extract parasite transcriptomes from publicly availab ...[more]

PMID: 30634978

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Project description:ObjectiveThe apical membrane antigen-1 (AMA-1) is considered as a promising candidate for development of a malaria vaccine against Plasmodium parasites. The correct conformation of this protein appears to be necessary for the stimulation of parasite-inhibitory responses, and these responses, in turn, seem to be antibody-mediated. Therefore, in the present investigation, we expressed the Plasmodium vivax AMA-1 (PvAMA-1) ectodomain in Escherichia coli (E. coli), purified it using standard procedures and characterized it to determine its biological activities for it to be used as a potential target for developing a protective and safe vivax malaria vaccine.Materials and methodsIn this experimental investigation, the ectodomain of PvAMA-1 antigen (GenBank accession no. JX624741) was expressed in the E. coli M15pQE30 expression system and purified with immobilized-metal affinity chromatography. The correct conformation of the recombinant protein was evaluated by Western blotting and indirect immunofluorescence antibody (IFA) test. In addition, the immunogenic properties of PvAMA-1 were evaluated in BALB/c mice with the purified protein emulsified in Freund's adjuvant.ResultsIn the present study, the PvAMA-1 ectodomain was expressed at a high-level (65 mg/L) using a bacterial system. Reduced and non-reduced sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) as well as Western blot analysis confirmed the appropriate conformation and folding of PvAMA-1. The evaluation of immunogenic properties of PvAMA-1 showed that both T helper-1 and 2 cells (Th1 and Th2) responses were present in mice after three immunizations and persisted up to one year after the first immunization. Moreover, the antibodies raised against the recombinant PvAMA-1 in injected mice could recognize the native protein localized on P. vivax parasites.ConclusionWe demonstrate that our recombinant protein had proper conformation and folding. Also, there were common epitopes in the recombinant forms corresponding to native proteins. These results; therefore, indicate that the expressed PvAMA-1 has the potential to be used as a vivax malaria vaccine.

Project description:BACKGROUND:Plasmodium vivax imposes substantial morbidity and mortality burdens in endemic zones. Detailed understanding of the contemporary spatial distribution of this parasite is needed to combat it. We used model based geostatistics (MBG) techniques to generate a contemporary map of risk of Plasmodium vivax malaria in Indonesia in 2010. METHODS:Plasmodium vivax Annual Parasite Incidence data (2006-2008) and temperature masks were used to map P. vivax transmission limits. A total of 4,658 community surveys of P. vivax parasite rate (PvPR) were identified (1985-2010) for mapping quantitative estimates of contemporary endemicity within those limits. After error-checking a total of 4,457 points were included into a national database of age-standardized 1-99 year old PvPR data. A Bayesian MBG procedure created a predicted PvPR(1-99) endemicity surface with uncertainty estimates. Population at risk estimates were derived with reference to a 2010 human population surface. RESULTS:We estimated 129.6 million people in Indonesia lived at risk of P. vivax transmission in 2010. Among these, 79.3% inhabited unstable transmission areas and 20.7% resided in stable transmission areas. In western Indonesia, the predicted P. vivax prevalence was uniformly low. Over 70% of the population at risk in this region lived on Java and Bali islands, where little malaria transmission occurs. High predicted prevalence areas were observed in the Lesser Sundas, Maluku and Papua. In general, prediction uncertainty was relatively low in the west and high in the east. CONCLUSION:Most Indonesians living with endemic P. vivax experience relatively low risk of infection. However, blood surveys for this parasite are likely relatively insensitive and certainly do not detect the dormant liver stage reservoir of infection. The prospects for P. vivax elimination would be improved with deeper understanding of glucose-6-phosphate dehydrogenase deficiency (G6PDd) distribution, anti-relapse therapy practices and manageability of P. vivax importation risk, especially in Java and Bali.

Project description:BackgroundControl of vivax malaria in endemic areas requires management of recurrence. The Brazilian National Malaria Surveillance System (SIVEP-Malária) records every case of malaria in Brazil, but is not designed to differentiate between primary and recurrent infections. The aim of this study was to explore whether the information provided by SIVEP-Malária could be used to identify Plasmodium vivax recurrences, its risk factors and evaluate the effectiveness of short course primaquine (7-9 days: total dose 3-4.2 mg/kg) in preventing relapses.MethodsIn this observational retrospective cohort study, data matching of SIVEP-Malária records was undertaken using bloom filters to identify potential recurrences defined as microscopically-confirmed P. vivax episodes from the same individual occurring within a year. Generalized Estimation Equation (GEE) models were used to determine predictors of recurrence. Extended Cox-based conditional Prentice-Williams-Peterson models (PWP) models were used to evaluate time to recurrence.ResultsBetween June 1, 2014 and May 31, 2015, 26,295 episodes fulfilled the criteria of potential recurrence among 154,970 reported malaria episodes. Age ≤ 3 years, being male, literate, not-indigenous and having domestic working activities were identified as risk factors for recurrence. There was no difference in time to recurrence or recurrence frequency between patients treated with 14-day or 7-9 day primaquine regimens (HR = 1.02, 0.96-1.09) and RR = 0.97 (0.90-1.04), respectively. The use of chloroquine alone was associated with a 1.43 (1.29-1.58, p < 0.0001) increased risk of P. vivax recurrence compared to patients who used chloroquine combined with short-course primaquine, the Brazilian standard of care. This was RR = 2.06 (1.48-2.86, p < 0.0001), RR = 1.90 (1.60-2.25, p = 0.0001) and RR = 1.14 (1.00-1.29, p = 0.05) for recurrences occurring between 3-28, 29-60 and > 60 days, respectively. PWP models showed that the time to recurrence was longer in recipients of both primaquine and artemisinin-based combination therapy (ACT) compared to patients treated with chloroquine alone or with concomitant primaquine, HR = 2.2 (1.62-2.99, p < 0.0001), HR = 1.27 (0.97-1.66, p = 0.08), respectively.ConclusionShort course primaquine was as effective as 14-day regimens and associated with a halving of the risk and delay in time to recurrence of P. vivax infections in comparison to chloroquine alone. The study demonstrates the feasibility of using record linkage on routine surveillance data to identify potential P. vivax recurrences, associated risk factors and impact of treatment.

Project description:BackgroundMalaria-associated anaemia, arising from symptomatic, asymptomatic and submicroscopic infections, is a significant cause of morbidity worldwide. Induced blood stage malaria volunteer infection studies (IBSM-VIS) provide a unique opportunity to evaluate the haematological response to early Plasmodium falciparum and Plasmodium vivax infection.MethodsThis study was an analysis of the haemoglobin, red cell counts, and parasitaemia data from 315 participants enrolled in IBSM-VIS between 2012 and 2019, including 269 participants inoculated with the 3D7 strain of P. falciparum (Pf3D7), 15 with an artemisinin-resistant P. falciparum strain (PfK13) and 46 with P. vivax. Factors associated with the fractional fall in haemoglobin (Hb-FF) were evaluated, and the malaria-attributable erythrocyte loss after accounting for phlebotomy-related losses was estimated. The relative contribution of parasitized erythrocytes to the malaria-attributable erythrocyte loss was also estimated.ResultsThe median peak parasitaemia prior to treatment was 10,277 parasites/ml (IQR 3566-27,815), 71,427 parasites/ml [IQR 33,236-180,213], and 34,840 parasites/ml (IQR 13,302-77,064) in participants inoculated with Pf3D7, PfK13, and P. vivax, respectively. The median Hb-FF was 10.3% (IQR 7.8-13.3), 14.8% (IQR 11.8-15.9) and 11.7% (IQR 8.9-14.5) in those inoculated with Pf3D7, PfK13 and P. vivax, respectively, with the haemoglobin nadir occurring a median 12 (IQR 5-21), 15 (IQR 7-22), and 8 (IQR 7-15) days following inoculation. In participants inoculated with P. falciparum, recrudescence was associated with a greater Hb-FF, while in those with P. vivax, the Hb-FF was associated with a higher pre-treatment parasitaemia and later day of anti-malarial treatment. After accounting for phlebotomy-related blood losses, the estimated Hb-FF was 4.1% (IQR 3.1-5.3), 7.2% (IQR 5.8-7.8), and 4.9% (IQR 3.7-6.1) in participants inoculated with Pf3D7, PfK13, and P. vivax, respectively. Parasitized erythrocytes were estimated to account for 0.015% (IQR 0.006-0.06), 0.128% (IQR 0.068-0.616) and 0.022% (IQR 0.008-0.082) of the malaria-attributable erythrocyte loss in participants inoculated with Pf3D7, PfK13, and P. vivax, respectively.ConclusionEarly experimental P. falciparum and P. vivax infection resulted in a small but significant fall in haemoglobin despite parasitaemia only just at the level of microscopic detection. Loss of parasitized erythrocytes accounted for < 0.2% of the total malaria-attributable haemoglobin loss.

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Plasmodium vivax readiness to transmit: implication for malaria eradication.

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Plasmodium vivax readiness to transmit: implication for malaria eradication.

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