Identification of plant-like galactolipids in Chromera velia, a photosynthetic relative of malaria parasites

Apicomplexa are protist parasites that include Plasmodium spp., the causative agents of malaria, and Toxoplasma gondii, responsible for toxoplasmosis. Most Apicomplexa possess a relict plastid, the apicoplast, which was acquired by secondary endosymbiosis of a red alga. Despite being nonphotosynthetic, the apicoplast is otherwise metabolically similar to algal and plant plastids and is essential for parasite survival. Previous studies of Toxoplasma gondii identified membrane lipids with some structural features of plastid galactolipids, the major plastid lipid class. However, direct evidence for the plant-like enzymes responsible for galactolipid synthesis in Apicomplexan parasites has not been obtained. Chromera velia is an Apicomplexan relative recently discovered in Australian corals. C. velia retains a photosynthetic plastid, providing a unique model to study the evolution of the apicoplast. Here, we report the unambiguous presence of plant-like monogalactosyldiacylglycerol and digalactosyldiacylglycerol in C. velia and localize digalactosyldiacylglycerol to the plastid. We also provide evidence for a plant-like biosynthesis pathway and identify candidate galactosyltranferases responsible for galactolipid synthesis. Our study provides new insights in the evolution of these important enzymes in plastid-containing eukaryotes and will help reconstruct the evolution of glycerolipid metabolism in important parasites such as Plasmodium and Toxoplasma.     

Peroxiredoxins in malaria parasites: parasitologic aspects

Malaria is one of the most debilitating and life threatening diseases in tropical regions of the world. Over 500 million clinical cases occur, and 2-3 million people die of the disease each year. Because Plasmodium lacks genuine glutathione peroxidase and catalase, the two major antioxidant enzymes in the eukaryotic cell, malaria parasites are likely to utilize members of the peroxiredoxin (Prx) family as the principal enzymes to reduce peroxides, which increase in the parasite cell due to metabolism and parasitism during parasite development. In addition to its function of protecting macromolecules from H(2)O(2), Prx has also been reported to regulate H(2)O(2) as second messenger in transmission of redox signals, which mediate cell proliferation, differentiation, and apoptosis. In the malaria parasite, several lines of experimental data have suggested that the parasite uses Prxs as multifunctional molecules to adapt themselves to asexual and sexual development. In this review, we summarize the accumulated knowledge on the Prx family with respect to their functions in mammalian cells and their possible function(s) in malaria parasites.     

Engineering mosquito resistance to malaria parasites: the avian malaria model

Genetic approaches to controlling the transmission of mosquito-borne diseases are being developed to augment the available chemical control practices and environmental manipulation methods. Much progress has been made in laboratory-based research that seeks to develop antipathogen or antivector effector genes and methods for genetically manipulating host vector strains. Research is summarized here in the development of a malaria-resistant phenotype using as a model system the avian parasite, Plasmodium gallinaceum, and the mosquito, Aedes aegypti. Robust transformation technology based on a number of transposable elements, the identification of promoter regions derived from endogenous mosquito genes, and the development of single-chain antibodies as effector genes have made it possible to produce malaria-resistant mosquitoes. Future challenges include discovery of methods for spreading antiparasite genes through mosquito populations, determining the threshold levels below which parasite intensities of infection must be held, and defining the circumstances in which a genetic control strategy would be employed in the field.     

Influence of Schistosoma mansoni and Hookworm Infection Intensities on Anaemia in Ugandan Villages

BackgroundThe association of anaemia with intestinal schistosomiasis and hookworm infections are poorly explored in populations that are not limited to children or pregnant women.MethodsWe sampled 1,832 individuals aged 5–90 years from 30 communities in Mayuge District, Uganda. Demographic, village, and parasitological data were collected. Infection risk factors were compared in ordinal logistic regressions. Anaemia and infection intensities were analyzed in multilevel models, and population attributable fractions were estimated.FindingsHousehold and village-level predictors of Schistosoma mansoni and hookworm were opposite in direction or significant for single infections. S. mansoni was found primarily in children, whereas hookworm was prevalent amongst the elderly. Anaemia was more prevalent in individuals with S. mansoni and increased by 2.86 fold (p-value<0.001) with heavy S. mansoni infection intensity. Individuals with heavy hookworm were 1.65 times (p-value = 0.008) more likely to have anaemia than uninfected participants. Amongst individuals with heavy S. mansoni infection intensity, 32.0% (p-value<0.001) of anaemia could be attributed to S. mansoni. For people with heavy hookworm infections, 23.7% (p-value = 0.002) of anaemia could be attributed to hookworm. A greater fraction of anaemia (24.9%, p-value = 0.002) was attributable to heavy hookworm infections in adults (excluding pregnant women) as opposed to heavy hookworm infections in school-aged children and pregnant women (20.2%, p-value = 0.001).ConclusionCommunity-based surveys captured anaemia in children and adults affected by S. mansoni and hookworm infections. For areas endemic with schistosomiasis or hookworm infections, WHO guidelines should include adults for treatment in helminth control programmes.     

Additional observations on the blood parasites of Ugandan birds.

One thousand and seventy-six birds of 26 families and 127 species were examined for hemoprotozoa; 404 birds (37%) of 41 species representing 17 families harbored one or more blood parasites. Most parasites were species of Haemoproteus which represented 95% of all parasitic infections detected. Prevalence of blood parasites in birds collected from four areas over a period of six years was relatively stable.     

Protein export in malaria parasites: an update

Symptomatic malaria is caused by the infection of human red blood cells (RBCs) with Plasmodium parasites. The RBC is a peculiar environment for parasites to thrive in as they lack many of the normal cellular processes and resources present in other cells. Because of this, Plasmodium spp. have adapted to extensively remodel the host cell through the export of hundreds of proteins that have a range of functions, the best known of which are virulence‐associated. Many exported parasite proteins are themselves involved in generating a novel trafficking system in the RBC that further promotes export. In this review we provide an overview of the parasite synthesized export machinery as well as recent developments in how different classes of exported proteins are recognized by this machinery.     

Fit for fertilization: Mating in malaria parasites

The human malaria parasite Plasmodium falciparum has an obligate sexual phase in its life cycle. Male and female gametes must mate in the mosquito midgut for transmission to occur. When mosquitoes ingest a mixture of two parasite clones, the inheritance of nuclear genes suggests that mating between gametes is random. Both cross-fertilization (between unlike male and female gametes) and selfing occur. However, it has been suggested that the inheritance of mitochondrial markers indicates non-random mating. An alternative hypothesis, which is presented here by Lisa Ranford-Cartwright, is that mating is random, but differences in the relative fitnesses of the gametocytes can explain the inheritance patterns observed.     

Cognition,behaviour and academic skills after cognitive rehabilitation in Ugandan children surviving severe malaria: a randomised trial

Background  

Infection with severe malaria in African children is associated with not only a high mortality but also a high risk of cognitive deficits. There is evidence that interventions done a few years after the illness are effective but nothing is known about those done immediately after the illness. We designed a study in which children who had suffered from severe malaria three months earlier were enrolled into a cognitive intervention program and assessed for the immediate benefit in cognitive, academic and behavioral outcomes.     

Combinations of host biomarkers predict mortality among Ugandan children with severe malaria: a retrospective case-control study

Background

Severe malaria is a leading cause of childhood mortality in Africa. However, at presentation, it is difficult to predict which children with severe malaria are at greatest risk of death. Dysregulated host inflammatory responses and endothelial activation play central roles in severe malaria pathogenesis. We hypothesized that biomarkers of these processes would accurately predict outcome among children with severe malaria.

Methodology/Findings

Plasma was obtained from children with uncomplicated malaria (n = 53), cerebral malaria (n = 44) and severe malarial anemia (n = 59) at time of presentation to hospital in Kampala, Uganda. Levels of angiopoietin-2, von Willebrand Factor (vWF), vWF propeptide, soluble P-selectin, soluble intercellular adhesion molecule-1 (ICAM-1), soluble endoglin, soluble FMS-like tyrosine kinase-1 (Flt-1), soluble Tie-2, C-reactive protein, procalcitonin, 10 kDa interferon gamma-induced protein (IP-10), and soluble triggering receptor expressed on myeloid cells-1 (TREM-1) were determined by ELISA. Receiver operating characteristic (ROC) curve analysis was used to assess predictive accuracy of individual biomarkers. Six biomarkers (angiopoietin-2, soluble ICAM-1, soluble Flt-1, procalcitonin, IP-10, soluble TREM-1) discriminated well between children who survived severe malaria infection and those who subsequently died (area under ROC curve>0.7). Combinational approaches were applied in an attempt to improve accuracy. A biomarker score was developed based on dichotomization and summation of the six biomarkers, resulting in 95.7% (95% CI: 78.1–99.9) sensitivity and 88.8% (79.7–94.7) specificity for predicting death. Similar predictive accuracy was achieved with models comprised of 3 biomarkers. Classification tree analysis generated a 3-marker model with 100% sensitivity and 92.5% specificity (cross-validated misclassification rate: 15.4%, standard error 4.9%).

Conclusions

We identified novel host biomarkers of pediatric severe and fatal malaria (soluble TREM-1 and soluble Flt-1) and generated simple biomarker combinations that accurately predicted death in an African pediatric population. While requiring validation in further studies, these results suggest the utility of combinatorial biomarker strategies as prognostic tests for severe malaria.     

Inferred relatedness and heritability in malaria parasites

Malaria parasites vary in phenotypic traits of biomedical or biological interest such as growth rate, virulence, sex ratio and drug resistance, and there is considerable interest in identifying the genes that underlie this variation. An important first step is to determine trait heritability (H²). We evaluate two approaches to measuring H² in natural parasite populations using relatedness inferred from genetic marker data. We collected single-clone Plasmodium falciparum infections from 185 patients from the Thailand–Burma border, monitored parasite clearance following treatment with artemisinin combination therapy (ACT), measured resistance to six antimalarial drugs and genotyped parasites using 335 microsatellites. We found strong relatedness structure. There were 27 groups of two to eight clonally identical (CI) parasites, and 74 per cent of parasites showed significant relatedness to one or more other parasites. Initially, we used matrices of allele sharing and variance components (VC) methods to estimate H². Inhibitory concentrations (IC₅₀) for six drugs showed significant H² (0.24 to 0.79, p = 0.06 to 2.85 × 10⁻⁹), demonstrating that this study design has adequate power. However, a phenotype of current interest—parasite clearance following ACT—showed no detectable heritability (H² = 0–0.09, ns) in this population. The existence of CI parasites allows the use of a simple ANOVA approach for quantifying H², analogous to that used in human twin studies. This gave similar results to the VC method and requires considerably less genotyping information. We conclude (i) that H² can be effectively measured in malaria parasite populations using minimal genotype data, allowing rational design of genome-wide association studies; and (ii) while drug response (IC₅₀) shows significant H², parasite clearance following ACT was not heritable in the population studied.     

The relative contribution of co-infection to focal infection risk in children

Co-infection is ubiquitous in people in the developing world but little is known regarding the potential for one parasite to act as a risk factor for another. Using generalized linear mixed modelling approaches applied to data from school-aged children from Zanzibar, Tanzania, we determined the strength of association between four focal infections (i.e. Ascaris lumbricoides, Trichuris trichiura, hookworm and self-reported fever, the latter used as a proxy for viral, bacterial or protozoal infections) and the prevalence or intensity of each of the helminth infections. We compared these potential co-infections with additional risk factors, specifically, host sex and age, socioeconomic status and physical environment, and determined what the relative contribution of each risk factor was. We found that the risk of infection with all four focal infections was strongly associated with at least one other infection, and that this was frequently dependent on the intensity of that other infection. In comparison, no other incorporated risk factor was associated with all focal infections. Successful control of infectious diseases requires identification of infection risk factors. This study demonstrates that co-infection is likely to be one of these principal risk factors and should therefore be given greater consideration when designing disease-control strategies. Future work should also incorporate other potential risk factors, including host genetics which were not available in this study and, ideally, assess the risks via experimental manipulation.     

Prevalence of intestinal protozoan parasites among school children in africa: A systematic review and meta-analysis

IntroductionParasitic infections, especially intestinal protozoan parasites (IPPs) remain a significant public health issue in Africa, where many conditions favour the transmission and children are the primary victims. This systematic review and meta-analysis was carried out with the objective of assessing the prevalence of IPPs among school children in Africa.MethodsRelevant studies published between January 2000 and December 2020 were identified by systematic online search on PubMed, Web of Science, Embase and Scopus databases without language restriction. Pooled prevalence was estimated using a random-effects model. Heterogeneity of studies were assessed using Cochrane Q test and I² test, while publication bias was evaluated using Egger’s test.ResultsOf the 1,645 articles identified through our searches, 46 cross-sectional studies matched our inclusion criteria, reported data from 29,968 school children of Africa. The pooled prevalence of intestinal protozoan parasites amongst African school children was 25.8% (95% CI: 21.2%-30.3%) with E. histolytica/ dispar (13.3%; 95% CI: 10.9%-15.9%) and Giardia spp. (12%; 95% CI: 9.8%-14.3%) were the most predominant pathogenic parasites amongst the study participants. While E. coli was the most common non-pathogenic protozoa (17.1%; 95% CI: 10.9%-23.2%).ConclusionsThis study revealed a relatively high prevalence of IPPs in school children, especially in northern and western Africa. Thus, poverty reduction, improvement of sanitation and hygiene and attention to preventive control measures will be the key to reducing protozoan parasite transmission.     

Protein kinases of malaria parasites: an update

Protein kinases (PKs) play crucial roles in the control of proliferation and differentiation in eukaryotic cells. Research on protein phosphorylation has expanded tremendously in the past few years, in part as a consequence of the realization that PKs represent attractive drug targets in a variety of diseases. Activity in Plasmodium PK research has followed this trend, and several reports on various aspects of this subject were delivered at the Molecular Approaches to Malaria 2008 meeting (MAM2008), a sharp increase from the previous meeting. Here, the authors of most of these communications join to propose an integrated update of the development of the rapidly expanding field of Plasmodium kinomics.