Malaria screening: what is the contribution of molecular biology?

INTRODUCTION: According to the World Health Organization, Microscopy is the gold standard for diagnosing malaria. However, the performance of this examination depends on the experience of the microscopist and the level of parasitemia. Thus, molecular biology detection of malaria could be an alternative technique. AIM: evaluate the contribution of molecular biology in detecting imported malaria. METHODS: This was a descriptive, prospective study, including all students, from the Monastir region, and foreigners, from countries endemic to malaria. The study period was from September 2020 to April 2021. Each subject was screened for malaria by three methods: direct microscopic detection of Plasmodium, detection of plasmodial antigens, and detection of plasmodial DNA by nested PCR. RESULTS: Among the 127 subjects screened, only one had a positive microscopic examination for Plasmodium falciparum. Among the 126 subjects with a negative microscopic examination, twelve students had a positive nested PCR result, i.e. 9.5%. Molecular sequencing allowed the identification of ten isolates of Plasmodium falciparum, one Plasmodium malariae and one Plasmodium ovale. Our study showed that the results of nested PCR agreed with those of microscopy in 90.6% of cases. CONCLUSION: Nested PCR seems more sensitive for the detection of low parasitemias. Hence the importance of including molecular biology as a malaria screening tool to ensure better detection of imported cases.

Inhibition of malaria and babesiosis parasites by putative red blood cell targeting small molecules.

Background: Chemotherapies for malaria and babesiosis frequently succumb to the emergence of pathogen-related drug-resistance. Host-targeted therapies are thought to be less susceptible to resistance but are seldom considered for treatment of these diseases. Methods: Our overall objective was to systematically assess small molecules for host cell-targeting activity to restrict proliferation of intracellular parasites. We carried out a literature survey to identify small molecules annotated for host factors implicated in Plasmodium falciparum infection. Alongside P. falciparum, we implemented in vitro parasite susceptibility assays also in the zoonotic parasite Plasmodium knowlesi and the veterinary parasite Babesia divergens. We additionally carried out assays to test directly for action on RBCs apart from the parasites. To distinguish specific host-targeting antiparasitic activity from erythrotoxicity, we measured phosphatidylserine exposure and hemolysis stimulated by small molecules in uninfected RBCs. Results: We identified diverse RBC target-annotated inhibitors with Plasmodium-specific, Babesia-specific, and broad-spectrum antiparasitic activity. The anticancer MEK-targeting drug trametinib is shown here to act with submicromolar activity to block proliferation of Plasmodium spp. in RBCs. Some inhibitors exhibit antimalarial activity with transient exposure to RBCs prior to infection with parasites, providing evidence for host-targeting activity distinct from direct inhibition of the parasite. Conclusions: We report here characterization of small molecules for antiproliferative and host cell-targeting activity for malaria and babesiosis parasites. This resource is relevant for assessment of physiological RBC-parasite interactions and may inform drug development and repurposing efforts.

Malaria infection and predictor factors among Chadian nomads' children.

BACKGROUND: In Chad, malaria remains a significant public health concern, particularly among nomadic populations. Geographical factors and the mobility of human populations have shown to be associated with the diversity of Plasmodium species. The study aims to describe the malaria prevalence among nomadic children and to investigate its associated factors. METHODS: A cross-sectional study was conducted in February and October 2021 among nomadic communities in Chad. Blood sample were collected and tested from 187 Arab, Fulani and Dazagada nomadic children aged 3-59 months using malaria rapid diagnostic test (RDT). A structured electronic questionnaire was administered to their parents to collect information about the socio­economic data. Malaria testing results were categorized according to the SD BIOLINE Malaria Ag Pf/Pan RDT procedures. Logistic regression analysis was used to determine key risk factors explaining the prevalence of malaria. STATA version IC 13 was used for statistical analysis. RESULTS: The overall malaria prevalence in nomadic children was 24.60%, with 65.20% being Plasmodium falciparum species and 34.8% mixed species. Boys were twice as likely (COR = 1.83; 95% CI, 0.92-3.62; p = 0.083) to have malaria than girls. Children whose parents used to seek traditional drugs were five times more likely (AOR = 5.59; 95% CI, 1.40-22.30, p = 0.015) to have malaria than children whose parents used to seek health facilities. Children whose parents reported spending the last night under a mosquito net were one-fifth as likely (AOR = 0.17; 95% CI, 0.03-0.90, p = 0.037) to have malaria compared to children whose parents did not used a mosquito net. Furthermore, Daza children were seventeen times (1/0.06) less likely (AOR = 0.06; 95% CI, 0.01-0.70, p = 0.024) to have malaria than Fulani children and children from households piped water as the main source were seven times more likely (AOR = 7.05; 95% CI, 1.69-29.45; p = 0.007) to have malaria than those using surface water. CONCLUSIONS: Malaria remains a significant public health issue in the nomadic communities of Chad. Community education and sensitization programs within nomad communities are recommended to raise awareness about malaria transmission and control methods, particularly among those living in remote rural areas. The National Malaria Control Program (NMCP) should increase both the coverage and use of long-lasting insecticidal nets (LLINs) and seasonal malaria chemoprevention (SMC) in addition to promoting treatment-seeking behaviors in nomadic communities.

Epigenetic regulation as a therapeutic target in the malaria parasite Plasmodium falciparum.

Over the past thirty years, epigenetic regulation of gene expression has gained increasing interest as it was shown to be implicated in illnesses ranging from cancers to parasitic diseases. In the malaria parasite, epigenetics was shown to be involved in several key steps of the complex life cycle of Plasmodium, among which asexual development and sexual commitment, but also in major biological processes like immune evasion, response to environmental changes or DNA repair. Because epigenetics plays such paramount roles in the Plasmodium parasite, enzymes involved in these regulating pathways represent a reservoir of potential therapeutic targets. This review focuses on epigenetic regulatory processes and their effectors in the malaria parasite, as well as the inhibitors of epigenetic pathways and their potential as new anti-malarial drugs. Such types of drugs could be formidable tools that may contribute to malaria eradication in a context of widespread resistance to conventional anti-malarials.

A Time Point Proteomic Analysis Reveals Protein Dynamics of Plasmodium Oocysts.

The oocyst is a sporogonic stage of Plasmodium development that takes place in the mosquito midgut in about 2 weeks. The cyst is protected by a capsule of unknown composition, and little is known about oocyst biology. We carried out a proteomic analysis of oocyst samples isolated at early, mid, and late time points of development. Four biological replicates for each time point were analyzed, and almost 600 oocyst-specific candidates were identified. The analysis revealed that, in young oocysts, there is a strong activity of protein and DNA synthesis, whereas in mature oocysts, proteins involved in oocyst and sporozoite development, gliding motility, and invasion are mostly abundant. Among the proteins identified at early stages, 17 candidates are specific to young oocysts. Thirty-four candidates are common to oocyst and the merosome stages (sporozoite proteins excluded), sharing common features as replication and egress. Western blot and immunofluorescence analyses of selected candidates confirm the expression profile obtained by proteomic analysis.

Changes in hypothalamic-pituitary-adrenal axis function, immunity, and glucose during acute Plasmodium relictum infection in house sparrows (Passer domesticus).

Hosts of the same species vary in physiological responses to the same parasite, and some groups of individuals can disproportionately affect disease dynamics; however, the underlying pathophysiology of host-parasite interactions is poorly understood in wildlife. We tested the hypothesis that the hypothalamic-pituitary-adrenal (HPA) axis mediates host resistance and tolerance to avian malaria during the acute phase of infection by evaluating whether individual variation in circulating glucocorticoids predicted resistance to avian malaria in a songbird. We experimentally inoculated wild-caught house sparrows (Passer domesticus) with naturally sourced Plasmodium relictum and quantified baseline and restraint-induced circulating corticosterone, negative feedback ability, cellular and humoral immune function, and baseline and restraint-induced glycemia, prior to and during acute malaria infection. During peak parasitemia, we also evaluated the expression of several liver cytokines that are established pathological hallmarks of malaria in mammals: two pro-inflammatory (IFN-γ and TNF-α) and two anti-inflammatory (IL-10 and TGF-ß). Although most of the host metrics we evaluated were not correlated with host resistance or tolerance to avian malaria, this experiment revealed novel relationships between malarial parasites and the avian immune system that further our understanding of the pathology of malaria infection in birds. Specifically, we found that: (1) TNF-α liver expression was positively correlated with parasitemia; (2) sparrows exhibited an anti-inflammatory profile during malaria infection; and (3) IFN-γ and circulating glucose were associated with several immune parameters, but only in infected sparrows. We also found that, during the acute phase of infection, sparrows increased the strength of corticosterone negative feedback at the level of the pituitary. In the context of our results, we discuss future methodological considerations and aspects of host physiology that may confer resistance to avian malaria, which can help inform conservation and rehabilitation strategies for avifauna at risk.

Plasmodium female gamete surface HSP90 is a key determinant for fertilization.

Plasmodium fertilization, an essential step for the development of the malaria parasite in the mosquito, is a prime target for blocking pathogen transmission. Using phage peptide display screening, we identified MG1, a peptide that binds to male gametes and inhibits fertilization, presumably by competing with a female gamete ligand. Anti-MG1 antibodies bind to the female gamete surface and, by doing so, also inhibit fertilization. We determined that this antibody recognizes HSP90 on the surface of Plasmodium female gametes. Our findings establish Plasmodium HSP90 as a prime target for the development of a transmission-blocking vaccine.IMPORTANCEMalaria kills over half a million people every year and this number has not decreased in recent years. The development of new tools to combat this disease is urgently needed. In this article, we report the identification of a key molecule-HSP90-on the surface of the parasite's female gamete that is required for fertilization to occur and for the completion of the parasite cycle in the mosquito. HSP90 is a promising candidate for the development of a transmission-blocking vaccine.

Semi-mechanistic population pharmacokinetic/pharmacodynamic modeling of a Plasmodium elongation factor 2 inhibitor cabamiquine for prevention and cure of malaria.

Cabamiquine is a novel antimalarial agent that demonstrates the potential for chemoprevention and treatment of malaria. In this article, the dose-exposure-response relationship of cabamiquine was characterized using a population pharmacokinetic (PK)/pharmacodynamic (PD) model, incorporating the effects of cabamiquine on parasite dynamics at the liver and blood stages of malaria infection. Modeling was performed sequentially. First, a three-compartmental population PK model was developed, comprising linear elimination, a transit absorption model in combination with first-order absorption, and a recirculation model. Second, this model was expanded into a PK/PD model using parasitemia data from an induced blood stage malaria (IBSM) human challenge model. To describe the parasite growth and killing in the blood, a turnover model was used. Finally, the liver stage parasite dynamics were characterized using data from a sporozoite challenge model (SpzCh), and system parameters were fixed based on biological plausibility. Cabamiquine concentration in the central compartment was used to drive parasite killing at the blood and liver stages. Blood stage minimum inhibitory concentrations (MICb) were estimated at 7.12 ng/mL [95% confidence interval (CI95%): 6.26-7.88 ng/mL] and 1.28 ng/mL (CI95%: 1.12-1.43 ng/mL) for IBSM and SpzCh populations, respectively, while liver stage MICl was lower (0.61 ng/mL; CI95%: 0.24-0.96 ng/mL). In conclusion, a population PK/PD model was developed by incorporating parasite dynamics and drug activity at the blood and liver stages based on clinical data and biological knowledge. This model can potentially facilitate antimalarial agent development by supporting the efficient selection of the optimal dosing regimen.

Architecture, domain organization, and functional signatures of trypanosomatid keIF4A1s and Plasmodium peIF4A1s suggest conserved functions.

Initiation of translation is the first of the three obligatory steps required for protein synthesis and is carried out by a large number of protein factors called initiation factors in conjunction with ribosomes. One of the key conserved protein factors in eukaryotes that plays a role in this process is eIF4A, which has three homologues in humans with eIF4A1 being the primary factor playing a role in translation initiation. eIF4As are members of the family of DEAD-box helicases that carry out different biological functions. eIF4A1s are recruited to translation initiation complexes via association with eIF4G and have ATP binding, ATP hydrolysis, RNA binding, and unwinding activities. Plasmodium and trypanosomatids such as Leishmania and Trypanosoma are parasites that cause human disease. While mechanistically the function of eIF4A1s in eukaryotes is wellunderstood, the orthologues peIF4A1s and keIF4A1s in Plasmodium and trypanosomatids are not well-studied. Here, we have used bioinformatics tools and homology modelling/structure prediction to study the motifs and functional signatures of Plasmodium and trypanosomatid peIF4A1s/keIF4A1s. We report a high degree of sequence conservation, structural conservation, and conservation of protein-protein interaction signatures of Plasmodium and trypanosomatid peIF4A1s/keIF4A1s in comparison with human eIF4A1. Thus, in spite of the great divergence in evolution between these parasites and higher eukaryotes, there is remarkable conservation of motifs and functional signatures in Plasmodium and trypanosomatid peIF4A1s/keIF4A1s.

IgM antibody responses against Plasmodium antigens in neotropical primates in the Brazilian Atlantic Forest.

Introduction: Zoonotic transmission is a challenge for the control and elimination of malaria. It has been recorded in the Atlantic Forest, outside the Amazon which is the endemic region in Brazil. However, only very few studies have assessed the antibody response, especially of IgM antibodies, in Neotropical primates (NP). Therefore, in order to contribute to a better understanding of the immune response in different hosts and facilitate the identification of potential reservoirs, in this study, naturally acquired IgM antibody responses against Plasmodium antigens were evaluated, for the first time, in NP from the Atlantic Forest. Methods: The study was carried out using 154 NP samples from three different areas of the Atlantic Forest. IgM antibodies against peptides of the circumsporozoite protein (CSP) from different Plasmodium species and different erythrocytic stage antigens were detected by ELISA. Results: Fifty-nine percent of NP had IgM antibodies against at least one CSP peptide and 87% against at least one Plasmodium vivax erythrocytic stage antigen. Levels of antibodies against PvAMA-1 were the highest compared to the other antigens. All families of NP showed IgM antibodies against CSP peptides, and, most strikingly, against erythrocytic stage antigens. Generalized linear models demonstrated that IgM positivity against PvCSP and PvAMA-1 was associated with PCR-detectable blood-stage malaria infection and the host being free-living. Interestingly, animals with IgM against both PvCSP and PvAMA-1 were 4.7 times more likely to be PCR positive than animals that did not have IgM for these two antigens simultaneously. Discussion: IgM antibodies against different Plasmodium spp. antigens are present in NP from the Atlantic Forest. High seroprevalence and antibody levels against blood-stage antigens were observed, which had a significant association with molecular evidence of infection. IgM antibodies against CSP and AMA-1 may be used as a potential marker for the identification of NP infected with Plasmodium, which are reservoirs of malaria in the Brazilian Atlantic Forest.

[Autochthonous Case of Malaria Prediagnosed as Leukemia]. / Lösemi Ön Tanili Yerli Sitma Olgusu.

Malaria is a parasitic disease transmitted by infected female Anopheles mosquitoes. There are five species of Plasmodium species that can infect humans. Of these species, especially P.falciparum and P.vivax pose the greatest threat to human health. In the 2014 report of the World Health Organization, it was reported that there were no locally acquired cases of malaria in 16 countries including Türkiye. Malaria cases originating from outside the country and imported due to migration, travel and working abroad are reported as import cases. In this report, a case of non-imported malaria followed with a preliminary diagnosis of leukemia was presented. A 14-year-old female patient who was admitted to a health institution with complaints of high fever, headache, chills, nausea-vomiting, and diarrhea that had been going on for two weeks, was pre-diagnosed as leukemia and was referred to Manisa Celal Bayar University Faculty of Medicine, Hafsa Sultan Hospital, Department of Pediatric Hematology and after pancytopenia was detected in the complete blood count. The anamnesis of the patient revealed that she had no history of international travel and that she had been prescribed medications such as paracetamol, amoxicillin, and metoclopramide for flu-like complaints while working in the Southeastern Anatolia, Aegean, and Mediterranean Regions of Türkiye. Bone marrow aspiration was performed for the etiological examination of pancytopenia. Giemsa-stained blood smears, rapid diagnostics, and real-time quantative polymerase chain reaction (qRt-PCR) analyses were performed in the medical parasitology laboratory and malaria was suspected in both bone marrow and peripheral blood smears. P.vivax erythrocytic forms and gametocytes were present in abundance in smear preparations stained with Giemsa, and rapid diagnosis kit was positive for P.vivax. The strain was genotyped as P.vivax by qRt-PCR analysis. For the treatment of the patient, airalam (artemether + lumefantrine) tablets were provided with 2 x 4 daily posology for three days after the diagnosis, and primaquine was provided after one week of the diagnosis as 1 x 2 tablets (1 x 15 mg) for 14 days, and the patient was discharged without complications following the treatment regimen. The fight against malaria continues uninterruptedly since the establishment of the Republic of Türkiye. Tropical diseases, especially malaria, is of great importance for Türkiye due to numerous reasons such as its location in the subtropical region where Anopheles mosquitoes are capable of malaria transmission, it is situated at the crossroads on the migration routes between continents where human traffic is busy, there are many people who go abroad for work and most importantly rising temperatures due to climate change. For this reason, this case report is important to emphasize the importance of malaria for the country and to increase the awareness of clinicians and laboratories about malaria and the possibility of autochthonous malaria transmission in Türkiye.

Identification of potential inhibitors of casein kinase 2 alpha of Plasmodium falciparum with potent in vitro activity.

Drug resistance to commercially available antimalarials is a major obstacle in malaria control and elimination, creating the need to find new antiparasitic compounds with novel mechanisms of action. The success of kinase inhibitors for oncological treatments has paved the way for the exploitation of protein kinases as drug targets in various diseases, including malaria. Casein kinases are ubiquitous serine/threonine kinases involved in a wide range of cellular processes such as mitotic checkpoint signaling, DNA damage response, and circadian rhythm. In Plasmodium, it is suggested that these protein kinases are essential for both asexual and sexual blood-stage parasites, reinforcing their potential as targets for multi-stage antimalarials. To identify new putative PfCK2α inhibitors, we utilized an in silico chemogenomic strategy involving virtual screening with docking simulations and quantitative structure-activity relationship predictions. Our investigation resulted in the discovery of a new quinazoline molecule (542), which exhibited potent activity against asexual blood stages and a high selectivity index (>100). Subsequently, we conducted chemical-genetic interaction analysis on yeasts with mutations in casein kinases. Our chemical-genetic interaction results are consistent with the hypothesis that 542 inhibits yeast Cka1, which has a hinge region with high similarity to PfCK2α. This finding is in agreement with our in silico results suggesting that 542 inhibits PfCK2α via hinge region interaction.

Plasmodium curtails autoimmune nephritis via lasting bone marrow alterations, independent of hemozoin accumulation.

The host response against infection with Plasmodium commonly raises self-reactivity as a side effect, and antibody deposition in kidney has been cited as a possible cause of kidney injury during severe malaria. In contrast, animal models show that infection with the parasite confers long-term protection from lethal lupus nephritis initiated by autoantibody deposition in kidney. We have limited knowledge of the factors that make parasite infection more likely to induce kidney damage in humans, or the mechanisms underlying protection from autoimmune nephritis in animal models. Our experiments with the autoimmune-prone FcγR2B[KO] mice have shown that a prior infection with P. yoelii 17XNL protects from end-stage nephritis for a year, even when overall autoreactivity and systemic inflammation are maintained at high levels. In this report we evaluate post-infection alterations, such as hemozoin accumulation and compensatory changes in immune cells, and their potential role in the kidney-specific protective effect by Plasmodium. We ruled out the role of pigment accumulation with the use of a hemozoin-restricted P. berghei ANKA parasite, which induced a self-resolved infection that protected from autoimmune nephritis with the same mechanism as parasitic infections that accumulated normal levels of hemozoin. In contrast, adoptive transfer experiments revealed that bone marrow cells were altered by the infection and could transmit the kidney protective effect to a new host. While changes in the frequency of bone marrow cell populations after infection were variable and unique to a particular parasite strain, we detected a sustained bias in cytokine/chemokine expression that suggested lower fibrotic potential and higher Th1 bias likely affecting multiple cell populations. Sustained changes in bone marrow cell activation profile could have repercussions in immune responses long after the infection was cleared.

Structural Analysis of Plasmodium falciparum Hexokinase Provides Novel Information about Catalysis Due to a Plasmodium-Specific Insertion.

The protozoan parasite Plasmodium falciparum is the causative pathogen of the most severe form of malaria, for which novel strategies for treatment are urgently required. The primary energy supply for intraerythrocytic stages of Plasmodium is the production of ATP via glycolysis. Due to the parasite's strong dependence on this pathway and the significant structural differences of its glycolytic enzymes compared to its human counterpart, glycolysis is considered a potential drug target. In this study, we provide the first three-dimensional protein structure of P. falciparum hexokinase (PfHK) containing novel information about the mechanisms of PfHK. We identified for the first time a Plasmodium-specific insertion that lines the active site. Moreover, we propose that this insertion plays a role in ATP binding. Residues of the insertion further seem to affect the tetrameric interface and therefore suggest a special way of communication among the different monomers. In addition, we confirmed that PfHK is targeted and affected by oxidative posttranslational modifications (oxPTMs). Both S-glutathionylation and S-nitrosation revealed an inhibitory effect on the enzymatic activity of PfHK.

Perfil de notificações de malária em gestantes de Oiapoque, Amapá / Profile of malaria reports in pregnant women from Oiapoque, Amapá / Perfil de notificaciones de malaria en gestantes de Oiapoque, Amapá

Objetivo: caracterizar as notificações de malária em gestantes no município de Oiapoque. Método: estudo documental, descritivo, retrospectivo e com abordagem quantitativa, realizado a partir de dados secundários do Sistema de Vigilância Epidemiológica da Malária em Oiapoque-Amapá, Brasil, no período de 2013 a 2017. Abordam-se as seguintes variáveis de casos autóctones de malária em gestantes: ano, mês de ocorrência, idade gestacional, espécie infectante de Plasmodium e unidade de notificação. Os dados foram apresentados e analisados mediante estatística descritiva e formulação de mapas de distribuição espacial, gerados pelo software ArcGIS. Resultados: predominaram notificações em áreas urbanas, especialmente no bairro Paraíso (74%), sendo o Plasmodium vivax o principal agente (88%), e de maior incidência entre outubro a dezembro (33%), no terceiro trimestre gestacional (35%). Conclusão: o perfil de notificações de malária em gestante desse munícipio assemelha-se a estudos anteriores nessa região quanto ao local de concentração e período de maior ocorrência. No entanto, a introdução gradativa do protozoário Plasmodium falciparum traz um alerta para a mobilização de gestores e profissionais.

Objective: to characterize the notifications of malaria in pregnant women in the municipality of Oiapoque. Method: documentary, descriptive, retrospective and quantitative study, conducted from secondary data of the Epidemiological Surveillance System of Malaria in Oiapoque-Amapá, Brazil, from 2013 to 2017. The following variables of autochthonous cases of malaria in pregnant women are addressed: year, month of occurrence, gestational age, Plasmodium infecting species and notification unit. Data were presented and analyzed using descriptive statistics and formulation of spatial distribution maps, generated by ArcGIS software. Results: notifications predominated in urban areas, especially in the Paraíso neighborhood (74%), with Plasmodium Vivax being the main agent (88%), and with a higher incidence between October and December (33%), in the third gestational quarter (35%). Conclusion: the profile of reports of malaria in pregnant women of this municipality resembles previous studies in this region, regarding the place of concentration and period of greater occurrence. However, the gradual introduction of the protozoan Plasmodium falciparum brings an alert to the mobilization of managers and professionals.

Developing kinase inhibitors for malaria: an opportunity or liability?

Highly druggable and essential to almost all aspects of cellular life, the protein and phosphoinositide kinase gene families offer a wealth of potential targets for pharmacological modulation for both noncommunicable and infectious diseases. Despite the success of kinase inhibitors in oncology and other disease indications, targeting kinases comes with significant challenges. Key hurdles for kinase drug discovery include selectivity and acquired resistance. The phosphatidylinositol 4-kinase beta inhibitor MMV390048 showed good efficacy in Phase 2a clinical trials, demonstrating the potential of kinase inhibitors for malaria treatment. Here we argue that the potential benefits of Plasmodium kinase inhibitors outweigh the risks, and we highlight the opportunity for designed polypharmacology to reduce the risk of resistance.

Radial spoke protein 9 is necessary for axoneme assembly in Plasmodium but not in trypanosomatid parasites.

Flagella are important for eukaryote cell motility, including in sperm, and are vital for life cycle progression of many unicellular eukaryotic pathogens. The '9+2' axoneme in most motile flagella comprises nine outer doublet and two central-pair singlet microtubules. T-shaped radial spokes protrude from the outer doublets towards the central pair and are necessary for effective beating. We asked whether there were radial spoke adaptations associated with parasite lineage-specific properties in apicomplexans and trypanosomatids. Following an orthologue search for experimentally uncharacterised radial spoke proteins (RSPs), we identified and analysed RSP9. Trypanosoma brucei and Leishmania mexicana have an extensive RSP complement, including two divergent RSP9 orthologues, necessary for flagellar beating and swimming. Detailed structural analysis showed that neither orthologue is needed for axoneme assembly in Leishmania. In contrast, Plasmodium has a reduced set of RSPs including a single RSP9 orthologue, deletion of which in Plasmodium berghei leads to failure of axoneme formation, failed male gamete release, greatly reduced fertilisation and inefficient life cycle progression in the mosquito. This indicates contrasting selection pressures on axoneme complexity, likely linked to the different mode of assembly of trypanosomatid versus Plasmodium flagella.

Targeting Myeloperoxidase Activity and Neutrophil ROS Production to Modulate Redox Process: Effect of Ellagic Acid and Analogues.

Malaria is an infectious disease caused by a Plasmodium genus parasite that remains the most widespread parasitosis. The spread of Plasmodium clones that are increasingly resistant to antimalarial molecules is a serious public health problem for underdeveloped countries. Therefore, the search for new therapeutic approaches is necessary. For example, one strategy could consist of studying the redox process involved in the development of the parasite. Regarding potential drug candidates, ellagic acid is widely studied due to its antioxidant and parasite-inhibiting properties. However, its low oral bioavailability remains a concern and has led to pharmacomodulation and the synthesis of new polyphenolic compounds to improve antimalarial activity. This work aimed at investigating the modulatory effect of ellagic acid and its analogues on the redox activity of neutrophils and myeloperoxidase involved in malaria. Overall, the compounds show an inhibitory effect on free radicals as well as on the enzyme horseradish peroxidase- and myeloperoxidase (HRP/MPO)-catalyzed oxidation of substrates (L-012 and Amplex Red). Similar results are obtained with reactive oxygen species (ROS) produced by phorbol 12-mystate acetate (PMA)-activated neutrophils. The efficiency of ellagic acid analogues will be discussed in terms of structure-activity relationships.

[Progress of researches on antimalarial peptides].

Malaria remains a major global public health concern, and nearly half of the global populations are still at risk of malaria infection. However, continuous emergence and spread of drug-resistant malaria parasite strains lead to ineffectiveness of conventional antimalarials. Therefore, development of novel antimalarial agents is of urgent need for malaria elimination. As an important component of the host natural immune defense system, antibacterial peptides provide the first line of defense against pathogenic invasion, and the mechanism of preferentially attacking the cell membrane makes them difficult to develop drug resistance. Antimicrobial peptides are therefore considered as a promising candidate for novel antimalarial agents. This review summarizes the advances in researches on antimicrobial peptides with antimalarial actions and discusses the potential of antimalarial peptides as novel antimalarials.