Search Results (57)

Objective: Falciparum malaria is a major global health concern, affecting more than half of the world’s population and causing over half a million deaths annually. Red cell invasion is a crucial step in the parasite’s life cycle, where the parasite invade human erythrocytes to sustain infection and ensure survival. Two parasite proteins, Apical Membrane Antigen 1 (AMA-1) and Rhoptry Neck Protein 2 (RON2), are involved in tight junction formation, which is an essential step in parasite invasion of the red blood cell. Targeting the AMA-1 and RON2 interaction with inhibitors halts the formation of the tight junction, thereby preventing parasite invasion, which is detrimental to parasite survival. This study leverages machine learning (ML) to predict potential small molecule inhibitors of the AMA-1–RON2 interaction, providing putative antimalaria compounds for further chemotherapeutic exploration. Method: Data was retrieved from the PubChem database (AID 720542), comprising 364,447 inhibitors and non-inhibitors of the AMA-1–RON2 interaction. The data was processed by computing Morgan fingerprints and divided into training and testing with an 80:20 ratio, and the classes in the training data were balanced using the Synthetic Minority Oversampling Technique. Five ML models developed comprised Random Forest (RF), Gradient Boost Machines (GBMs), CatBoost (CB), AdaBoost (AB) and Support Vector Machine (SVM). The performances of the models were evaluated using accuracy, F1 score, and receiver operating characteristic—area under the curve (ROC-AUC) and validated using held-out data and a y-randomization test. An applicability domain analysis was carried out using the Tanimoto distance with a threshold set at 0.04 to ascertain the sample space where the models predict with confidence. Results: The GBMs model emerged as the best, achieving 89% accuracy and a ROC-AUC of 92%. CB and RF had accuracies of 88% and 87%, and ROC-AUC scores of 93% and 91%, respectively. Conclusions: Experimentally validated inhibitors of the AMA-1–RON2 interaction could serve as starting blocks for the next-generation antimalarial drugs. The models were deployed as a web-based application, known as PLASMOpred. Full article

The journey toward a viable malaria vaccine, initiated in 1965, reached a major milestone in 2021 with the WHO’s endorsement of RTS,S/AS01, a recombinant protein-based malaria vaccine. This progress continued with the 2023 approval of the R21/Matrix-M vaccine, which is more cost-effective, more potent due it is higher protein content, and easier to manufacture. Though these achievements signal hope, malaria’s intricate life cycle and its prevalence in underprivileged regions make vaccine development and equitable distribution challenging. This review explains the lifecycle of malaria and explores the evolution of various treatment strategies aimed at reducing malaria-related mortality. This scoping review aims to provide a comprehensive overview of malaria vaccines, examining their development, efficacy, safety, and implementation challenges. Using a structured literature search across PubMed, Web of Science, and Scopus, we identified key themes related to malaria vaccines trials, policy implications, and future research needs. Peer-reviewed publications on PubMed, Scopus, and Web of Science from 1970 to 2024 were searched without any limitations. Search and Boolean search terms were modified to include terms like “malaria vaccines”, “malaria vaccination”, “malaria immunisation”, “malaria immunisation AND malaria-endemic countries”, “malaria endemic low-income countries AND malaria control”, “malaria public health control”, “malaria chemoprophylaxis AND early diagnosis of malaria”, “screening for malaria”, and “laboratory diagnosis of malaria in endemic countries” in order to find pertinent studies. Preliminary insights suggest that although vaccines are crucial, comprehensive strategies involving health education, hygiene, and timely medical intervention remain essential to malaria control. Full article

Haemosporidian parasites (Apicomplexa, Haemosporida) are diverse obligatory heteroxenous protists, which infect all major groups of terrestrial vertebrates and use dipterous blood-sucking insects as vectors. These pathogens are responsible for various diseases, including malaria, which remains an important human and animal illness. In the wild, haemosporidians are particularly diverse in reptiles and birds in tropical countries, where they are flourishing. Avian haemosporidians have been particularly extensively investigated, especially due to their high prevalence and global distribution, including the countries with cold climates. The general scheme of the life cycle of haemosporidians is known, but the details of development remain insufficiently investigated or even unknown in most of the described parasite species, suggesting the existence of knowledge gaps. This attracts attention to some recent observations, which remain fragmentary but suggest the existence of formerly neglected or underestimated modes of the haemosporidians’ survival in vertebrates. Such findings are worth discussion as they indicate the novel directions in wildlife haemosporidian research. This article overviews some recent findings, which call for broadening of the orthodox views on modes of existence of haemosporidian parasites in avian hosts. Among them are the role of blood merogony in the long-lasting persistence of malaria parasites in birds, the role of gametocytes in the long-lasting survival of Haemoproteus species in vertebrates, the possible reasons of undetectable avian Haemoproteus infections due to peculiarities of exo-erythrocytic development, and the plausible factors driving the narrow vertebrate host specificity of Haemoproteus species. Full article

Malaria primarily affects developing nations and is one of the most destructive and pervasive tropical parasite infections. Antimalarial drug resistance, characterized by a parasite’s ability to survive and reproduce despite recommended medication doses, poses a significant challenge. Along with resistance to antimalarial drugs, the rate of mutation a parasite undergoes, overall parasite load, drug potency, adherence to treatment, dosing accuracy, drug bioavailability, and the presence of poor-quality counterfeit drugs are some of the contributing factors that elicit opposition to treatment. The ubiquitin-proteasome system (UPS) has become a promising drug target for malaria because of its central importance in the parasite’s life cycle and its contribution to artemisinin resistance. Polymorphisms in the Kelch13 gene of Plasmodium falciparum are the best-known markers for artemisinin resistance and are associated with a highly active UPS. Certain proteasome inhibitors, which are the other key players of the UPS, have demonstrated activity against malarial parasites and the ability to work with artemisinin. This work describes how, through targeting the UPS, the greater effectiveness of antimalarial drugs—especially where there is strong resistance—can be achieved, which contributes to overcoming the drug resistance phenomenon in malaria. Full article

Malaria disease affects millions of people annually, making the Amazon Basin a major hotspot in the Americas. While traditional control strategies rely on physical and chemical methods, the Anopheles microbiome offers a promising avenue for biological control, as certain bacteria can inhibit parasite development and alter vector immune and reproductive systems, disrupting the transmission cycle. For this reason, this study aimed to explore the bacterial communities in An. darlingi and An. triannulatus s.l., including breeding sites, immature stages, and adults from San Pedro de los Lagos (Leticia, Amazonas) through next-generation sequencing of the 16S rRNA gene. The results revealed a higher bacterial genus richness in the L1–L2 larvae of An. triannulatus s.l. Aeromonas and Enterobacter were prevalent in most samples, with abundances of 52.51% in L3–L4 larvae and 48.88% in pupae of An. triannulatus s.l., respectively. In breeding site water, Verrucomicrobiota bacteria were the most dominant (52.39%). We also identified Delftia (15.46%) in An. triannulatus s.l. pupae and Asaia (98.22%) in An. triannulatus, linked to Plasmodium inhibition, and Elizabethkingia, in low abundances, along with Klebsiella and Serratia, known for paratransgenesis potential. Considering the high bacterial diversity observed across the different mosquito life stages, identifying bacterial composition is the first step towards developing new strategies for malaria control. However, the specific roles of these bacteria in anophelines and the malaria transmission cycle remain to be elucidated. Full article

Proteinopathies, characterized by the misfolding, aggregation, and deposition of proteins, are hallmarks of various neurodegenerative and systemic diseases. Increasingly, research has highlighted the role of protein misfolding in parasitic infections, unveiling intricate interactions between host and parasite that exacerbate disease pathology and contribute to chronic outcomes. The life cycles of parasitic protozoa, including Plasmodium, Toxoplasmosis, and Leishmania species, are complicated and involve frequent changes between host and vector environments. Their proteomes are severely stressed during these transitions, which calls for highly specialized protein quality control systems. In order to survive harsh intracellular conditions during infection, these parasites have been demonstrated to display unique adaptations in the unfolded protein response, a crucial pathway controlling endoplasmic reticulum stress. In addition to improving parasite survival, these adaptations affect host cell signaling and metabolism, which may jeopardize cellular homeostasis. By causing oxidative stress, persistent inflammation, and disturbance of cellular proteostasis, host–parasite interactions also contribute to proteinopathy. For instance, Plasmodium falciparum disrupts normal protein homeostasis and encourages the accumulation of misfolded proteins by influencing host redox systems involved in protein folding. In addition to interfering with host chaperone systems, the parasitic secretion of effector proteins exacerbates protein misfolding and aggregate formation. Autophagy, apoptosis regulation, organelle integrity, and other vital cellular processes are all disrupted by these pathological protein aggregates. Long-term misfolding and aggregation can cause irreversible tissue damage, which can worsen the clinical course of illnesses like visceral leishmaniasis, cerebral malaria, and toxoplasmosis. Treating parasite-induced proteinopathies is a potentially fruitful area of therapy. According to recent research, autophagy modulators, proteasome enhancers, and small-molecule chaperones may be repurposed to lessen these effects. Pharmacological agents that target the UPR, for example, have demonstrated the ability to decrease parasite survival while also reestablishing host protein homeostasis. Targeting the proteins secreted by parasites that disrupt host proteostasis may also offer a novel way to stop tissue damage caused by proteinopathies. In conclusion, the intersection of protein misfolding and parasitic infections represents a rapidly advancing field of research. Dissecting the molecular pathways underpinning these processes offers unprecedented opportunities for developing innovative therapies. These insights could not only transform the management of parasitic diseases but also contribute to a broader understanding of proteinopathies in infectious and non-infectious diseases alike. Full article

Malaria remains a critical global health issue due to high mortality rates, drug resistance, and low treatment efficacy. The genetic variability of Plasmodium proteins complicates the development of long-lasting immunity, as it impedes the human immune system’s ability to sustain effective responses. T cells play a crucial role in combating malaria, but the parasite’s complex life cycle—spanning liver and blood stages—presents significant challenges in effectively activating and targeting these cells. Immunotherapy, which enhances the immune response and promotes durable T cell activity, offers a promising avenue for more effective and lasting malaria treatments. This review systematically analyzed 63 studies published in the last decade, focusing on the role of T cells in malaria. Among the studies, 87.2% targeted T cells as immunotherapy candidates, with CD4+ and CD8+ T cells each accounting for 47.6% of the studies. γδ T cells were the focus in 7.9% of cases, while 12.7% explored non-T cell contributions to enhancing T cell-mediated responses. The findings underscore the potential of T cells, particularly CD8+ T cells, in liver-stage defense and advocate for the exploration of advanced vaccine platforms and novel therapies, such as mRNA-based vectors and monoclonal antibodies. Full article

Malaria, a severe vector-borne disease, affects billions of people globally and claims over half a million lives annually. Climate change can impact lifespan and the development of vectors. There is a gap in organized, multidisciplined research on climate change’s impact on malaria incidence and transmission. This review assesses and summarizes research on the effects of change in climate on human health, specifically on malaria. Results suggest that higher temperatures accelerate larval development, promote reproduction, enhance blood feed frequency, increase digestion, shorten vector life cycles, and lower mortality rates. Rainfall provides aquatic stages, extends mosquitoes’ lifespans, and increases cases. Mosquito activity increases with high humidity, which facilitates malaria transmission. Flooding can lead to increased inhabitation development, vector population growth, and habitat diversion, increasing breeding sites and the number of cases. Droughts can increase vector range by creating new breeding grounds. Strong storms wash Anopheles’ eggs and reproduction habitat. It limits reproduction and affects disease outbreaks. The Indian Ocean Dipole (IOD) and El Nino Southern Oscillation (ENSO) indirectly alter malaria transmission. The study recommends strengthening collaboration between policymakers, researchers, and stakeholders to reduce malaria risks. It also suggests strengthening control mechanisms and improved early warnings. Full article

Post-translational modifications (PTMs) are essential for regulating protein functions, influencing various fundamental processes in eukaryotes. These include, but are not limited to, cell signaling, protein trafficking, the epigenetic control of gene expression, and control of the cell cycle, as well as cell proliferation, differentiation, and interactions between cells. In this review, we discuss protein PTMs that play a key role in the malaria parasite biology and its pathogenesis. Phosphorylation, acetylation, methylation, lipidation and lipoxidation, glycosylation, ubiquitination and sumoylation, nitrosylation and glutathionylation, all of which occur in malarial parasites, are reviewed. We provide information regarding the biological significance of these modifications along all phases of the complex life cycle of Plasmodium spp. Importantly, not only the parasite, but also the host and vector protein PTMs are often crucial for parasite growth and development. In addition to metabolic regulations, protein PTMs can result in epitopes that are able to elicit both innate and adaptive immune responses of the host or vector. We discuss some existing and prospective results from antimalarial drug discovery trials that target various PTM-related processes in the parasite or host. Full article

Ion channels serve many cellular functions including ion homeostasis, volume regulation, signaling, nutrient acquisition, and developmental progression. Although the complex life cycles of malaria parasites necessitate ion and solute flux across membranes, the whole-genome sequencing of the human pathogen Plasmodium falciparum revealed remarkably few orthologs of known ion channel genes. Contrasting with this, biochemical studies have implicated the channel-mediated flux of ions and nutritive solutes across several membranes in infected erythrocytes. Here, I review advances in the cellular and molecular biology of ion channels in malaria parasites. These studies have implicated novel parasite genes in the formation of at least two ion channels, with additional ion channels likely present in various membranes and parasite stages. Computational approaches that rely on homology to known channel genes from higher organisms will not be very helpful in identifying the molecular determinants of these activities. Given their unusual properties, novel molecular and structural features, and essential roles in pathogen survival and development, parasite channels should be promising targets for therapy development. Full article

The malaria parasite resides within erythrocytes during one stage of its life cycle. During this intraerythrocytic period, the parasite ingests the erythrocyte cytoplasm and digests approximately two-thirds of the host cell hemoglobin. This digestion occurs within a lysosome-like organelle called the digestive vacuole. Several proteases are localized to the digestive vacuole and these proteases sequentially breakdown hemoglobin into small peptides, dipeptides, and amino acids. The peptides are exported into the host cytoplasm via the chloroquine-resistance transporter and an amino acid transporter has also been identified on the digestive vacuole membrane. The environment of the digestive vacuole also provides appropriate conditions for the biocrystallization of toxic heme into non-toxic hemozoin by a poorly understood process. Hemozoin formation is an attribute of Plasmodium and Haemoproteus and is not exhibited by other intraerythrocytic protozoan parasites. The efficient degradation of hemoglobin and detoxification of heme likely plays a major role in the high level of replication exhibited by malaria parasites within erythrocytes. Unique features of the digestive vacuole and the critical importance of nutrient acquisition provide therapeutic targets for the treatment of malaria. Full article

Malaria continues to pose a significant global health burden despite concerted efforts to combat it. In 2020, nearly half of the world’s population faced the risk of malaria, underscoring the urgency of innovative strategies to tackle this pervasive threat. One of the major challenges lies in the emergence of the resistance of parasites to existing antimalarial drugs. This challenge necessitates the discovery of new, effective treatments capable of combating the Plasmodium parasite at various stages of its life cycle. Advanced computational approaches have been utilized to accelerate drug development, playing a crucial role in every stage of the drug discovery and development process. We have witnessed impressive and groundbreaking achievements, with GNNs applied to graph data and BERT from transformers across diverse NLP text analysis tasks. In this study, to facilitate a more efficient and effective approach, we proposed the integration of an NLP based model for SMILES (i.e., BERT) and a GNN model (i.e., RGCN) to predict the effect of antimalarial drugs against Plasmodium. The GNN model was trained using designed antimalarial drug and potential target (i.e., PfAcAS, F/GGPPS, and PfMAGL) graph-structured data with nodes representing antimalarial drugs and potential targets, and edges representing relationships between them. The performance of BERT-RGCN was further compared with that of Mordred-RGCN to evaluate its effectiveness. The BERT-RGCN and Mordred-RGCN models performed consistently well across different feature combinations, showcasing high accuracy, sensitivity, specificity, MCC, AUROC, and AUPRC values. These results suggest the effectiveness of the models in predicting antimalarial drugs against Plasmodium falciparum in various scenarios based on different sets of features of drugs and potential antimalarial targets. Full article

The complex life cycle of the malaria parasite Plasmodium requires the parasite to adequately adapt to different conditions. For this reason, Plasmodium strictly controls its gene expression, and given its evolutionary distance from the human host, the involved factors may figure as attractive potential drug targets. In recent years, several unique transcription factors and chromatin modifiers have been identified and partially characterized in Plasmodium falciparum and in the murine species P. yoelii and P. berghei. This review unites data from studies focusing on drug development against enigmatic plant-like AP2-transcription factors and chromatin modifiers, such as histone acetyl transferases and deacetylases and histone methyltransferases and demethylases. Considering the reported success of inhibition of both factors, these may be included as targets to effectively combat the parasite by perturbing its control of gene expression. Full article

Plasmodium knowlesi (Pk) causes zoonotic malaria and is known as the “fifth human malaria parasite”. Pk malaria is an emerging threat because infections are increasing and can be fatal. While most infections are in Southeast Asia (SEA), especially Malaysia, travelers frequently visit this region and can present with Pk malaria around the world. So, clinicians need to know (1) patients who present with fever after recent travel to SEA might be infected with Pk and (2) Pk is often misdiagnosed as P. malariae (which typically causes less severe malaria). Here we review the history, pathophysiology, clinical features, diagnosis, and treatment of Pk malaria. Severe disease is most common in adults. Signs and symptoms can include fever, abdominal pain, jaundice, acute kidney injury, acute respiratory distress syndrome, hyponatremia, hyperparasitemia, and thrombocytopenia. Dengue is one of the diseases to be considered in the differential. Regarding pathophysiologic mechanisms, when Pk parasites invade mature red blood cells (RBCs, i.e., normocytes) and reticulocytes, changes in the red blood cell (RBC) surface can result in life-threatening cytoadherence, sequestration, and reduced RBC deformability. Since molecular mechanisms involving the erythrocytic stage are responsible for onset of severe disease and lethal outcomes, it is biologically plausible that manual exchange transfusion (ET) or automated RBC exchange (RBCX) could be highly beneficial by replacing “sticky” parasitized RBCs with uninfected, deformable, healthy donor RBCs. Here we suggest use of special Pk-resistant donor RBCs to optimize adjunctive manual ET/RBCX for malaria. “Therapeutically-rational exchange transfusion” (T-REX) is proposed in which Pk-resistant RBCs are transfused (instead of disease-promoting RBCs). Because expression of the Duffy antigen on the surface of human RBCs is essential for parasite invasion, T-REX of Duffy-negative RBCs—also known as Fy(a-b-) RBCs—could replace the majority of the patient’s circulating normocytes with Pk invasion-resistant RBCs (in a single procedure lasting about 2 h). When sequestered or non-sequestered iRBCs rupture—in a 24 h Pk asexual life cycle—the released merozoites cannot invade Fy(a-b-) RBCs. When Fy(a-b-) RBC units are scarce (e.g., in Malaysia), clinicians can consider the risks and benefits of transfusing plausibly Pk-resistant RBCs, such as glucose-6-phosphate dehydrogenase deficient (G6PDd) RBCs and Southeast Asian ovalocytes (SAO). Patients typically require a very short recovery time (<1 h) after the procedure. Fy(a-b-) RBCs should have a normal lifespan, while SAO and G6PDd RBCs may have mildly reduced half-lives. Because SAO and G6PDd RBCs come from screened blood donors who are healthy and not anemic, these RBCs have a low-risk for hemolysis and do not need to be removed after the patient recovers from malaria. T-REX could be especially useful if (1) antimalarial medications are not readily available, (2) patients are likely to progress to severe disease, or (3) drug-resistant strains emerge. In conclusion, T-REX is a proposed optimization of manual ET/RBCX that has not yet been utilized but can be considered by physicians to treat Pk malaria patients. Full article

Malaria parasites must acquire all necessary nutrients from the vertebrate and mosquito hosts to successfully complete their life cycle. Failure to acquire these nutrients can limit or even block parasite development and presents a novel target for malaria control. One such essential nutrient is pantothenate, also known as vitamin B5, which the parasite cannot synthesize de novo and is required for the synthesis of coenzyme A (CoA) in the parasite. This review examines pantothenate and the CoA biosynthesis pathway in the human–mosquito–malaria parasite triad and explores possible approaches to leverage the CoA biosynthesis pathway to limit malaria parasite development in both human and mosquito hosts. This includes a discussion of sources for pantothenate for the mosquito, human, and parasite, examining the diverse strategies used by the parasite to acquire substrates for CoA synthesis across life stages and host resource pools and a discussion of drugs and alternative approaches being studied to disrupt CoA biosynthesis in the parasite. The latter includes antimalarial pantothenate analogs, known as pantothenamides, that have been developed to target this pathway during the human erythrocytic stages. In addition to these parasite-targeted drugs, we review studies of mosquito-targeted allosteric enzymatic regulators known as pantazines as an approach to limit pantothenate availability in the mosquito and subsequently deprive the parasite of this essential nutrient. Full article