Search Results (55)

Malaria remains a major global health challenge. While treatments targeting parasite replication exist, effective interventions for neurological manifestations are scarce, necessitating new strategies for cerebral malaria. In this study, we investigated the effect of a single-chain variable fragment (scFv) against glycosylphosphatidylinositol (GPI) as an intervention tool to mitigate the effects of Plasmodium in a preclinical model. We used C57BL/6J mice infected with Plasmodium berghei-ANKA (PbA) and treated them with anti-GPI scFv or phosphate-buffered saline (PBS) on days 0, 3, and 6 post-infection. Uninfected controls were treated on the same days with scFv or PBS. The animals were evaluated for morbidity and mortality, body weight, parasitemia, blood count, cytokines, and histopathology. Results show that anti-GPI scFv prevented lethality in 71.4% of infected animals and promoted recovery from weight loss. Furthermore, the intervention inhibited neurological and systemic signs, reduced parasitemia, and improved hematological and histopathological parameters in the brain, lungs, and kidneys. In conclusion, anti-GPI scFv exerts a significant systemic effect on experimental cerebral malaria (ECM) pathology, representing a promising tool for severe manifestations of the disease. Full article

Background/Objectives: Malaria remains a major cause of hospitalization in rural Madagascar, yet data on in-hospital clinical presentation, management, and patient outcomes remain limited. Methods: We conducted a three-year retrospective study (2023–2025) at a rural district hospital in Ambatoboeny, Madagascar, including patients of all ages hospitalized with malaria confirmed by rapid diagnostic testing and microscopy. Sociodemographic, clinical, laboratory, and treatment data were extracted from routine records. Length of hospital stay (LOS) was analyzed continuously and categorized as ≤2, 3–4, or ≥5 days. Seasonal admission patterns and factors associated with LOS were assessed using chi-square or Fisher’s exact tests, and associations with rainfall seasonality were explored using Spearman’s correlation. Results: Among 134 hospitalized patients, median age was 15 years (interquartile range (IQR) 7–25) and 52.2% were female. Plasmodium falciparum predominated (94.0%), while mixed-species infections were identified in 6.0% of cases; 20.1% of cases were classified as severe malaria, including 10.4% with cerebral malaria. Co-infections were frequent (52.2%), most commonly Schistosoma haematobium infection (14.2%) and typhoid fever (12.7%). Intravenous artesunate was initiated in 97.8% of patients; all received paracetamol and 94.8% received intravenous fluids. Median LOS was 2 days (IQR 2–3); 12.7% had prolonged hospitalization (≥5 days). Prolonged LOS was significantly associated with cerebral malaria, high parasitemia (≥5%), blood transfusion, and age < 15 years (all p ≤ 0.034), while co-infection and nutritional status were not. Conclusions: Hospitalized malaria in rural Madagascar presents with heterogeneous clinical phenotypes and a high burden of co-infections. Prolonged LOS is primarily driven by markers of severe disease and supportive care requirements, underscoring the need for early severity recognition and resource planning in low-resource hospitals. Full article

Background: Cerebral malaria (CM) is a severe and often fatal complication of Plasmodium falciparum infection that causes devastating brain injury largely through immune-mediated mechanisms. Pathogenic brain-infiltrating CD8⁺ T cells are key drivers of CM pathology, yet the intracellular signals enabling their harmful autoimmune-like activity remain poorly defined. Here, we identify protein kinase C θ (PKCθ), a central antigen receptor-signalling mediator, as a critical contributor to experimental cerebral malaria (ECM). Methods/Results: Using a PKCθ null allele mouse strain on a C57BL/6N background, we demonstrate that PKCθ deficiency significantly improves survival in Plasmodium berghei ANKA (PbA)-infected mice without altering parasite burdens in the blood or brain. Mechanistically, loss of PKCθ skews T cell differentiation towards central memory (Tcm) rather than effector memory (Tem) phenotypes, thereby reducing effector differentiation and sequestration of CD8⁺ T cells in the cerebral microvasculature. This prevents extensive neurovascular damage, preserves neural tissue integrity, and alleviates neurological signs and symptoms. Our findings provide genetic evidence that PKCθ drives CD8⁺ T cell-mediated brain injury in ECM. Conclusions: These results underscore the potential for repurposing clinically PKCθ inhibitors as host-targeted interventions to protect against cerebral injury and improve outcomes in patients with CM. Full article

Plasmodium parasites are the causative agents of malaria and can infect humans and other vertebrates, impacting socioeconomic development and causing significant health issues globally. Plasmodium falciparum causes the most severe type of infection, which can lead to chronic morbidity and other severe complications like anemia and cerebral malaria. The onset of infection is marked by the injection of sporozoites into the skin through the bite of a female Anopheles mosquito. This triggers a cascade of reactions elicited both by the host immune system in response to infection and by the parasite in a bid to evade the host immune system, survive, and replicate. The dynamics of this host–parasite relationship have prompted extensive research in an attempt to understand and exploit it in the fight against malaria. Thus, understanding the temporal and spatial dimensions of adaptation in host–parasite relationships is critical for forecasting parasite evolution and spread within and between host populations. One such relationship is the complex interplay between malaria and cellular aging processes. Understanding this dynamic will provide novel insights into the pathophysiology of the disease. This comprehensive review takes us on that journey by providing an overview of the interaction between the Plasmodium parasite and its host and the interplay between infection mechanisms, host immune response, and parasite evasion strategies, narrowing it down to how it affects cellular aging biomarkers and how this can be explored as a platform in the fight against the disease. Full article

Background: Erythroblasts have recently been identified as host cells for malarial parasites, revealing a previously underappreciated host–parasite interaction. However, their extremely low abundance in peripheral blood has hindered progress, especially in elucidating the biological significance of parasitized erythroblasts (pEBs) in vivo. Methods: Here, we visualized pEBs in a murine model and established a method to increase their number in peripheral blood by immunizing mice with live Plasmodium yoelii 17XNL, followed by challenge with P. berghei ANKA. Results: Immunized mice were protected from cerebral malaria and survived longer, during which pEBs appeared in circulation and were detected using Giemsa-stained smears. All blood-stage parasite forms were identified within pEBs, including enucleating erythroblasts. Conclusions: This model enables in vivo/ex vivo analysis of pEB biology without bone marrow/spleen isolation, thus lowering technical/ethical barriers for the field. Full article

Cerebral malaria is a life-threatening neurological complication of Plasmodium falciparum infection and a leading cause of pediatric mortality in endemic regions of sub-Saharan Africa. It is defined clinically by coma accompanied by peripheral parasitemia, without alternative causes. Pathogenetically, cytoadherence of parasitized erythrocytes in the cerebral microvasculature, together with a widespread inflammatory response and endothelial activation, causes profound microvascular injury. This injury includes disruption of the blood–brain barrier and the development of multifactorial cerebral oedema (both vasogenic and cytotoxic), resulting in elevated intracranial pressure and often diffuse brain swelling as seen on imaging in fatal cases. Recent high-resolution MRI studies in pediatric cohorts from these endemic regions have identified characteristic neuroimaging findings such as basal ganglia infarcts, brainstem lesions, and corpus callosum abnormalities that strongly predict poor outcomes. Notably, circulating extracellular vesicles—released by parasitized erythrocytes and activated endothelial cells have emerged as potent mediators of microvascular inflammation. Extracellular vesicles contain parasite-derived antigens and host inflammatory signals, implicating them in disease mechanisms. These vesicles are under investigation as novel diagnostic and prognostic biomarkers for severe malaria. Importantly, survivors of cerebral malaria often endure persistent neurocognitive impairments, behavioral problems, and epilepsy, underscoring the need to prevent secondary neuronal injury during the acute phase to reduce long-term disability. Taken together, these insights highlight the interplay between cerebral microvascular pathology and neurological outcome in cerebral malaria. This review synthesizes recent advances in the pathophysiology of cerebral malaria and cutting-edge diagnostic modalities. It highlights novel therapeutic targets and neuroprotective strategies that may enable precision medicine approaches aimed at preventing lasting neurological disability in survivors. Full article

Cerebral malaria (CM) is the severe progression of an infection with Plasmodium falciparum, causing detrimental damage to brain tissue and is the most frequent cause of Plasmodium falciparum mortality. The critical role of brain-infiltrating CD8⁺ T cells in the pathophysiology of CM having been revealed, our investigation focuses on the role of NR2F6, an established immune checkpoint, as a candidate driver of CM pathology. We employed an experimental mouse model of CM based on Plasmodium berghei ANKA (PbA) infection to compare the relative susceptibility of Nr2f6-knock-out and wild-type C57BL6/N mice. As a remarkable result, Nr2f6 deficiency confers a significant survival benefit. In terms of mechanism, we detected less severe endotheliopathy and, hence, less damage to the blood–brain barrier (BBB), accompanied by decreased sequestered parasites and less cytotoxic T-lymphocytes within the brain, manifesting in a better disease outcome. We present evidence that NR2F6 deficiency renders mice more resistant to experimental cerebral malaria (ECM), confirming a causal and non-redundant role for NR2F6 in the progression of ECM disease. Consequently, pharmacological inhibitors of the NR2F6 pathway could be of use to bolster BBB integrity and protect against CM. Full article

Background: Experimental models using Plasmodium berghei ANKA (PbA)-infected mice have been essential for uncovering cerebral malaria (CM) pathogenesis. However, variability in experimental CM (ECM) incidence, onset, and mortality introduce challenges when analyses rely solely on infection day, which may reflect different disease stages among animals. Methods: We applied machine learning to predict ECM risk and onset in a cohort of 153 C57BL/6, 164 CBA, and 53 Swiss Webster mice. First, we fitted a logistic regression model to estimate the risk of ECM at any day using parasitemia data from day 1 to day 4. Next, we developed and trained a Random Forest Regressor model to predict the exact day of symptom onset. Results: A total of 64.5% of the cohort developed ECM, with onset ranging between 5 and 11 days. Early increases in parasitemia were strong predictors for the development of ECM, with an increase in parasitemia equal to or greater than 0.05 between day 1 and day 3 predicting the development of ECM with 97% sensitivity. The Random Forest model predicted the day of ECM onset with high precision (mean absolute error: 0.43, R²: 0.64). Conclusion: Parasitemia dynamics can effectively identify mice at high risk of ECM, enabling more accurate modeling of early pathological processes and improving the consistency of experimental analyses. Full article

Cerebral malaria (CM) is a life-threatening disease that affects mainly children in sub-Saharan Africa. Studies have shown that children who survive CM are often left with neurological disabilities after recovery, such as behavioral changes similar to attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD). However, diagnosis and treatments for ADHD are limited in many places in Africa. The purpose of this study was to assess behavioral changes following CM infection in Children in Malawi and parents’ acceptability of behavioral treatments. Twenty-one parents of children who had survived CM were compared to forty parents from the general population. Assessment instruments included the Disruptive Behavior Rating Scale (DBRS), Treatment Evaluation Inventory-Short Form (TEI-SF), and ADHD symptom checklist. The results showed that the most acceptable treatments among parents in Malawi were interrupt/redirect, discussion, and medication. Parents of CM-surviving children were significantly more accepting of medication (F(1,59) = 7.92, p < 0.007). The majority of the children who survived CM were rated above the clinical cut-off for ADHD and ODD symptoms. Full article

Sickle-cell disease (SCD) is a group of inherited blood disorders in which a mutation in the β-globin (HBB) gene causes red blood cells to produce abnormal hemoglobin, known as Hb S. SCD is characterized by an autosomal-recessive pattern of inheritance, implying that for a child to manifest the condition, they must inherit an Hb S allele from both parents (HbSS) or one Hb S allele and another β-globin variant, such as Hb C or β-thalassemia (HbSC, HbS/β-thal). It has been observed that (heterozygote) carriers of one copy of the sickle-cell trait (HbAS) are typically healthy and can even gain partial protection from severe malaria. The term “severe and complicated malaria” is delineated based on specific clinical and laboratory characteristics in the presence of Plasmodium falciparum parasitemia. The prevalent forms of severe malaria among African children include cerebral malaria, respiratory distress, and severe malaria anemia. Cerebral malaria is a rare complication of malaria infection and is associated with a high mortality rate. Full article

Cerebral malaria (CM) is a deadly complication of P. falciparum infection. Although adults with CM have a higher mortality rate, CM affects mostly children under the age of 5 years. Neurological symptoms and signs include impaired consciousness, coma, seizures, and increased intracranial hypertension. Upon survival of a CM episode, persistent neurologic deficits occur in a subset of surviving children. These sequelae include recurrent seizures, behavioral deficits, loss of developmental milestones, learning disabilities and attention deficit hyperactivity disorder, which can remain with the survivors. The underlying neuropathology of these post CM neurologic sequelae are unclear. Therefore, we probed the extensive neuronal damage that occurs in an experimental murine model of cerebral malaria (eCM), focusing on the hippocampus. In addition, we explored responses of neuro-progenitor cells (NPC’s) and potential repair mechanisms. We report here that Plasmodium infection causes extensive neuronal damage in the hippocampus, characterized by a loss of neuronal NeuN and double cortin (DCX) immunostaining in eCM mice. On day 6 of eCM we also observed increased neurofilament light chain staining, indicative of neuronal fragmentation, which was accompanied by an increase in neurofilament light chain in CSF but not seen in plasma. A concomitant increase in the influx of neuroprogenitor cells in eCM was observed, suggesting ongoing neuronal repair. 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

Background: Malaria remains a global health crisis, with the World Health Organization (WHO) reporting 241 million cases and 627,000 deaths worldwide in 2020, predominantly affecting Sub-Saharan Africa. The region accounted for 95% of cases and 96% of deaths, reflecting the immense challenges in malaria prevention and treatment. Plasmodium falciparum Schizont Egress Antigen-1 (PfSEA-1) is crucial in facilitating immune evasion and promoting the sequestration of infected red blood cells (RBCs), contributing to severe malaria symptoms, including cerebral malaria, and necessitates the urgent identification of novel or repurposed drugs targeting PfSEA1. Methods: The protein structure of PfSEA-1 (UniProt ID: A0A143ZXM2) was modelled in three dimensions, prepared, and subjected to a 50 ns molecular dynamics (MD) simulation to achieve a stable structure. The equilibrated structure was minimised for molecular docking against the DrugBank compound library. Docking analysis identified potential inhibitors, including Alparabinos, Dihycid, Ambenzyne, Amiflupipquamine, Ametchomine, and Chlobenethyzenol, with docking scores ranging from −8.107 to −4.481 kcal/mol. Advanced analyses such as interaction fingerprints, density functional theory (DFT), and pharmacokinetics evaluations were conducted. Finally, a 100 ns MD simulation in the NPT ensemble was performed to assess the stability of protein–ligand complexes, with binding free energy and total energy calculations derived from the simulation trajectories. Results and Discussion: The identified compounds exhibited satisfactory pharmacokinetic profiles and binding interactions with PfSEA-1. The MD simulations demonstrated overall stability, with minor fluctuations in some instances. Key intermolecular interactions were observed, supporting the binding stability of the identified compounds. Binding free energy calculations confirmed favourable interactions, underscoring their potential as therapeutic agents against Plasmodium falciparum. While the in silico results are promising, experimental validation is essential to confirm their efficacy and safety for clinical use. Conclusion: These findings highlight PfSEA-1 as a promising antimalarial target and identify potential inhibitors with strong binding affinities and favourable pharmacokinetics. While the computational results are encouraging, further in vitro and in vivo validation is necessary to confirm their therapeutic potential and facilitate future drug development. Full article

Cerebral malaria (CM), the most lethal clinical syndrome of Plasmodium falciparum infection, mostly affects children under 5 in sub-Saharan Africa. CM is characterized by seizures and impaired consciousness that lead to death in 15–20% of cases if treated quickly, but it is completely fatal when untreated. Brain magnetic resonance imaging (MRI) is an invaluable source of information on the pathophysiology of brain damage, but, due to limited access to scanners in endemic regions, only until very recently have case reports of CM patients studied with advanced MRI methods been published. The murine model of experimental cerebral malaria (ECM) shares many common features with the human disease and has been extensively used to study the pathogenic mechanisms of the neurological syndrome. In vivo MRI studies on this model, the first of which was published in 2005, have contributed to a better understanding of brain lesion formation in CM and identified disease markers that were confirmed by MRI studies published from 2013 onwards in pediatric patients from endemic areas. In this review, we recapitulate the main findings and critically discuss the contributions of MRI studies in the ECM model to the understanding of human CM. Full article

Two-thirds of children with cerebral malaria (CM) exhibit retinopathy characterized by whitening, vessel color changes, and/or hemorrhages. The pathogenesis of malarial retinopathy is not fully understood. This study aimed to assess the relationship between malarial retinopathy and the severity of its components (macular whitening, retinal hemorrhages, and vessel color changes) with the total, circulating, or sequestered parasite load in children with CM. Total parasite burden was estimated by measuring plasma levels of Plasmodium falciparum histidine-rich protein 2 (PfHRP2), while the sequestered load was calculated as the difference between the total burden and circulating parasitemia. Children with retinopathy-positive CM (n = 172) had higher total and sequestered parasite burdens compared to retinopathy-negative children (n = 42) (both p = 0.049). In a subgroup with detailed retinopathy grading (n = 52), more extensive vessel color changes correlated with higher total, sequestered, and circulating parasite loads (p = 0.0057, p = 0.0068, and p = 0.0433, respectively). Peripheral retinal whitening was also associated with increased total and sequestered loads (p = 0.0017 and p = 0.0012). No association was found between retinal hemorrhages and parasite burden, indicating that other factors may influence their pathogenesis. Full article