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Search Results (487)

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10 pages, 1975 KiB  
Communication
Measuring Asymmetric Ionic Current Waveform Through Micropores for Detecting Reduced Red Blood Cell Deformability Due to Plasmodium falciparum Infection
by Kazumichi Yokota, Ken Hirano, Kazuaki Kajimoto and Muneaki Hashimoto
Sensors 2025, 25(15), 4722; https://doi.org/10.3390/s25154722 - 31 Jul 2025
Viewed by 159
Abstract
The mechanisms underlying reduced deformability of red blood cells (RBCs) in Plasmodium falciparum remain unclear. The decrease in RBC deformability associated with malarial infection was measured using ektacytometry, and only mean values were evaluated. In this study, we report the development of a [...] Read more.
The mechanisms underlying reduced deformability of red blood cells (RBCs) in Plasmodium falciparum remain unclear. The decrease in RBC deformability associated with malarial infection was measured using ektacytometry, and only mean values were evaluated. In this study, we report the development of a microfluidic sensing device that can evaluate decreased RBC deformability at the single-cell level by measuring ionic current waveforms through micropores. Using an in vitro culture system, we found that when RBC deformability was reduced by P. falciparum infection, ionic current waveforms changed. As RBC deformability decreased, waveforms became asymmetric. Computer simulations suggested that these waveform parameters are largely independent of RBC size and may represent a reliable indicator of diminished deformability. This novel microfluidic RBC deformability sensor allows for detailed single-cell analysis of malaria-associated deformability reduction, potentially aiding in elucidating its pathology. Full article
(This article belongs to the Special Issue Recent Advances in Microfluidic Sensing Devices)
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8 pages, 855 KiB  
Case Report
Severe Malaria Due to Plasmodium falciparum in an Immunocompetent Young Adult: Rapid Progression to Multiorgan Failure
by Valeria Sanclemente-Cardoza, Harold Andrés Payán-Salcedo and Jose Luis Estela-Zape
Life 2025, 15(8), 1201; https://doi.org/10.3390/life15081201 - 28 Jul 2025
Viewed by 263
Abstract
Plasmodium falciparum malaria remains a major cause of morbidity and mortality, particularly in endemic regions. We report the case of a 21-year-old male with recent travel to an endemic area (Guapi, Colombia), who presented with febrile symptoms, severe respiratory distress, and oxygen saturation [...] Read more.
Plasmodium falciparum malaria remains a major cause of morbidity and mortality, particularly in endemic regions. We report the case of a 21-year-old male with recent travel to an endemic area (Guapi, Colombia), who presented with febrile symptoms, severe respiratory distress, and oxygen saturation below 75%, necessitating orotracheal intubation. During the procedure, he developed pulseless electrical activity cardiac arrest, achieving return of spontaneous circulation after advanced resuscitation. Diagnosis was confirmed by thick blood smear, demonstrating P. falciparum infection. The patient progressed to multiorgan failure, including acute respiratory distress syndrome with capillary leak pulmonary edema, refractory distributive shock, acute kidney injury with severe hyperkalemia, and consumptive thrombocytopenia. Management included invasive mechanical ventilation, vasopressor support, sedation-analgesia, neuromuscular blockade, methylene blue, unsuccessful hemodialysis due to hemorrhagic complications, and platelet transfusions. Despite these interventions, the patient experienced a second cardiac arrest and died. This case highlights the severity and rapid progression of severe malaria with multisystem involvement, underscoring the critical importance of early diagnosis and intensive multidisciplinary management. It also emphasizes the need for preventive strategies for travelers to endemic areas and the development of clinical protocols to improve outcomes in complicated malaria. Full article
(This article belongs to the Section Medical Research)
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30 pages, 1348 KiB  
Review
Emerging Molecular Mechanisms in Malaria Pathogenesis and Novel Therapeutic Approaches: A Focus on P. falciparum Malaria
by Adekunle Sanyaolu, Aleksandra Marinkovic, Stephanie Prakash, Vyshnavy Balendra, Omar Shazley, Tatiana Gardellini, Abdul Jan, Kokab Younis, Chuku Okorie and Ricardo Izurieta
Biomolecules 2025, 15(7), 1038; https://doi.org/10.3390/biom15071038 - 17 Jul 2025
Viewed by 933
Abstract
Malaria is still one of the biggest global health problems, especially in parts of the world, such as sub-Saharan Africa, which remains most heavily affected. Despite significant advancements in testing, treatment, and prevention, malaria continues to seriously impact millions, primarily young children and [...] Read more.
Malaria is still one of the biggest global health problems, especially in parts of the world, such as sub-Saharan Africa, which remains most heavily affected. Despite significant advancements in testing, treatment, and prevention, malaria continues to seriously impact millions, primarily young children and populations in rural and impoverished areas. This paper looks at how the malaria parasite works inside the body, how it avoids the immune system, and how it becomes resistant to current drugs. Thanks to new advances in genetic and biochemical research, scientists are discovering new weak points in the parasite that could lead to better treatments. New vaccines, like RTS, S and R21, along with antibody-based therapies, offer renewed hope; however, extending the duration of the immunity they induce and ensuring effectiveness across diverse parasite strains remain significant challenges. Solving the malaria crisis will require more than science—it also necessitates equitable and timely access to treatments, robust health systems, and international collaboration. Continued research and global cooperation bring the world closer to ending malaria for good. Full article
(This article belongs to the Special Issue New Insights into Molecular Mechanisms and Therapeutics for Malaria)
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24 pages, 1889 KiB  
Article
In Silico Approach for Early Antimalarial Drug Discovery: De Novo Design of Virtual Multi-Strain Antiplasmodial Inhibitors
by Valeria V. Kleandrova, M. Natália D. S. Cordeiro and Alejandro Speck-Planche
Microorganisms 2025, 13(7), 1620; https://doi.org/10.3390/microorganisms13071620 - 9 Jul 2025
Viewed by 345
Abstract
Plasmodium falciparum is the causative agent of malaria, a parasitic disease that affects millions of people in terms of prevalence and is associated with hundreds of thousands of deaths. Current antimalarial medications, in addition to exhibiting moderate to serious adverse reactions, are not [...] Read more.
Plasmodium falciparum is the causative agent of malaria, a parasitic disease that affects millions of people in terms of prevalence and is associated with hundreds of thousands of deaths. Current antimalarial medications, in addition to exhibiting moderate to serious adverse reactions, are not efficacious enough due to factors such as drug resistance. In silico approaches can speed up the discovery and design of new molecules with wide-spectrum antimalarial activity. Here, we report a unified computational methodology combining a perturbation theory machine learning model based on multilayer perceptron networks (PTML-MLP) and the fragment-based topological design (FBTD) approach for the prediction and design of novel molecules virtually exhibiting versatile antiplasmodial activity against diverse P. falciparum strains. Our PTML-MLP achieved an accuracy higher than 85%. We applied the FBTD approach to physicochemically and structurally interpret the PTML-MLP, subsequently extracting several suitable molecular fragments and designing new drug-like molecules. These designed molecules were predicted as multi-strain antiplasmodial inhibitors, thus representing promising chemical entities for future synthesis and biological experimentation. The present work confirms the potential of combining PTML modeling and FBTD for early antimalarial drug discovery while opening new horizons for extended computational applications for antimicrobial research and beyond. Full article
(This article belongs to the Special Issue Infectious Diseases: New Approaches to Old Problems, 3rd Edition)
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19 pages, 1938 KiB  
Article
Identification of Pharmacophore Groups with Antimalarial Potential in Flavonoids by QSAR-Based Virtual Screening
by Adriana de Oliveira Fernandes, Valéria Vieira Moura Paixão, Yria Jaine Andrade Santos, Eduardo Borba Alves, Ricardo Pereira Rodrigues, Daniela Aparecida Chagas-Paula, Aurélia Santos Faraoni, Rosana Casoti, Marcus Vinicius de Aragão Batista, Marcel Bermudez, Silvio Santana Dolabella and Tiago Branquinho Oliveira
Drugs Drug Candidates 2025, 4(3), 33; https://doi.org/10.3390/ddc4030033 - 4 Jul 2025
Viewed by 419
Abstract
Background/Objectives: Severe malaria, mainly caused by Plasmodium falciparum, remains a significant therapeutic challenge due to increasing drug resistance and adverse effects. Flavonoids, known for their wide range of bioactivities, offer a promising route for antimalarial drug discovery. The aim of this [...] Read more.
Background/Objectives: Severe malaria, mainly caused by Plasmodium falciparum, remains a significant therapeutic challenge due to increasing drug resistance and adverse effects. Flavonoids, known for their wide range of bioactivities, offer a promising route for antimalarial drug discovery. The aim of this study was to elucidate key structural features associated with antimalarial activity in flavonoids and to develop accurate, interpretable predictive models. Methods: Curated databases of flavonoid structures and their activity against P. falciparum strains and enzymes were constructed. Molecular fingerprinting and decision tree analyses were used to identify key pharmacophoric groups. Subsequently, molecular descriptors were generated and reduced to build multiple classification and regression models. Results: These models demonstrated high predictive accuracy, with test set accuracies ranging from 92.85% to 100%, and R2 values from 0.64 to 0.97. Virtual screening identified novel flavonoid candidates with potential inhibitory activity. These were further evaluated using molecular docking and molecular dynamics simulations to assess binding affinity and stability with Plasmodium proteins (FabG, FabZ, and FabI). The predicted active ligands exhibited stable pharmacophore interactions with key protein residues, providing insights into binding mechanisms. Conclusions: This study provides highly predictive models for antimalarial flavonoids and enhances the understanding of structure–activity relationships, offering a strong foundation for further experimental validation. Full article
(This article belongs to the Section In Silico Approaches in Drug Discovery)
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36 pages, 2017 KiB  
Article
Anti-Infective Properties, Cytotoxicity, and In Silico ADME Parameters of Novel 4′-(Piperazin-1-yl)benzanilides
by Theresa Hermann, Sarah Harzl, Robin Wallner, Elke Prettner, Eva-Maria Pferschy-Wenzig, Monica Cal, Pascal Mäser and Robert Weis
Pharmaceuticals 2025, 18(7), 1004; https://doi.org/10.3390/ph18071004 - 3 Jul 2025
Viewed by 667
Abstract
Background: The benzamide MMV030666 from MMV’s Malaria Box Project, the starting point of herein presented study, was initially tested against various Plasmodium falciparum strains as well as Gram-positive and Gram-negative bacteria. It exhibits multi-stage antiplasmodial potencies and lacks resistance development. Methods: [...] Read more.
Background: The benzamide MMV030666 from MMV’s Malaria Box Project, the starting point of herein presented study, was initially tested against various Plasmodium falciparum strains as well as Gram-positive and Gram-negative bacteria. It exhibits multi-stage antiplasmodial potencies and lacks resistance development. Methods: The favorable structural features from previous series were kept while the influence of the N-Boc-piperazinyl substituent per se, as well as its ring position and its replacement by various heteroaromatic rings, was evaluated. Thus, this paper describes the preparation of the MMV030666-derived 4′-(piperazin-1-yl)benzanilides for the first time, exhibiting broad-spectrum activity not only against plasmodia but also various bacterial strains. Results: A series of insightful structure–activity relationships were determined. Furthermore, pharmacokinetic and physicochemical parameters of the new compounds were determined experimentally or in silico. Drug-likeliness according to Lipinski’s rules was calculated as well. Conclusions: A diarylthioether derivative of the lead compound was promisingly active against P. falciparum and exhibited broad-spectrum antibacterial activity against Gram-positive as well as Gram-negative bacteria. It is considered for testing against multi-resistant bacterial strains and in vivo studies. Full article
(This article belongs to the Special Issue Next-Generation Antinfective Agents)
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14 pages, 1548 KiB  
Article
Spatial Distribution of Microsporidia MB Along Clinal Gradient and the Impact of Its Infection on Pyrethroid Resistance in Anopheles gambiae s.l. Mosquitoes from Nigeria and Niger Republic
by Lamine M. Moustapha, Muhammad M. Mukhtar, Abdoul-Nasser H. Sanda, Shuaibu Adamu, Yusuf Y. Aliyu, Hadizat K. Einoi, Maryam U. Maigari, Peter C. Okeke, David E. Nwele, Abiodun Obembe, Udoka C. Nwangwu, Jeremy K. Herren and Sulaiman S. Ibrahim
Parasitologia 2025, 5(3), 31; https://doi.org/10.3390/parasitologia5030031 - 28 Jun 2025
Viewed by 289
Abstract
Microsporidia MB (MB), a promising biological control agent, suppresses Plasmodium falciparum transmission in Anopheles mosquitoes. This study examined the spatial distribution of MB infection in natural populations of An. gambiae s.l. mosquitoes collected in Nigeria and Niger Republic, and its association [...] Read more.
Microsporidia MB (MB), a promising biological control agent, suppresses Plasmodium falciparum transmission in Anopheles mosquitoes. This study examined the spatial distribution of MB infection in natural populations of An. gambiae s.l. mosquitoes collected in Nigeria and Niger Republic, and its association with insecticide susceptibility in the mosquitoes. Microsporidia MB has wide geographic distribution across Nigeria and Niger Republic. The overall prevalence of MB in F0 mosquitoes was 12.25% (95% CI: 7.76–16.75%); 25 mosquitoes out of 204 were positive. Geographic variation was observed, with a higher prevalence (5/15 mosquitoes) in Ebonyi State (33.33%, CI: 9.48–57.19%, Fisher’s exact test, p = 0.008). Infection rates were higher in An. coluzzii mosquitoes (21/133 mosquitoes), estimated at 15.79% (CI: 9.59–21.99%) compared to An. gambiae s.s. mosquitoes (4/71), with approximately 5.63% (CI: 0.27–11.00%, χ2 = 4.44; df = 1, p = 0.035). Resistant mosquitoes had a significantly higher prevalence of MB infection than susceptible mosquitos at 28.57% (CI: 16.74–40.40%) with an odds ratio of 3.33 (CI: 1.23–9.03, p = 0.017). These findings suggests that MB can be exploited as an alternative for vector control in Nigeria and Niger, but its possible association with pyrethroid resistance suggests that it should be taken into account as a potential confounder when designing insecticide resistance management strategies. Full article
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17 pages, 1278 KiB  
Article
Antimalarial Drug Repurposing of Epirubicin and Pelitinib in Combination with Artemether and Lumefantrine
by Douglas O. Ochora, Reagan M. Mogire, Bernard M. Murithi, Farid Abdi, Erick N. Ondari, Rael J. Masai, Edwin Mwakio, Agnes Cheruyiot, Abiy Yenesew and Hoseah M. Akala
Pharmaceuticals 2025, 18(7), 956; https://doi.org/10.3390/ph18070956 - 25 Jun 2025
Viewed by 394
Abstract
Background: Drug therapy remains the principal management strategy for malaria but is increasingly challenged by the emergence of drug-resistant malaria parasites. The need for new antimalarial drugs is urgent, yet drug discovery and development are hindered by high costs, long durations, and safety [...] Read more.
Background: Drug therapy remains the principal management strategy for malaria but is increasingly challenged by the emergence of drug-resistant malaria parasites. The need for new antimalarial drugs is urgent, yet drug discovery and development are hindered by high costs, long durations, and safety concerns that prevent approval. The current study aimed to determine antiplasmodial activities of approved drugs in combination with artemether (ART) and lumefantrine (LU). Methods: Using the SYBR Green I assay test, this study investigated the efficacy of epirubicin (EPI) and pelitinib (PEL) combined with ART and LU at fixed drug–drug ratios (4:1, 3:1, 1:1, 1:2, 1:3 and 1:4) and volume/volume. These combinations, as well as single drug treatments, were tested against cultured strains of Plasmodium falciparum (W2, DD2, D6, 3D7 and F32-ART) and fresh and cultured clinical isolates. The fifty percent inhibition concentration (IC50) and a mean sum of fifty percent fractional inhibition concentration (FIC50) were determined. Results: Synergism was observed when EPI was combined with both ART and LU across all fixed ratios with a mean of mean FIC50 values of <0.6. The combination of LU and EPI against the 3D7 strain demonstrated the highest efficacy with a synergism FIC50 value of 0.18. Most combinations of PEL with ART and LU showed antagonism (FIC50 > 1) when tested against strains of P. falciparum and clinical isolates. Conclusions: This study underscores the utility of alternative drug discovery and development strategies to bypass cost, time, and safety barriers, thereby enriching the antimalarial drug pipeline and accelerating the transition from lab to market. Full article
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15 pages, 972 KiB  
Article
Tracking Drug Resistance in Plasmodium falciparum: Genetic Diversity of Key Resistance Markers in Brazilian Malaria Hotspots
by Rebecca de Abreu-Fernandes, Lucas Tavares de Queiroz, Natália Ketrin Almeida-de-Oliveira, Aline Rosa de Lavigne Mello, Jacqueline de Aguiar Barros, Lilian Rose Pratt-Riccio, Gisely Cardoso de Melo, Patrícia Brasil, Cláudio Tadeu Daniel-Ribeiro, Didier Menard and Maria de Fátima Ferreira-da-Cruz
Int. J. Mol. Sci. 2025, 26(13), 5977; https://doi.org/10.3390/ijms26135977 - 21 Jun 2025
Viewed by 518
Abstract
Malaria remains a health problem, with Plasmodium falciparum accounting for 96% of cases in Africa and 15% in Brazil. The growing threat of drug resistance to artemisinin-based combination therapies (ACTs) jeopardizes progress toward elimination. This study examined P. falciparum samples collected from 141 [...] Read more.
Malaria remains a health problem, with Plasmodium falciparum accounting for 96% of cases in Africa and 15% in Brazil. The growing threat of drug resistance to artemisinin-based combination therapies (ACTs) jeopardizes progress toward elimination. This study examined P. falciparum samples collected from 141 patients in Brazil (2013–2023) by PCR and DNA sequencing to identify single-nucleotide polymorphisms in the pfcrt, pfmdr1, and pfk13 genes. Half of the samples carried the SVMNTMCGI haplotype in pfcrt, and none of the samples showed C350R mutations. In pfmdr1, the NYCDY haplotype was dominant (70%), with low occurrences of N86Y (4%) and no Y184F polymorphisms. No mutations linked to artemisinin partial resistance were detected in pfk13. Only one Amazonas sample exhibited wild-type haplotypes across all genes. Genetic diversity was more pronounced in pfcrt than pfmdr1, reflecting selective drug pressure. Significant linkage disequilibrium (LD) was observed within pfcrt (C72S and K76T) and pfmdr1 (S1034C and N1042D), but not between the two genes. The absence of pfk13-resistant mutations and the low prevalence of key pfmdr1 markers support the efficacy of ACTs. The persistence of diverse haplotypes and intragenic LD reflects ongoing drug pressure, underscoring the need for continuous genetic surveillance to anticipate emerging resistance. Full article
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14 pages, 1847 KiB  
Communication
The Plasmodium falciparum RING Finger Protein PfRNF1 Forms an Interaction Network with Regulators of Sexual Development
by Afia Farrukh, Sherihan Musa, Ute Distler, Stefan Tenzer, Gabriele Pradel and Che Julius Ngwa
Int. J. Mol. Sci. 2025, 26(12), 5470; https://doi.org/10.3390/ijms26125470 - 7 Jun 2025
Viewed by 604
Abstract
RNA-binding E3 ubiquitin ligases (RBULs) provide a link between RNA metabolic processes and the ubiquitin proteasome system (UPS). In humans, RBULs are involved in various biological processes, such as cell proliferation and differentiation, as well as sexual development. To date, little is known [...] Read more.
RNA-binding E3 ubiquitin ligases (RBULs) provide a link between RNA metabolic processes and the ubiquitin proteasome system (UPS). In humans, RBULs are involved in various biological processes, such as cell proliferation and differentiation, as well as sexual development. To date, little is known about their role in the protozoan parasite Plasmodium falciparum, the causative agent of malaria tropica. We previously identified a novel P. falciparum RBUL, the RING finger E3 ligase PfRNF1, which is highly expressed during gametocyte development. Here, we conducted BioID-based proximity interaction studies to unveil the PfRNF1 interactome. We show that in immature gametocytes, PfRNF1 forms an interaction network that is mainly composed of RNA-binding proteins, including the translational repressors DOZI and CITH and members of the CCR4-NOT complex, as well as UPS-related proteins. In particular, PfRNF1 interacts with recently identified regulators of sexual development like the zinc finger protein PfMD3, with which it shares the majority of interactors. The common interactome of PfRNF1 and PfMD3 comprises several uncharacterized proteins predominantly expressed in male or female gametocytes. Our results demonstrate that PfRNF1 engages with RNA-binding proteins crucial for sex determination in gametocytes, thereby linking posttranscriptional regulation with the UPS. Full article
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19 pages, 974 KiB  
Article
Design, Synthesis and Antiplasmodial Activities of a Library of Fluorine-Based 3-Benzylmenadiones
by Matthieu Roignant, Jimmy Richard, Maxime Donzel, Matthias Rottmann, Pascal Mäser and Elisabeth Davioud-Charvet
Molecules 2025, 30(11), 2446; https://doi.org/10.3390/molecules30112446 - 3 Jun 2025
Viewed by 531
Abstract
Plasmodione is a potent early antiplasmodial compound. A metabolic study on mice treated with plasmodione revealed that 6-hydroxy–plasmodione was the main metabolite eliminated in the urine of treated mice. To block the metabolic pathway in the host, the introduction of fluorine at C-6 [...] Read more.
Plasmodione is a potent early antiplasmodial compound. A metabolic study on mice treated with plasmodione revealed that 6-hydroxy–plasmodione was the main metabolite eliminated in the urine of treated mice. To block the metabolic pathway in the host, the introduction of fluorine at C-6 of the 3-benzylmenadione core was applied and showed potent antiplasmodial activity similar to that of the plasmodione analogue in vitro. In this work, a library of 38 6-fluoro-3-benzylmenadione analogues (a series) was constructed by incorporating structurally diverse groups in place of the 4-(trifluoromethyl) substituent present in the antiplasmodial plasmodione, via three synthetic routes. All new compounds were tested against the P. falciparum NF54 strain and for cytotoxicity with the rat L6 line. With a fluorine atom at C-6, A-a-21 was revealed to be the only compound from the a series, superior to the 6-H- analogue from the b series, with an IC50 value of 70 nM versus 200 nM. Then, five other fluorine-based 3-benzylmenadiones, in which the fluorine was introduced in various positions of the 3-benzylmenadione core, were synthetized to assist our understanding of the impact of fluorine on antiplasmodial potencies in vitro; in particular, the aim here was to compare the effects of human serum and P. berghei species in these drug screens. This was also conducted in vivo with the P. berghei-infected mouse model. In the P. berghei species assay, PD and the 4′-fluoro-3′-trifluoromethyl-benzylmenadione A-b-9 exhibited a similar antiplasmodial behavior toward P. falciparum versus P. berghei. In the human serum versus Albumax assays, only the 6-fluoro–plasmodione showed a lower shift factor between Albumax assays and human serum conditions, suggesting a lower protein binding for the 6-F-PD compared to plasmodione or A-b-9. In vivo, 6-fluoro–plasmodione proved to be the most potent 3-benzylmenadione, reducing parasitemia by 50% after oral administration at 50 mg/kg. Full article
(This article belongs to the Special Issue Synthesis of Bioactive Compounds, 3rd Edition)
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16 pages, 3636 KiB  
Article
Neuronal Damage in Murine Experimental Cerebral Malaria, Implications for Neuronal Repair and Sequelae
by Monique F. Stins, Irene Gramaglia, Joyce Velez, Carlos A. Pardo and Henri van der Heyde
Cells 2025, 14(11), 807; https://doi.org/10.3390/cells14110807 - 30 May 2025
Viewed by 593
Abstract
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. [...] Read more.
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
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14 pages, 1406 KiB  
Article
Zika Virus in Malaria-Endemic Populations: A Climate Change-Driven Syndemic in the Sudan Savannah, Nigeria
by Rebecca B. Atai, Maryam Aminu, Elijah E. Ella, Grace S. N. Kia, Emmanuel T. Obishakin, Helen G. Luka, Ganih S. Joel and Anyebe B. Onoja
Microbiol. Res. 2025, 16(6), 109; https://doi.org/10.3390/microbiolres16060109 - 27 May 2025
Viewed by 1005
Abstract
Zika and malaria are important vector-borne febrile illnesses in humans. In this study, we determined the circulation of Zika virus and malaria infections, their hotspots, and their predominant clinical features. A cross-sectional study was carried out in six Local Government Areas (LGAs) in [...] Read more.
Zika and malaria are important vector-borne febrile illnesses in humans. In this study, we determined the circulation of Zika virus and malaria infections, their hotspots, and their predominant clinical features. A cross-sectional study was carried out in six Local Government Areas (LGAs) in Kaduna State, Nigeria, from September 2018 to May 2019. Four hundred and twenty sera were screened for Zika virus (ZV) IgM and IgG, and Plasmodium falciparum antigen using ELISA and immunochromatographic test, respectively. Overall, a seroprevalence of 14.5% was found for Zika, and 9.3% for malaria. Nineteen (4.5%) and thirty-five (8.3%) patients were seropositive for ZV IgM and IgG, respectively. Co-infection rates for Zika (ZV IgM) and malaria (0.5%: 2/420), and for ZV IgG and malaria (0.7%: 3/420) were observed. Lere (10%: 7/70 for ZV IgM), Kachia (14.3%: 10/70 for ZV IgG) and Zaria (18.6%: 13/70 for malaria) LGAs were identified as hotspots for Zika and malaria. Age was significantly associated with malaria (p = 0.008) and ZV IgG (p = 0.004). Patients aged 1–10 years had the highest malaria seroprevalence (18.4%), while those aged 21–30 years had the highest ZV IgM prevalence (6.1%: 7/114). Out of the pregnant patients (56/420) tested, 5.37% (3/56) had antibodies to both recent and past ZV infection. A significant association was found between maculopapular rash (p = 0.021) and Zika, as well as between duration of the fever and recent Zika infection (p = 0.041). We highlight that malaria is endemic in Kaduna and that ZV is silently circulating, providing baseline data for further molecular epidemiological studies. Full article
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19 pages, 12141 KiB  
Article
A High-Throughput Inhibitor Screen Targeting CLAG3 Export and Membrane Insertion on Human Erythrocytes Infected with Malaria Parasites
by Jinfeng Shao, Jonathan Chu, Kashif Mohammad and Sanjay A. Desai
Pathogens 2025, 14(6), 520; https://doi.org/10.3390/pathogens14060520 - 23 May 2025
Viewed by 821
Abstract
To facilitate intracellular growth and replication, the virulent human malaria parasite P. falciparum remodels its host erythrocyte by exporting many proteins into the host cell cytosol. Along with a few other exported proteins, the parasite CLAG3 protein is then inserted in the host [...] Read more.
To facilitate intracellular growth and replication, the virulent human malaria parasite P. falciparum remodels its host erythrocyte by exporting many proteins into the host cell cytosol. Along with a few other exported proteins, the parasite CLAG3 protein is then inserted in the host erythrocyte membrane, exposing a small variant loop to host plasma and contributing to essential nutrient acquisition via the plasmodial surface anion channel (PSAC). To explore trafficking mechanisms and develop therapies that block host cell remodeling, we have now used a split NanoLuc reporter and performed a high-throughput screen for inhibitors of parasite CLAG3 trafficking and insertion at the host membrane. We screened ~52,000 small molecules and uncovered 65 chemically diverse hits. Hits that inhibit the NanoLuc reporter without blocking protein export were filtered out by a secondary screen whose signal does not depend on protein export. Because chemicals that interfere with parasite maturation were found to compromise CLAG3 export indirectly, a third screen using a NanoLuc reporter-tagged intracellular protein was used to evaluate nonspecific toxicity. Although our relatively small chemical screen did not identify bona fide inhibitors of CLAG3 host membrane insertion, these studies establish a framework for larger screens to identify novel export inhibitors. Such novel inhibitors will provide important insights into how Plasmodia remodel their host cells and may seed the development of therapies that block the export and membrane insertion of proteins needed for intracellular parasite survival. Full article
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17 pages, 2400 KiB  
Article
Generation of a Transgenic Plasmodium cynomolgi Parasite Expressing Plasmodium vivax Circumsporozoite Protein for Testing P. vivax CSP-Based Malaria Vaccines in Non-Human Primates
by Maya Aleshnick, Shreeya Hegde, Charlie Jennison, Sebastian A. Mikolajczak, Ashley M. Vaughan, Derek Haumpy, Thomas Martinson, Judith Straimer and Brandon K. Wilder
Vaccines 2025, 13(5), 536; https://doi.org/10.3390/vaccines13050536 - 17 May 2025
Viewed by 954
Abstract
Background/Objectives: Malaria, caused by infection with Plasmodium parasites, exacts a heavy toll worldwide. There are two licensed vaccines for malaria as well as two monoclonal antibodies that have shown promising efficacy in field trials. The vaccines and monoclonal antibodies target the major [...] Read more.
Background/Objectives: Malaria, caused by infection with Plasmodium parasites, exacts a heavy toll worldwide. There are two licensed vaccines for malaria as well as two monoclonal antibodies that have shown promising efficacy in field trials. The vaccines and monoclonal antibodies target the major surface protein (circumsporozoite protein, CSP) of Plasmodium falciparum. Yet P. falciparum is only one of the four major species of Plasmodium that infect humans. Plasmodium vivax is the second leading cause of malaria, but the P. vivax vaccine and monoclonal development lags far behind that for P. falciparum owing to the lack of basic preclinical tools such as in vitro culture or mouse models that replicate the key biological features of P. vivax. Notably among these features is the ability to form dormant liver stages (hypnozoites) that reactivate and drive the majority of the P. vivax malaria burden. Plasmodium cynomolgi is a simian parasite which is genotypically very close and phenotypically similar to P. vivax; it can infect non-human primates commonly used in research and replicates many features of P. vivax, including relapsing hypnozoites. Methods: Recently, a strain of P. cynomolgi has been adapted to in vitro cultures allowing parasite transgenesis. Here, we created a transgenic P. cynomolgi parasite in which the endogenous P. cynomolgi CSP has been replaced with P. vivax CSP, with the goal of enabling the preclinical study of anti-P. vivax CSP interventions to protect against primary and relapse infections. Results: We show that the in vitro-generated transgenic Pcy[PvCSP] parasite expresses both serotypes of P. vivax CSP and retains full functionality in vivo, including the ability to transmit to laboratory-reared Anopheles mosquitoes and cause relapsing infections in rhesus macaques. To our knowledge, this is the first gene replacement in a relapsing Plasmodium species. Conclusions: This work can directly enable the in vivo development of anti-P. vivax CSP interventions and provide a blueprint for the study of relapsing malaria through reverse genetics. Full article
(This article belongs to the Special Issue Recent Advances in Malaria Vaccine Development)
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