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JCI Insight Dec 2019Despite an unprecedented 2 decades of success, the combat against malaria - the mosquito-transmitted disease caused by Plasmodium parasites - is no longer progressing....
Despite an unprecedented 2 decades of success, the combat against malaria - the mosquito-transmitted disease caused by Plasmodium parasites - is no longer progressing. Efforts toward eradication are threatened by the lack of an effective vaccine and a rise in antiparasite drug resistance. Alternative approaches are urgently needed. Repurposing of available, approved drugs with distinct modes of action are being considered as viable and immediate adjuncts to standard antimicrobial treatment. Such strategies may be well suited to the obligatory and clinically silent first phase of Plasmodium infection, where massive parasite replication occurs within hepatocytes in the liver. Here, we report that the widely used antidiabetic drug, metformin, impairs parasite liver stage development of both rodent-infecting Plasmodium berghei and human-infecting P. falciparum parasites. Prophylactic treatment with metformin curtails parasite intracellular growth in vitro. An additional effect was observed in mice with a decrease in the numbers of infected hepatocytes. Moreover, metformin provided in combination with conventional liver- or blood-acting antimalarial drugs further reduced the total burden of P. berghei infection and substantially lessened disease severity in mice. Together, our findings indicate that repurposing of metformin in a prophylactic regimen could be considered for malaria chemoprevention.
Topics: Animals; Antimalarials; Cells, Cultured; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Repositioning; Drug Therapy, Combination; Hepatocytes; Humans; Inhibitory Concentration 50; Liver; Malaria; Male; Mefloquine; Metformin; Mice; Parasite Load; Parasitic Sensitivity Tests; Plasmodium berghei; Plasmodium falciparum; Primaquine; Primary Cell Culture
PubMed: 31852843
DOI: 10.1172/jci.insight.127441 -
PeerJ 2022and tissue dwelling helminth parasites are endemic in sub-Saharan Africa (SSA). The geographical overlap in co-infection is a common phenomenon. However, there is...
BACKGROUND
and tissue dwelling helminth parasites are endemic in sub-Saharan Africa (SSA). The geographical overlap in co-infection is a common phenomenon. However, there is continued paucity of information on how the co-infection influence the blood glucose and insulin profiles in the infected host. Animal models are ideal to elucidate effects of co-infection on disease outcomes and hence, blood glucose, insulin and glycogen profiles were assessed in Sprague-Dawley rats co-infected with ANKA (Pb) and (Tz), a tissue-dwelling nematode.
METHODS
One-hundred-and-sixty-eight male Sprague-Dawley rats (weight range 90-150 g) were randomly divided into four separate experimental groups: Control ( = 42), Pb-infected ( = 42), Tz-infected ( = 42) and Pb- + Tz-infected group ( = 42). Measurement of Pb parasitaemia was done daily throughout the experimental study period for the Pb and the Pb + Tz group. Blood glucose was recorded every third day in all experimental groups throughout the experimental study period. Liver and skeletal muscle samples were harvested, snap frozen for determination of glycogen concentration.
RESULTS
Results showed that Tz mono-infection and Tz + Pb co-infection did not have blood glucose lowering effect in the host as expected. This points to other possible mechanisms through which tissue-dwelling parasites up-regulate the glucose store without decreasing the blood glucose concentration as exhibited by the absence of hypoglycaemia in Tz + Pb co-infection group. Hypoinsulinemia and an increase in liver glycogen content was observed in Tz mono-infection and Tz + Pb co-infection groups of which the triggering mechanism remains unclear.
CONCLUSIONS
To get more insights into how glucose, insulin and glycogen profiles are affected during plasmodium-helminths co-infections, further studies are recommended where other tissue-dwelling helminths such as which has strobilocercus as the metacestode in the liver to mimic infections such as hydatid disease in humans are used.
Topics: Rats; Humans; Animals; Male; Blood Glucose; Trichinella; Rats, Sprague-Dawley; Insulin; Plasmodium berghei; Glycogen; Coinfection; Lead; Malaria; Glucose; Insulin, Regular, Human
PubMed: 35923890
DOI: 10.7717/peerj.13713 -
BioMed Research International 2023Emergence of resistance to antimalarial drugs presents a major drawback in efforts to control malaria. To address this problem, there is an urgent and continuous need...
BACKGROUND
Emergence of resistance to antimalarial drugs presents a major drawback in efforts to control malaria. To address this problem, there is an urgent and continuous need for the development of new and effective antimalarial agents. (L.) link extract has exhibited antiplasmodial activity in many pharmacological studies. To our knowledge, data on its antimalarial efficacy is still very limited. A recent study demonstrated that polar extracts from the plant roots inhibit proliferation in a mouse model. This study further describes the efficacy and safety of a methanolic root extract of the plant as an antimalarial agent by demonstrating its effect on hematological, biochemical, and histological parameters of -infected BALB/c mice.
METHODS
Rane's test, a curative approach, was used to evaluate the antimalarial efficacy of methanolic root extract in -infected BALB/c mice. The effect of the extract on both hematological and biochemical parameters was evaluated using automated analyzers. Kidney, liver, lung, spleen, and brain tissues were harvested from euthanized mice and examined for changes in organ architecture.
RESULTS
This study demonstrates that methanolic root extract of significantly inhibited parasitemia in BALB/c mice ( < 0.01). Infected mice that were treated with the extract depicted a significantly low level of total leucocytes ( < 0.01), red blood cell distribution width ( < 0.01), and a significantly high hemoglobin concentration ( < 0.001) compared to the infected animals that were administered with the vehicle only. The infected animals that were treated with the extract exhibited a significantly low level of urea, creatinine, bilirubin, and alkaline phosphatase ( < 0.05), compared to the infected animals that were given the vehicle only. The level of sodium, potassium and chloride ions, lymphocytes, granulocytes, hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration, total protein, albumin, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total platelets, mean platelet volume (MPV), and platelet distribution width of the infected animals treated with the extract was not significantly different from those of the infected animals that were given the vehicle only ( > 0.05). The extract alleviated organ pathological changes in the infected mice. The extract did not induce any remarkable adverse effect on the growth, hematological, and biochemical parameters of uninfected animals ( > 0.05). In addition, administration of the extract did not alter the gross appearance and histological architecture of the organs, implying that the extract was well tolerated in mice.
CONCLUSIONS
methanolic root extract exhibited good antimalarial activity against and may be safe in mice.
Topics: Mice; Animals; Antimalarials; Plasmodium berghei; Senna Plant; Mice, Inbred BALB C; Alkaline Phosphatase; Plant Extracts
PubMed: 37583959
DOI: 10.1155/2023/8296195 -
Journal of Cell Science Jun 2024Plasmodium sporozoites are the infective forms of the malaria parasite in the mosquito and vertebrate host. Gliding motility allows sporozoites to migrate and invade...
Plasmodium sporozoites are the infective forms of the malaria parasite in the mosquito and vertebrate host. Gliding motility allows sporozoites to migrate and invade mosquito salivary glands and mammalian hosts. Motility and invasion are powered by an actin-myosin motor complex linked to the glideosome, which contains glideosome-associated proteins (GAPs), MyoA and the myosin A tail-interacting protein (MTIP). However, the role of several proteins involved in gliding motility remains unknown. We identified that the S14 gene is upregulated in sporozoite from transcriptome data of Plasmodium yoelii and further confirmed its transcription in P. berghei sporozoites using real-time PCR. C-terminal 3×HA-mCherry tagging revealed that S14 is expressed and localized on the inner membrane complex of the sporozoites. We disrupted S14 in P. berghei and demonstrated that it is essential for sporozoite gliding motility, and salivary gland and hepatocyte invasion. The gliding and invasion-deficient S14 knockout sporozoites showed normal expression and organization of inner membrane complex and surface proteins. Taken together, our data show that S14 plays a role in the function of the glideosome and is essential for malaria transmission.
Topics: Sporozoites; Plasmodium berghei; Protozoan Proteins; Animals; Mice; Malaria; Salivary Glands; Anopheles
PubMed: 38832798
DOI: 10.1242/jcs.261857 -
Medicinal Chemistry (Shariqah (United... 2023A series of novel, substituted tetracyclic benzothiazepines were designed and prepared in an effort to optimize the potency of this chemical class against drug-resistant...
OBJECTIVE
A series of novel, substituted tetracyclic benzothiazepines were designed and prepared in an effort to optimize the potency of this chemical class against drug-resistant strains of the malaria parasite.
METHODS
Tetracyclic benzothiazepines bearing structural modification at seven distinct positions within the structure were synthesized in Knoevenagel condensation reactions followed by sequential intermolecular thio-Michael and then intramolecular imine formation reactions. Following purification and chemical characterization, the novel compounds were tested for in vitro efficacy against blood-stage P. falciparum and liver-stage P. berghei and also for in vivo efficacy against P. berghei.
RESULTS
Benzothiazepines bearing structural modification at the sulfur atom and at the three carbocycles within the molecule were successfully synthesized. The majority of analogs inhibited bloodstage P. falciparum with submicromolar IC values. The potency of an 8-methoxy-substituted analog 12 exceeded that of chloroquine in all three P. falciparum strains tested. The parent benzothiazepine 1 possessed liver-stage activity, inhibiting P. berghei sporozoites infecting HepG2 cells with an IC of 106.4 nM and an IC of 408.9 nM, but failed to enhance the longevity of P. berghei infected mice compared to the controls. Compounds displayed modest toxicity toward HepG2 cells and were tolerated by mice at the highest dose tested, 640 mg/kg/dose once daily for three days.
CONCLUSION
The tetracyclic benzothiazepine described, which inhibits P. berghei infected hepatic cells with an IC of 106.4 nM, would appear to warrant further investigation. Optimization of ADME properties may be required since the most active analogs are probably excessively lipophilic.
Topics: Animals; Mice; Plasmodium falciparum; Antimalarials; Malaria; Plasmodium berghei; Liver
PubMed: 35993460
DOI: 10.2174/1573406418666220820112324 -
BMC Microbiology Sep 2023Plasmodium berghei has been used as a preferred model for studying human malaria, but only a limited number of disease-associated genes of P. berghei have been reported...
BACKGROUND
Plasmodium berghei has been used as a preferred model for studying human malaria, but only a limited number of disease-associated genes of P. berghei have been reported to date. Identification of new disease-related genes as many as possible will provide a landscape for better understanding the pathogenesis of P. berghei.
METHODS
Network module analysis method was developed and applied to identify disease-related genes in P. berghei genome. Sequence feature identification, gene ontology annotation, and T-cell epitope analysis were performed on these genes to illustrate their functions in the pathogenesis of P. berghei.
RESULTS
33,314 genes were classified into 4,693 clusters. 4,127 genes shared by six malaria parasites were identified and are involved in many aspects of biological processes. Most of the known essential genes belong to shared genes. A total of 63 clusters consisting of 405 P. berghei genes were enriched in rodent malaria parasites. These genes participate in various stages of parasites such as liver stage development and immune evasion. Combination of these genes might be responsible for P. berghei infecting mice. Comparing with P. chabaudi, none of the clusters were specific to P. berghei. P. berghei lacks some proteins belonging to P. chabaudi and possesses some specific T-cell epitopes binding by class-I MHC, which might together contribute to the occurrence of experimental cerebral malaria (ECM).
CONCLUSIONS
We successfully identified disease-associated P. berghei genes by network module analysis. These results will deepen understanding of the pathogenesis of P. berghei and provide candidate parasite genes for further ECM investigation.
Topics: Humans; Animals; Mice; Plasmodium berghei; Gene Ontology; Genes, Essential; Immune Evasion; Molecular Sequence Annotation
PubMed: 37735351
DOI: 10.1186/s12866-023-03019-0 -
Molecular and Biochemical Parasitology Sep 2023The parasite responsible for causing malaria infection, Plasmodium, is known to exhibit resistance to a number of already available treatments. This has prompted the...
The parasite responsible for causing malaria infection, Plasmodium, is known to exhibit resistance to a number of already available treatments. This has prompted the continue search for new antimalarial drugs ranging from medicinal plant parts to synthetic compounds. In lieu of this, the mitigative action of the bioactive compound, eugenol towards P. berghei-induced anaemia and oxidative organ damage was investigated following a demonstration of in vitro and in vivo antiplasmodial effects. Mice were infected with chloroquine-sensitive strain of P. berghei and thereafter treated with eugenol at doses of 10 and 20 mg/kg body weight (BW) for seven days. The packed cell volume and redox sensitive biomarkers in the liver, brain and spleen were measured. Our result demonstrated that eugenol significantly (p < 0.05) ameliorated the P. berghei-associated anaemia at a dose of 10 mg/kg BW. In addition, the compound, at a dose of 10 mg/kg BW, significantly (p < 0.05) alleviated the P. berghei-induced organ damage. This evidently confirmed that eugenol plays an ameliorative role towards P. berghei-related pathological alterations. Hence, the study opens up a new therapeutic use of eugenol against plasmodium parasite.
Topics: Mice; Animals; Plasmodium berghei; Eugenol; Plant Extracts; Antimalarials; Oxidative Stress; Anemia
PubMed: 37329986
DOI: 10.1016/j.molbiopara.2023.111577 -
MSphere Aug 2023During invasion, parasites secrete proteins from rhoptry and microneme apical end organelles, which have crucial roles in attaching to and invading target cells. A...
During invasion, parasites secrete proteins from rhoptry and microneme apical end organelles, which have crucial roles in attaching to and invading target cells. A sporozoite stage-specific gene silencing system revealed that rhoptry neck protein 2 (RON2), RON4, and RON5 are important for sporozoite invasion of mosquito salivary glands. Here, we further investigated the roles of RON4 during sporozoite infection of the liver . Following intravenous inoculation of RON4-knockdown sporozoites into mice, we demonstrated that sporozoite RON4 has multiple functions during sporozoite traversal of sinusoidal cells and infection of hepatocytes. infection experiments using a hepatoma cell line revealed that secreted RON4 is involved in sporozoite adhesion to hepatocytes and has an important role in the early steps of hepatocyte infection. In addition, motility assays indicated that RON4 is required for sporozoite attachment to the substrate and the onset of migration. These findings indicate that RON4 is crucial for sporozoite migration toward and invasion of hepatocytes via attachment ability and motility.IMPORTANCEMalarial parasite transmission to mammals is established when sporozoites are inoculated by mosquitoes and migrate through the bloodstream to infect hepatocytes. Many aspects of the molecular mechanisms underpinning migration and cellular invasion remain largely unelucidated. By applying a sporozoite stage-specific gene silencing system in the rodent malarial parasite, , we demonstrated that rhoptry neck protein 4 (RON4) is crucial for sporozoite infection of the liver . Combined with investigations, it was revealed that RON4 functions during a crossing of the sinusoidal cell layer and invading hepatocytes, at an early stage of liver infection, by mediating the sporozoite capacity for adhesion and the onset of motility. Since RON4 is also expressed in merozoites and tachyzoites, our findings contribute to understanding the conserved invasion mechanisms of parasites.
Topics: Animals; Mice; Plasmodium berghei; Liver; Malaria; Sporozoites; Protozoan Proteins; Hepatocytes
PubMed: 37272704
DOI: 10.1128/msphere.00587-22 -
Molecular Microbiology Mar 2024Plasmodium parasites, the eukaryotic pathogens that cause malaria, feature three distinct invasive forms tailored to the host environment they must navigate and invade...
Plasmodium parasites, the eukaryotic pathogens that cause malaria, feature three distinct invasive forms tailored to the host environment they must navigate and invade for life cycle progression. One conserved feature of these invasive forms is the micronemes, apically oriented secretory organelles involved in egress, motility, adhesion, and invasion. Here we investigate the role of GPI-anchored micronemal antigen (GAMA), which shows a micronemal localization in all zoite forms of the rodent-infecting species Plasmodium berghei. ∆GAMA parasites are severely defective for invasion of the mosquito midgut. Once formed, oocysts develop normally, however, sporozoites are unable to egress and exhibit defective motility. Epitope-tagging of GAMA revealed tight temporal expression late during sporogony and showed that GAMA is shed during sporozoite gliding motility in a similar manner to circumsporozoite protein. Complementation of P. berghei knockout parasites with full-length P. falciparum GAMA partially restored infectivity to mosquitoes, indicating conservation of function across Plasmodium species. A suite of parasites with GAMA expressed under the promoters of CTRP, CAP380, and TRAP, further confirmed the involvement of GAMA in midgut infection, motility, and vertebrate infection. These data show GAMA's involvement in sporozoite motility, egress, and invasion, implicating GAMA as a regulator of microneme function.
Topics: Animals; Culicidae; Parasites; Protozoan Proteins; Oocysts; Plasmodium berghei; Sporozoites
PubMed: 37314965
DOI: 10.1111/mmi.15078 -
Nature Communications Dec 2023Gametogenesis in Plasmodium spp. occurs within the Anopheles mosquito and is essential for sexual reproduction / differentiation and onwards transmission to mammalian...
Gametogenesis in Plasmodium spp. occurs within the Anopheles mosquito and is essential for sexual reproduction / differentiation and onwards transmission to mammalian hosts. To better understand the 3D organisation of male gametogenesis, we used serial block face scanning electron microscopy (SBF-SEM) and serial-section cellular electron tomography (ssET) of P. berghei microgametocytes to examine key structures during male gamete formation. Our data reveals an elaborate organisation of axonemes coiling around the nucleus in opposite directions forming a central axonemal band in microgametocytes. Furthermore, we discover the nucleus of microgametes to be tightly coiled around the axoneme in a complex structure whose formation starts before microgamete emergence during exflagellation. Our discoveries of the detailed 3D organisation of the flagellated microgamete and the haploid genome highlight some of the atypical mechanisms of axoneme assembly and haploid genome organisation during male gamete formation in the malaria parasite.
Topics: Male; Animals; Plasmodium berghei; Haploidy; Germ Cells; Anopheles; Flagella; Mammals
PubMed: 38092766
DOI: 10.1038/s41467-023-43877-w