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Life Science Alliance Jun 2024Increasing numbers of antimalarial compounds are being identified that converge mechanistically at inhibition of cytoplasmic translation, regardless of the molecular...
Increasing numbers of antimalarial compounds are being identified that converge mechanistically at inhibition of cytoplasmic translation, regardless of the molecular target or mechanism. A deeper understanding of how their effectiveness as liver stage translation inhibitors relates to their chemoprotective potential could prove useful. Here, we probed that relationship using the -HepG2 liver stage infection model. After determining translation inhibition ECs for five compounds, we tested them at equivalent effective concentrations to compare the parasite response to, and recovery from, a brief period of translation inhibition in early schizogony, followed by parasites to 120 h post-infection to assess antiplasmodial effects of the treatment. We show compound-specific heterogeneity in single parasite and population responses to translation inhibitor treatment, with no single metric strongly correlated to the release of hepatic merozoites for all compounds. We also demonstrate that DDD107498 is capable of exerting antiplasmodial effects on translationally arrested liver stage parasites and uncover unexpected growth dynamics during the liver stage. Our results demonstrate that translation inhibition efficacy does not determine antiplasmodial efficacy for these compounds.
Topics: Animals; Plasmodium berghei; Parasites; Antimalarials; Liver; Merozoites
PubMed: 38575357
DOI: 10.26508/lsa.202302540 -
Current Opinion in Microbiology Jun 2024Malaria blood stage parasites commit to either one of two distinct cellular fates while developing within erythrocytes of their mammalian host: they either undergo... (Review)
Review
Malaria blood stage parasites commit to either one of two distinct cellular fates while developing within erythrocytes of their mammalian host: they either undergo another round of asexual replication or they differentiate into nonreplicative transmissible gametocytes. Depending on the state of infection, either path may support or impair the ultimate goal of human-to-human transmission via the mosquito vector. Malaria parasites therefore evolved strategies to control investments into asexual proliferation versus gametocyte formation. Recent work provided fascinating molecular insight into shared and unique mechanisms underlying the control and environmental modulation of sexual commitment in the two most widely studied malaria parasite species, Plasmodium falciparum and P. berghei. With this review, we aim at placing these findings into a comparative mechanistic context.
Topics: Plasmodium falciparum; Animals; Humans; Plasmodium berghei; Malaria; Erythrocytes
PubMed: 38574448
DOI: 10.1016/j.mib.2024.102469 -
Molecular Microbiology Jun 2024The protozoan parasite Plasmodium, the causative agent of malaria, undergoes an obligatory stage of intra-hepatic development before initiating a blood-stage infection....
The protozoan parasite Plasmodium, the causative agent of malaria, undergoes an obligatory stage of intra-hepatic development before initiating a blood-stage infection. Productive invasion of hepatocytes involves the formation of a parasitophorous vacuole (PV) generated by the invagination of the host cell plasma membrane. Surrounded by the PV membrane (PVM), the parasite undergoes extensive replication. During intracellular development in the hepatocyte, the parasites provoke the Plasmodium-associated autophagy-related (PAAR) response. This is characterized by a long-lasting association of the autophagy marker protein, and ATG8 family member, LC3B with the PVM. LC3B localization at the PVM does not follow the canonical autophagy pathway since upstream events specific to canonical autophagy are dispensable. Here, we describe that LC3B localization at the PVM of Plasmodium parasites requires the V-ATPase and its interaction with ATG16L1. The WD40 domain of ATG16L1 is crucial for its recruitment to the PVM. Thus, we provide new mechanistic insight into the previously described PAAR response targeting Plasmodium liver stage parasites.
Topics: Vacuoles; Plasmodium berghei; Animals; Autophagy-Related Proteins; Microtubule-Associated Proteins; Liver; Mice; Autophagy; Hepatocytes; Vacuolar Proton-Translocating ATPases; Malaria; Protozoan Proteins; Humans
PubMed: 38574236
DOI: 10.1111/mmi.15259 -
The Journal of Veterinary Medical... May 2024Plasmodium parasites within mosquitoes are exposed to various physiological processes, such as blood meal digestion activity, the gonotrophic cycle, and host responses...
Plasmodium parasites within mosquitoes are exposed to various physiological processes, such as blood meal digestion activity, the gonotrophic cycle, and host responses preventing the entry of parasites into the midgut wall. However, when in vitro-cultured ookinetes are injected into the hemocoel of mosquitoes, Plasmodium parasites are not affected by the vertebrate host's blood contents and do not pass through the midgut epithelial cells. This infection method might aid in identifying mosquito-derived factors affecting Plasmodium development within mosquitoes. This study investigated novel mosquito-derived molecules related to parasite development in Anopheles mosquitoes. We injected in vitro-cultured Plasmodium berghei (ANKA strain) ookinetes into female and male Anopheles stephensi (STE2 strain) mosquitoes and found that the oocyst number was significantly higher in males than in females, suggesting that male mosquitoes better support the development of parasites. Next, RNA-seq analysis was performed on the injected female and male mosquitoes to identify genes exhibiting changes in expression. Five genes with different expression patterns between sexes and greatest expression changes were identified as being potentially associated with Plasmodium infection. Two of the five genes also showed expression changes with infection by blood-feeding, indicating that these genes could affect the development of Plasmodium parasites in mosquitoes.
Topics: Animals; Anopheles; Female; Male; Plasmodium berghei; Malaria; Mosquito Vectors; Mice; Host-Parasite Interactions
PubMed: 38569883
DOI: 10.1292/jvms.24-0008 -
International Immunopharmacology May 2024RTS,S is the first malaria vaccine recommended for implementation among young children at risk. However, vaccine efficacy is modest and short-lived. To mitigate the risk...
RTS,S is the first malaria vaccine recommended for implementation among young children at risk. However, vaccine efficacy is modest and short-lived. To mitigate the risk of cerebral malaria (CM) among children under the age of 5, it is imperative to develop new vaccines. EVs are potential vaccine candidates as they obtain the ability of brain-targeted delivery and transfer plasmodium antigens and immunomodulators during infections. This study extracted EVs from BALB/c mice infected with Plasmodium yoelii 17XNL (P.y17XNL). C57BL/6J mice were intravenously immunized with EVs (EV-I.V. + CM group) or subcutaneously vaccinated with the combination of EVs and CpG ODN-1826 (EV + CPG ODN-S.C. + CM group) on days 0 and 20, followed by infection with Plasmodium berghei ANKA (P.bANKA) on day 20 post-second immunization. We monitored Parasitemia and survival rate. The integrity of the Blood-brain barrier (BBB) was examined using Evans blue staining.The levels of cytokines and adhesion molecules were evaluated using Luminex, RT-qPCR, and WB. Brain pathology was evaluated by hematoxylin and eosin and immunohistochemical staining. The serum levels of IgG, IgG1, and IgG2a were analyzed by enzyme-linked immunosorbent assay. Compared with those in the P.bANKA-infected group, parasitemia increased slowly, death was delayed (day 10 post-infection), and the survival rate reached 75 %-83.3 % in the EV-I.V. + ECM and EV + CPG ODN-S.C. + ECM groups. Meanwhile, compared with the EV + CPG ODN-S.C. + ECM group, although parasitemia was almost the same, the survival rate increased in the EV-I.V. + ECM group.Additionally, EVs immunization markedly downregulated inflammatory responses in the spleen and brain and ameliorated brain pathological changes, including BBB disruption and infected red blood cell (iRBC) sequestration. Furthermore, the EVs immunization group exhibited enhanced antibody responses (upregulation of IgG1 and IgG2a production) compared to the normal control group. EV immunization exerted protective effects, improving the integrity of the BBB, downregulating inflammation response of brain tissue, result in reduces the incidence of CM. The protective effects were determined by immunological pathways and brain targets elicited by EVs. Intravenous immunization exhibited better performance than subcutaneous immunization, which perhaps correlated with EVs, which can naturally cross BBB to play a better role in brain protection.
Topics: Animals; Malaria, Cerebral; Plasmodium berghei; Mice, Inbred C57BL; Extracellular Vesicles; Erythrocytes; Blood-Brain Barrier; Mice; Mice, Inbred BALB C; Oligodeoxyribonucleotides; Malaria Vaccines; Female; Brain; Cytokines; Plasmodium yoelii; Antibodies, Protozoan; Parasitemia; Disease Models, Animal; Immunoglobulin G
PubMed: 38569430
DOI: 10.1016/j.intimp.2024.111982 -
Journal of Parasitology Research 2024The spread of drug resistance is a significant issue, particularly in endemic countries with limited resources. The aim of this study was to evaluate antimalarial and...
BACKGROUND
The spread of drug resistance is a significant issue, particularly in endemic countries with limited resources. The aim of this study was to evaluate antimalarial and antioxidant activity of in order to justify its use in traditional medicine.
METHODS
Evaluation of the antimalarial activity of was carried out according to the model of the suppressive and curative test of Peters' over 4 days in infected mice. Antioxidant parameters and stress were measured after intraperitoneal administration of 1 × 10 infected red blood cells.
RESULTS
At doses of 150 mg/kg, 300 mg/kg, and 600 mg/kg, administration of B. micrantha substantially produced suppression of infection by 67.75%, 73.46%, and 78.99%, respectively, while 84.64% of the untreated group (1% DMSO) had suppression from chloroquine. The curative test significantly decreased the levels of parasitaemia and death in the treated groups. Furthermore, after extract was given to infected mice, a noteworthy increase in total protein, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) was observed. On the other hand, hepatic catalase (CAT) and superoxide dismutase (SOD) productions were considerably greater than that of the healthy control. Mice had considerably lower levels of nonenzymatic antioxidant markers such as glutathione, NO, and MDA showing that the liver was protected.
CONCLUSION
The infected groups responded favorably to the ethanol extract of . This result justifies investigation for its use in Cameroon.
PubMed: 38566916
DOI: 10.1155/2024/8821019 -
JACS Au Mar 2024Malaria is one of the most widespread diseases worldwide. Besides a growing number of people potentially threatened by malaria, the consistent emergence of resistance...
Malaria is one of the most widespread diseases worldwide. Besides a growing number of people potentially threatened by malaria, the consistent emergence of resistance against established antimalarial pharmaceuticals leads to an urge toward new antimalarial drugs. Hybridization of two chemically diverse compounds into a new bioactive product is a successful concept to improve the properties of a hybrid drug relative to the parent compounds and also to overcome multidrug resistance. 1,2,3-Triazoles are a significant pharmacophore system among nitrogen-containing heterocycles with various applications, such as antiviral, antimalarial, antibacterial, and anticancer agents. Several marketed drugs possess these versatile moieties, which are used in a wide range of medical indications. While the synthesis of hybrid compounds containing a 1,2,3-triazole unit was described using Cu- and Ru-catalyzed azide-alkyne cycloaddition, an alternative metal-free pathway has never been reported for the synthesis of antimalarial hybrids. However, a metal-free pathway is a green method that allows toxic and expensive metals to be replaced with an organocatalyst. Herein, we present the synthesis of new artemisinin-triazole antimalarial hybrids a facile Ramachary-Bressy-Wang organocatalyzed azide-carbonyl [3 + 2] cycloaddition (organo-click) reaction. The prepared new hybrid compounds are highly potent against chloroquine (CQ)-resistant and multi-drug-resistant strains (IC (Dd2) down to 2.1 nM; IC (K1) down to 1.8 nM) compared to CQ (IC (Dd2) = 165.3 nM; IC (K1) = 302.8 nM). Moreover, the most potent hybrid drug was more efficacious in suppressing parasitemia and extending animal survival in -infected mice (up to 100% animal survival and up to 40 days of survival time) than the reference drug artemisinin, illustrating the potential of the hybridization concept as an alternative and powerful drug-discovery approach.
PubMed: 38559731
DOI: 10.1021/jacsau.3c00716 -
Nucleic Acids Research Jun 2024Gametocyte development of the Plasmodium parasite is a key step for transmission of the parasite. Male and female gametocytes are produced from a subpopulation of...
Gametocyte development of the Plasmodium parasite is a key step for transmission of the parasite. Male and female gametocytes are produced from a subpopulation of asexual blood-stage parasites, but the mechanisms that regulate the differentiation of sexual stages are still under investigation. In this study, we investigated the role of PbARID, a putative subunit of a SWI/SNF chromatin remodeling complex, in transcriptional regulation during the gametocyte development of P. berghei. PbARID expression starts in early gametocytes before the manifestation of male and female-specific features, and disruption of its gene results in the complete loss of gametocytes with detectable male features and the production of abnormal female gametocytes. ChIP-seq analysis of PbARID showed that it forms a complex with gSNF2, an ATPase subunit of the SWI/SNF chromatin remodeling complex, associating with the male cis-regulatory element, TGTCT. Further ChIP-seq of PbARID in gsnf2-knockout parasites revealed an association of PbARID with another cis-regulatory element, TGCACA. RIME and DNA-binding assays suggested that HDP1 is the transcription factor that recruits PbARID to the TGCACA motif. Our results indicated that PbARID could function in two chromatin remodeling events and paly essential roles in both male and female gametocyte development.
Topics: Animals; Female; Male; Mice; Chromatin Assembly and Disassembly; Plasmodium berghei; Protozoan Proteins; Transcription Factors; Genotype; Sequence Analysis, RNA; Chromatin; Amino Acid Sequence; Sequence Analysis, Protein; Phylogeny; Transcriptome; Genome, Protozoan
PubMed: 38554111
DOI: 10.1093/nar/gkae207 -
Microorganisms Feb 2024Membranolytic molecules constitute the first line of innate immune defense against pathogenic microorganisms. sporozoites are potentially exposed to these cytotoxic...
Membranolytic molecules constitute the first line of innate immune defense against pathogenic microorganisms. sporozoites are potentially exposed to these cytotoxic molecules in the hemolymph and salivary glands of mosquitoes, as well as in the skin, blood, and liver of the mammalian host. Here, we show that sporozoites are resistant to bacteriolytic concentration of cecropin B, a cationic amphipathic antimicrobial insect peptide. Intriguingly, anti-tumoral cell-penetrating peptides derived from the anti-apoptotic protein AAC11 killed and sporozoites. Using dynamic imaging, we demonstrated that the most cytotoxic peptide, called RT39, did not significantly inhibit the sporozoite motility until the occurrence of a fast permeabilization of the parasite membrane by the peptide. Concomitantly, the cytosolic fluorescent protein constitutively expressed by sporozoites leaked from the treated parasite body while To-Pro 3 and FITC-labeled RT39 internalized, respectively, binding to the nucleic acids and membranes of sporozoites. This led to an increase in the parasite granularity as assessed by flow cytometry. Most permeabilization events started at the parasite's posterior end, resulting in the appearance of a fluorescent dot in the anterior part of sporozoites. Understanding and exploiting the susceptibility of sporozoites and other plasmodial stages to membranolytic molecules might foster strategies to eliminate the parasite and block its transmission.
PubMed: 38543531
DOI: 10.3390/microorganisms12030480 -
Memorias Do Instituto Oswaldo Cruz 2024Malaria is an infectious disease caused by protozoan parasites belonging to the genus Plasmodium. Human-to-human transmission depends on a mosquito vector; thus, the...
BACKGROUND
Malaria is an infectious disease caused by protozoan parasites belonging to the genus Plasmodium. Human-to-human transmission depends on a mosquito vector; thus, the interruption of parasite transmission from humans to mosquitoes is an important approach in the fight against malaria. The parasite stages infectious to mosquitoes are the gametocytes, sexual stages that are ingested by the vector during a blood meal and transform into male and female gametes in the midgut. Immunity against sexual stage antigens expressed by gametocytes, gametes, and the zygote formed after fertilisation can interrupt the parasite sexual cycle in the mosquito. This transmission blocking immunity is mediated by specific antibodies ingested during the mosquito blood feed, inhibiting the parasite development in the midgut. Merozoite thrombospondin related anonymous protein (MTRAP) is a merozoite and gametocyte surface protein essential for gamete egress from erythrocytes and for parasite transmission to mosquitoes.
OBJECTIVES
Here, we evaluated the potential of the P. berghei MTRAP to elicit antibodies with the ability to inhibit gamete fertilisation in vitro.
METHODS
We expressed a soluble recombinant PbMTRAP and used it to immunise BALB/c mice. The transmission blocking activity of the anti-rPbMTRAP antibodies was tested through in vivo challenge experiments followed by in vitro conversion assays.
FINDINGS
Immunisations with the rPbMTRAP induced a strong antibody response and the antibodies recognised the native protein by Western Blot and IFA. Anti-rPbMTRAP present in the blood stream of immunised mice partially inhibited gamete conversion into ookinetes.
CONCLUSION
Our results indicate that antibodies to PbMTRAP may reduce but are not sufficient to completely block transmission.
Topics: Male; Female; Humans; Animals; Mice; Protozoan Proteins; Plasmodium berghei; Merozoites; Malaria; Culicidae
PubMed: 38537036
DOI: 10.1590/0074-02760230217