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International Journal of Molecular... Jun 2024Post-translational modifications (PTMs) are essential for regulating protein functions, influencing various fundamental processes in eukaryotes. These include, but are... (Review)
Review
Post-translational modifications (PTMs) are essential for regulating protein functions, influencing various fundamental processes in eukaryotes. These include, but are not limited to, cell signaling, protein trafficking, the epigenetic control of gene expression, and control of the cell cycle, as well as cell proliferation, differentiation, and interactions between cells. In this review, we discuss protein PTMs that play a key role in the malaria parasite biology and its pathogenesis. Phosphorylation, acetylation, methylation, lipidation and lipoxidation, glycosylation, ubiquitination and sumoylation, nitrosylation and glutathionylation, all of which occur in malarial parasites, are reviewed. We provide information regarding the biological significance of these modifications along all phases of the complex life cycle of spp. Importantly, not only the parasite, but also the host and vector protein PTMs are often crucial for parasite growth and development. In addition to metabolic regulations, protein PTMs can result in epitopes that are able to elicit both innate and adaptive immune responses of the host or vector. We discuss some existing and prospective results from antimalarial drug discovery trials that target various PTM-related processes in the parasite or host.
Topics: Protein Processing, Post-Translational; Life Cycle Stages; Humans; Animals; Protozoan Proteins; Plasmodium; Malaria; Host-Parasite Interactions
PubMed: 38892332
DOI: 10.3390/ijms25116145 -
International Journal of Molecular... May 2024is the only that causes zoonotic disease among the that cause infection in humans. It is fatal due to its short asexual growth cycle within 24 h. Lactate...
is the only that causes zoonotic disease among the that cause infection in humans. It is fatal due to its short asexual growth cycle within 24 h. Lactate dehydrogenase (LDH), an enzyme that catalyzes the final step of glycolysis, is a biomarker for diagnosing infection by spp. parasite. Therefore, this study aimed to efficiently produce the soluble form of LDH (PkLDH) using a bacterial expression system for studying malaria caused by . Recombinant pET-21a(+)- plasmid was constructed by inserting the gene into a pET-21a(+) expression vector. Subsequently, the recombinant plasmid was inserted into the protein-expressing Rosetta(DE3) strain, and the optimal conditions for overexpression of the PkLDH protein were established using this strain. We obtained a yield of 52.0 mg/L PkLDH from the Rosetta(DE3) strain and confirmed an activity of 483.9 U/mg through experiments. This methodology for high-efficiency PkLDH production can be utilized for the development of diagnostic methods and drug candidates for distinguishing malaria caused by .
Topics: Plasmodium knowlesi; L-Lactate Dehydrogenase; Cloning, Molecular; Malaria; Recombinant Proteins; Escherichia coli; Animals; Humans; Gene Expression; Protozoan Proteins
PubMed: 38891805
DOI: 10.3390/ijms25115615 -
Communications Biology Jun 2024Aminoacyl-tRNA synthetases (aaRSs) play a central role in the translation of genetic code, serving as attractive drug targets. Within this family, the lysyl-tRNA...
Aminoacyl-tRNA synthetases (aaRSs) play a central role in the translation of genetic code, serving as attractive drug targets. Within this family, the lysyl-tRNA synthetase (LysRS) constitutes a promising antimalarial target. ASP3026, an anaplastic lymphoma kinase (ALK) inhibitor was recently identified as a novel Plasmodium falciparum LysRS (PfLysRS) inhibitor. Here, based on cocrystal structures and biochemical experiments, we developed a series of ASP3026 analogues to improve the selectivity and potency of LysRS inhibition. The leading compound 36 showed a dissociation constant of 15.9 nM with PfLysRS. The inhibitory efficacy on PfLysRS and parasites has been enhanced. Covalent attachment of L-lysine to compound 36 resulted in compound 36K3, which exhibited further increased inhibitory activity against PfLysRS but significantly decreased activity against ALK. However, its inhibitory activity against parasites did not improve, suggesting potential future optimization directions. This study presents a new example of derivatization of kinase inhibitors repurposed to inhibit aaRS.
Topics: Plasmodium falciparum; Lysine-tRNA Ligase; Protein Kinase Inhibitors; Anaplastic Lymphoma Kinase; Antimalarials; Structure-Activity Relationship; Humans; Protozoan Proteins
PubMed: 38890421
DOI: 10.1038/s42003-024-06455-4 -
Nature Communications Jun 2024With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833),...
With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTART1 binding to the analogues is validated using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assays. Imaging of invading merozoites shows the inhibitors prevent the development of ring-stage parasites potentially by inhibiting the expansion of the encasing parasitophorous vacuole membrane. The PfSTART1-targeting compounds also block transmission to mosquitoes and with multiple stages of the parasite's lifecycle being affected, PfSTART1 represents a drug target with a new mechanism of action.
Topics: Plasmodium falciparum; Acetamides; Protozoan Proteins; Antimalarials; Animals; Carrier Proteins; Mutation; Malaria, Falciparum; Humans; Drug Resistance; Life Cycle Stages
PubMed: 38890312
DOI: 10.1038/s41467-024-49491-8 -
Nature Communications Jun 2024Resistance to clinical malaria takes years to develop even in hyperendemic regions and sterilizing immunity has rarely been observed. To evaluate the maturation of the...
Resistance to clinical malaria takes years to develop even in hyperendemic regions and sterilizing immunity has rarely been observed. To evaluate the maturation of the host response against controlled repeat exposures to P. falciparum (Pf) NF54 strain-infected mosquitoes, we systematically monitored malaria-naïve participants through an initial exposure to uninfected mosquitoes and 4 subsequent homologous exposures to Pf-infected mosquitoes over 21 months (n = 8 males) (ClinicalTrials.gov# NCT03014258). The primary outcome was to determine whether protective immunity against parasite infection develops following repeat CHMI and the secondary outcomes were to track the clinical signs and symptoms of malaria and anti-Pf antibody development following repeat CHMI. After two exposures, time to blood stage patency increases significantly and the number of reported symptoms decreases indicating the development of clinical tolerance. The time to patency correlates positively with both anti-Pf circumsporozoite protein (CSP) IgG and CD8 + CD69+ effector memory T cell levels consistent with partial pre-erythrocytic immunity. IFNγ levels decrease significantly during the participants' second exposure to high blood stage parasitemia and could contribute to the decrease in symptoms. In contrast, CD4-CD8 + T cells expressing CXCR5 and the inhibitory receptor, PD-1, increase significantly after subsequent Pf exposures, possibly dampening the memory response and interfering with the generation of robust sterilizing immunity.
Topics: Humans; Malaria, Falciparum; Plasmodium falciparum; Male; Protozoan Proteins; Animals; Adult; Antibodies, Protozoan; Interferon-gamma; Female; Immunoglobulin G; Young Adult; CD8-Positive T-Lymphocytes; Mosquito Vectors; Anopheles
PubMed: 38890271
DOI: 10.1038/s41467-024-49041-2 -
Expert Review of Vaccines 2024Malaria continues to remain a major global health problem with nearly a quarter of a billion clinical cases and more than 600,000 deaths in 2022. There has been... (Review)
Review
INTRODUCTION
Malaria continues to remain a major global health problem with nearly a quarter of a billion clinical cases and more than 600,000 deaths in 2022. There has been significant progress toward vaccine development, however, poor efficacy of approved vaccines requiring multiple immunizing doses emphasizes the need for continued efforts toward improved vaccines. Progress to date, nonetheless, has provided impetus for malaria elimination.
AREAS COVERED
In this review we will focus on diverse immune mechanisms targeting gametocytes in the human host and gametocyte-mediated malaria transmission via the mosquito vector.
EXPERT OPINION
To march toward the goal of malaria elimination it will be critical to target the process of malaria transmission by mosquitoes, mediated exclusively by the sexual stages, i.e. male, and female gametocytes, ingested from infected vertebrate host. Studies over several decades have established antigens in the parasite sexual stages developing in the mosquito midgut as attractive targets for the development of transmission blocking vaccines (TBVs). Immune clearance of gametocytes in the vertebrate host can synergize with TBVs and directly aid in maintaining effective transmission reducing immune potential.
Topics: Humans; Malaria Vaccines; Animals; Malaria; Vaccine Development; Mosquito Vectors; Plasmodium
PubMed: 38888098
DOI: 10.1080/14760584.2024.2369583 -
EXCLI Journal 2024Malaria has developed as a serious worldwide health issue as a result of the introduction of resistant species strains. Because of the common chemo resistance to most... (Review)
Review
Malaria has developed as a serious worldwide health issue as a result of the introduction of resistant species strains. Because of the common chemo resistance to most of the existing drugs on the market, it poses a severe health problem and significant obstacles in drug research. Malaria treatment has evolved during the last two decades in response to drug sensitivity and a return of the disease in tropical areas. is now highly resistant to the majority of antimalarial drugs. The parasite resistance drew focus to developing novel antimalarials to combat parasite resistance. The requirement for many novel antimalarial drugs in the future year necessitates adopting various drug development methodologies. Different innovative strategies for discovering antimalarial drugs are now being examined here. This review is primarily concerned with the description of newly synthesized antimalarial compounds, i.e. Tafenoquine, Cipargamin, Ferroquine, Artefenomel, DSM265, MMV390048 designed to improve the activity of pure antimalarial enantiomers. In this review, we selected the representative malarial drugs in clinical trials, classified them with detailed targets according to their action, discussed the relationship within the human trials, and generated a summative discussion with prospective expectations.
PubMed: 38887396
DOI: 10.17179/excli2023-6856 -
Parasites & Vectors Jun 2024Malaria transmission in Tanzania is driven by mosquitoes of the Anopheles gambiae complex and Anopheles funestus group. The latter includes An. funestus s.s., an...
BACKGROUND
Malaria transmission in Tanzania is driven by mosquitoes of the Anopheles gambiae complex and Anopheles funestus group. The latter includes An. funestus s.s., an anthropophilic vector, which is now strongly resistant to public health insecticides, and several sibling species, which remain largely understudied despite their potential as secondary vectors. This paper provides the initial results of a cross-country study of the species composition, distribution and malaria transmission potential of members of the Anopheles funestus group in Tanzania.
METHODS
Mosquitoes were collected inside homes in 12 regions across Tanzania between 2018 and 2022 using Centres for Disease Control and Prevention (CDC) light traps and Prokopack aspirators. Polymerase chain reaction (PCR) assays targeting the noncoding internal transcribed spacer 2 (ITS2) and 18S ribosomal DNA (18S rDNA) were used to identify sibling species in the An. funestus group and presence of Plasmodium infections, respectively. Where DNA fragments failed to amplify during PCR, we sequenced the ITS2 region to identify any polymorphisms.
RESULTS
The following sibling species of the An. funestus group were found across Tanzania: An. funestus s.s. (50.3%), An. parensis (11.4%), An. rivulorum (1.1%), An. leesoni (0.3%). Sequencing of the ITS2 region in the nonamplified samples showed that polymorphisms at the priming sites of standard species-specific primers obstructed PCR amplification, although the ITS2 sequences closely matched those of An. funestus s.s., barring these polymorphisms. Of the 914 samples tested for Plasmodium infections, 11 An. funestus s.s. (1.2%), and 2 An. parensis (0.2%) individuals were confirmed positive for P. falciparum. The highest malaria transmission intensities [entomological inoculation rate (EIR)] contributed by the Funestus group were in the north-western region [108.3 infectious bites/person/year (ib/p/y)] and the south-eastern region (72.2 ib/p/y).
CONCLUSIONS
Whereas An. funestus s.s. is the dominant malaria vector in the Funestus group in Tanzania, this survey confirms the occurrence of Plasmodium-infected An. parensis, an observation previously made in at least two other occasions in the country. The findings indicate the need to better understand the ecology and vectorial capacity of this and other secondary malaria vectors in the region to improve malaria control.
Topics: Anopheles; Animals; Tanzania; Mosquito Vectors; Malaria; Humans; RNA, Ribosomal, 18S; Polymerase Chain Reaction; Female; Plasmodium; DNA, Ribosomal Spacer
PubMed: 38886827
DOI: 10.1186/s13071-024-06348-9 -
JMIR Public Health and Surveillance Jun 2024The biological characteristics of mosquito vectors vary, impacting their response to control measures. Thus, having up-to-date information on vector bionomics is...
BACKGROUND
The biological characteristics of mosquito vectors vary, impacting their response to control measures. Thus, having up-to-date information on vector bionomics is essential to maintain the effectiveness of existing control strategies and tools, particularly as India aims for malaria elimination by 2030.
OBJECTIVE
This study aims to assess the proportions of vector species resting indoors and outdoors, determine their preference for host biting/feeding, identify transmission sites, and evaluate the susceptibility of vectors to insecticides used in public health programs.
METHODS
Mosquito collections were conducted in 13 districts across 8 Indian states from 2017 to 2020 using various methods to estimate their densities. Following morphological identification in the field, sibling species of Anopheles mosquitoes were identified molecularly using polymerase chain reaction (PCR)-specific alleles. Plasmodium falciparum and Plasmodium vivax infections in the vectors were detected using enzyme-linked immunosorbent assay (ELISA) and PCR assays. In addition, we assessed the insecticide susceptibility status of primary malaria vectors following the World Health Organization (WHO) protocol.
RESULTS
Anopheles culicifacies, a primary malaria vector, was collected (with a man-hour density ranging from 3.1 to 15.9) from all states of India except those in the northeastern region. Anopheles fluviatilis, another primary vector, was collected from the states of Madhya Pradesh, Maharashtra, Karnataka, and Odisha. In Haryana and Karnataka, An. culicifacies sibling species A predominated, whereas species C and E were predominant in Madhya Pradesh and Maharashtra. An. culicifacies displayed mainly endophilic behavior across all states, except in Madhya Pradesh, where the proportion of semigravid and gravid mosquitoes was nearly half of that of unfed mosquitoes. The human blood index of An. culicifacies ranged from 0.001 to 0.220 across all study sites. The sporozoite rate of An. culicifacies ranged from 0.06 to 4.24, except in Madhya Pradesh, where none of the vector mosquitoes were found to be infected with the Plasmodium parasite. In the study area, An. culicifacies exhibited resistance to DDT (dichlorodiphenyltrichloroethane; with <39% mortality). Moreover, it showed resistance to malathion (with mortality rates ranging from 49% to 78%) in all districts except Angul in Odisha and Palwal in Haryana. In addition, resistance to deltamethrin was observed in districts of Maharashtra, Gujarat, Haryana, and Karnataka.
CONCLUSIONS
Our study offers vital insights into the prevalence, resting behavior, and sibling species composition of malaria vectors in India. It is evident from our findings that resistance development in An. culicifacies, the primary vector, to synthetic pyrethroids is on the rise in the country. Furthermore, the results of our study suggest a potential change in the resting behavior of An. culicifacies in Madhya Pradesh, although further studies are required to confirm this shift definitively. These findings are essential for the development of effective vector control strategies in India, aligning with the goal of malaria elimination by 2030.
Topics: India; Animals; Mosquito Vectors; Malaria; Anopheles; Humans; Disease Eradication; Insecticides; Insecticide Resistance; Ecology
PubMed: 38885497
DOI: 10.2196/42050 -
F1000Research 2022Malaria in pregnancy leads to placental malaria. The primary pathogenesis of the complex fetal implications in placental malaria is tissue hypoxia due to sequestrations...
BACKGROUND
Malaria in pregnancy leads to placental malaria. The primary pathogenesis of the complex fetal implications in placental malaria is tissue hypoxia due to sequestrations of -infected erythrocytes in the placenta. However, the pathomechanism of placental infection has not been thoroughly investigated. Hypoxia-inducible factor-1α (HIF-1α) is a key transcriptional mediator of the response to hypoxic conditions, which interacts with the change and imbalances of many chemical mediators, including angiogenic factors, leading to fetal growth abnormality.
METHODS
This study was conducted cross-sectionally in Maumere, Sikka Regency, East Nusa Tenggara Province, previously known as one of the malaria endemic areas with a high incidence of low birth weight (LBW) cases. This study collected peripheral and umbilical blood samples and placental tissues from mothers who delivered their babies with LBW at the TC Hiller Regional Hospital. All of the blood samples were examined for parasites by microscopic and PCR techniques, while the plasma levels of VEGF, PlGF, VEGFR-1, VEGFR-2, and HIF-1α were determined using ELISA. The sequestration of infected erythrocytes and hemozoin was determined from placental histological slides, and the expression of placenta angiogenic factors was observed using the immunofluorescent technique.
RESULTS
In this study, 33 cases had complete data to be analyzed. Of them, 19 samples were diagnosed as vivax malaria and none of falciparum malaria. There were significant differences in Δ 10th percentile growth curve of baby's body weights and also all angiogenic factors in placental tissues {VEGF, PlGF, and VEGFR-1, VEGFR-2, and HIF-1α} between those infected and not infected cases (p<0.05), but not for VEGF and VEGFR-2 in the plasma.
CONCLUSION
This study indicated that sequestration may promote LBW through alterations and imbalances in angiogenic factors led by HIF-1α.
Topics: Humans; Female; Hypoxia-Inducible Factor 1, alpha Subunit; Malaria, Vivax; Pregnancy; Infant, Low Birth Weight; Placenta; Adult; Plasmodium vivax; Infant, Newborn; Angiogenesis Inducing Agents; Vascular Endothelial Growth Factor A; Pregnancy Complications, Parasitic; Cross-Sectional Studies; Vascular Endothelial Growth Factor Receptor-1
PubMed: 38884107
DOI: 10.12688/f1000research.73820.3