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Frontiers in Cellular and Infection... 2021Malaria, a disease caused by the protozoan parasites spp., is still causing serious problems in endemic regions in the world. Although the WHO recommends artemisinin... (Review)
Review
Malaria, a disease caused by the protozoan parasites spp., is still causing serious problems in endemic regions in the world. Although the WHO recommends artemisinin combination therapies for the treatment of malaria patients, the emergence of artemisinin-resistant parasites has become a serious issue and underscores the need for the development of new antimalarial drugs. On the other hand, new and re-emergences of infectious diseases, such as the influenza pandemic, Ebola virus disease, and COVID-19, are urging the world to develop effective chemotherapeutic agents against the causative viruses, which are not achieved to the desired level yet. In this review article, we describe existing drugs which are active against both spp. and microorganisms including viruses, bacteria, and fungi. We also focus on the current knowledge about the mechanism of actions of these drugs. Our major aims of this article are to describe examples of drugs that kill both parasites and other microbes and to provide valuable information to help find new ideas for developing novel drugs, rather than merely augmenting already existing drug repurposing efforts.
Topics: COVID-19; Drug Development; Humans; Pharmaceutical Preparations; Plasmodium; Plasmodium falciparum; SARS-CoV-2
PubMed: 35004357
DOI: 10.3389/fcimb.2021.797509 -
Frontiers in Bioscience (Landmark... Mar 2020Infectious diseases caused by numerous parasitic pathogens represent a global health conundrum. Several animal and plant pathogens are responsible for causing acute... (Review)
Review
Infectious diseases caused by numerous parasitic pathogens represent a global health conundrum. Several animal and plant pathogens are responsible for causing acute illness in humans and deadly plant infections. These pathogens have evolved a diverse array of infection strategies and survival methods within the host organism. Recent research has highlighted the role of protein kinases in the overall virulence and pathogenicity of the pathogens. Protein kinases (Pks) are a group of enzymes known to catalyse the phosphorylation of a wide variety of cellular substrates involved in different signalling cascades. They are also involved in regulating pathogen life cycle and infectivity. In this review, we attempt to address the role of parasite kinome in host infection, pathogen survival within the host tissue and thereby disease manifestation. The understanding of the parasite kinome can be a potential target for robust diagnosis and effective therapeutics.
Topics: Animals; Bacteria; Fungi; Host-Pathogen Interactions; Humans; Nematoda; Phosphorylation; Plant Diseases; Plasmodium; Protein Kinases; Virulence
PubMed: 32114442
DOI: 10.2741/4865 -
Cell Chemical Biology Feb 2022Acetyl-coenzyme A is an important metabolite and regulates diverse cellular processes, including metabolism and epigenetics. In this issue of Cell Chemical Biology,...
Acetyl-coenzyme A is an important metabolite and regulates diverse cellular processes, including metabolism and epigenetics. In this issue of Cell Chemical Biology, Summers et al. (2022) describe an essential parasite enzyme, acetyl-coenzyme A synthetase, as a target of two antimalarial small molecules active against liver and blood stages of the parasite.
Topics: Acetyl Coenzyme A; Animals; Antimalarials; Parasites; Plasmodium; Plasmodium falciparum
PubMed: 35180431
DOI: 10.1016/j.chembiol.2022.02.003 -
Malaria Journal Nov 2021Malaria is a complex parasitic disease, caused by Plasmodium spp. More than a century after the discovery of malaria parasites, this disease continues to pose a global... (Review)
Review
Malaria is a complex parasitic disease, caused by Plasmodium spp. More than a century after the discovery of malaria parasites, this disease continues to pose a global public health problem and the pathogenesis of the severe forms of malaria remains incompletely understood. Extracellular vesicles (EVs), including exosomes and microvesicles, have been increasingly researched in the field of malaria in a bid to fill these knowledge gaps. EVs released from Plasmodium-infected red blood cells and other host cells during malaria infection are now believed to play key roles in disease pathogenesis and are suggested as vital components of the biology of Plasmodium spp. Malaria-derived EVs have been identified as potential disease biomarkers and therapeutic tools. In this review, key findings of malaria EV studies over the last 20 years are summarized and critically analysed. Outstanding areas of research into EV biology are identified. Unexplored EV research foci for the future that will contribute to consolidating the potential for EVs as agents in malaria prevention and control are proposed.
Topics: Extracellular Vesicles; Humans; Malaria; Plasmodium
PubMed: 34801056
DOI: 10.1186/s12936-021-03969-8 -
Malaria Journal Apr 2017Parasite resistance to anti-malarials represents a great obstacle for malaria elimination. The majority of studies have investigated the association between... (Review)
Review
Assessment of copy number variation in genes related to drug resistance in Plasmodium vivax and Plasmodium falciparum isolates from the Brazilian Amazon and a systematic review of the literature.
BACKGROUND
Parasite resistance to anti-malarials represents a great obstacle for malaria elimination. The majority of studies have investigated the association between single-nucleotide polymorphisms (SNPs) and drug resistance; however, it is becoming clear that the copy number variation (CNV) is also associated with this parasite phenotype. To provide a baseline for molecular surveillance of anti-malarial drug resistance in the Brazilian Amazon, the present study characterized the genetic profile of both markers in the most common genes associated with drug resistance in Plasmodium falciparum and Plasmodium vivax isolates. Additionally, these data were compared to data published elsewhere applying a systematic review of the literature published over a 20-year time period.
METHODS
The genomic DNA of 67 patients infected by P. falciparum and P. vivax from three Brazilian States was obtained between 2002 and 2012. CNV in P. falciparum multidrug resistance gene-1 (pfmdr1), GTP cyclohydrolase 1 (pfgch1) and P. vivax multidrug resistance gene-1 (pvmdr1) were assessed by real-time PCR assays. SNPs in the pfmdr1 and pfcrt genes were assessed by PCR-RFLP. A literature search for studies that analysed CNP in the same genes of P. falciparum and P. vivax was conducted between May 2014 and March 2017 across four databases.
RESULTS
All analysed samples of P. falciparum carried only one copy of pfmdr1 or pfgch1. Although the pfcrt K76T polymorphism, a determinant of CQ resistance, was present in all samples genotyped, the pfmdr1 N86Y was absent. For P. vivax isolates, an amplification rate of 20% was found for the pvmdr1 gene. The results of the study are in agreement with the low amplification rates for pfmdr1 gene evidenced in the Americas and Africa, while higher rates have been described in Southeast Asia. For P. vivax, very low rates of amplification for pvmdr1 have been described worldwide, with exceptions in French Guiana, Cambodia, Thailand and Brazil.
CONCLUSIONS
The present study was the first to evaluate gch1 CNV in P. falciparum isolates from Brazil, showing an absence of amplification of this gene more than 20 years after the withdrawal of the Brazilian antifolates therapeutic scheme. Furthermore, the rate of pvmdr1 amplification was significantly higher than that previously reported for isolates circulating in Northern Brazil.
Topics: Adult; Brazil; Drug Resistance; Female; Gene Dosage; Gene Frequency; Humans; Male; Middle Aged; Plasmodium falciparum; Plasmodium vivax; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Protozoan Proteins; Real-Time Polymerase Chain Reaction
PubMed: 28420389
DOI: 10.1186/s12936-017-1806-z -
The EMBO Journal Aug 2019Microtubules are cytoskeletal filaments essential for many cellular processes, including establishment and maintenance of polarity, intracellular transport, division and...
Microtubules are cytoskeletal filaments essential for many cellular processes, including establishment and maintenance of polarity, intracellular transport, division and migration. In most metazoan cells, the number and length of microtubules are highly variable, while they can be precisely defined in some protozoan organisms. However, in either case the significance of these two key parameters for cells is not known. Here, we quantitatively studied the impact of modulating microtubule number and length in Plasmodium, the protozoan parasite causing malaria. Using a gene deletion and replacement strategy targeting one out of two α-tubulin genes, we show that chromosome segregation proceeds in the oocysts even in the absence of microtubules. However, fewer and shorter microtubules severely impaired the formation, motility and infectivity of Plasmodium sporozoites, the forms transmitted by the mosquito, which usually contain 16 microtubules. We found that α-tubulin expression levels directly determined the number of microtubules, suggesting a high nucleation barrier as supported by a mathematical model. Infectious sporozoites were only formed in parasite lines featuring at least 10 microtubules, while parasites with 9 or fewer microtubules failed to transmit.
Topics: Animals; Gene Deletion; Malaria; Mice; Models, Theoretical; Plasmodium; Protozoan Proteins; Sporozoites; Tubulin
PubMed: 31368598
DOI: 10.15252/embj.2018100984 -
Briefings in Functional Genomics Sep 2019Malaria parasites are characterized by a complex life cycle that is accompanied by dynamic gene expression patterns. The factors and mechanisms that regulate gene... (Review)
Review
Malaria parasites are characterized by a complex life cycle that is accompanied by dynamic gene expression patterns. The factors and mechanisms that regulate gene expression in these parasites have been searched for even before the advent of next generation sequencing technologies. Functional genomics approaches have substantially boosted this area of research and have yielded significant insights into the interplay between epigenetic, transcriptional and post-transcriptional mechanisms. Recently, considerable progress has been made in identifying sequence-specific transcription factors and DNA-encoded regulatory elements. Here, we review the insights obtained from these efforts including the characterization of core promoters, the involvement of sequence-specific transcription factors in life cycle progression and the mapping of gene regulatory elements. Furthermore, we discuss recent developments in the field of functional genomics and how they might contribute to further characterization of this complex gene regulatory network.
Topics: Gene Expression Regulation; Gene Regulatory Networks; Genomics; Life Cycle Stages; Plasmodium; Promoter Regions, Genetic; Regulatory Elements, Transcriptional; Transcription Factors
PubMed: 31220867
DOI: 10.1093/bfgp/elz004 -
Disease Models & Mechanisms Dec 2019Malaria is an infectious disease caused by parasitic protozoa in the genus. A complete understanding of the biology of these parasites is challenging in view of their... (Review)
Review
Malaria is an infectious disease caused by parasitic protozoa in the genus. A complete understanding of the biology of these parasites is challenging in view of their need to switch between the vertebrate and insect hosts. The parasites are also capable of becoming highly motile and of remaining dormant for decades, depending on the stage of their life cycle. Malaria elimination efforts have been implemented in several endemic countries, but the parasites have proven to be resilient. One of the major obstacles for malaria elimination is the development of antimalarial drug resistance. Ineffective treatment regimens will fail to remove the circulating parasites and to prevent the local transmission of the disease. Genomic epidemiology of malaria parasites has become a powerful tool to track emerging drug-resistant parasite populations almost in real time. Population-scale genomic data are instrumental in tracking the hidden pockets of in nationwide elimination efforts. However, genomic surveillance data can be useful in determining the threat only when combined with a thorough understanding of the malarial resistome - the genetic repertoires responsible for causing and potentiating drug resistance evolution. Even though long-term selection has been a standard method for drug target identification in laboratories, its implementation in large-scale exploration of the druggable space in , along with genome-editing technologies, have enabled mapping of the genetic repertoires that drive drug resistance. This Review presents examples of practical use and describes the latest technology to show the power of real-time genomic epidemiology in achieving malaria elimination.
Topics: Animals; Antimalarials; Culicidae; Disease Eradication; Drug Resistance; Genomics; Humans; International Cooperation; Malaria; Molecular Epidemiology; Mutation; Plasmodium; Plasmodium falciparum
PubMed: 31874839
DOI: 10.1242/dmm.040717 -
The FEBS Journal Jun 2022In the last few decades, considerable efforts have been made toward the development of efficient vaccines against malaria. Whole-sporozoite (Wsp) vaccines, which induce... (Review)
Review
In the last few decades, considerable efforts have been made toward the development of efficient vaccines against malaria. Whole-sporozoite (Wsp) vaccines, which induce efficient immune responses against the pre-erythrocytic (PE) stages (sporozoites and liver forms) of Plasmodium parasites, the causative agents of malaria, are among the most promising immunization strategies tested until present. Several Wsp PE vaccination approaches are currently under evaluation in the clinic, including radiation- or genetically-attenuated Plasmodium sporozoites, live parasites combined with chemoprophylaxis, or genetically modified rodent Plasmodium parasites. In addition to the assessment of their protective efficacy, clinical trials of Wsp PE vaccine candidates inevitably involve the thorough investigation of the immune responses elicited by vaccination, as well as the identification of correlates of protection. Here, we review the main methodologies employed to dissect the humoral and cellular immune responses observed in the context of Wsp PE vaccine clinical trials and discuss future strategies to further deepen the knowledge generated by these studies, providing a toolbox for the in-depth analysis of vaccine-induced immunogenicity.
Topics: Animals; Immunity, Cellular; Malaria; Malaria Vaccines; Plasmodium; Plasmodium falciparum; Sporozoites
PubMed: 33993649
DOI: 10.1111/febs.16016 -
Current Opinion in Microbiology Dec 2017Complete and long-lasting protective immunity against malaria can be achieved through vaccination with invasive live attenuated Plasmodium sporozoites, the motile stage... (Review)
Review
Complete and long-lasting protective immunity against malaria can be achieved through vaccination with invasive live attenuated Plasmodium sporozoites, the motile stage inoculated in the host skin during a mosquito bite. Protective immunity relies primarily on effector CD8 T cells targeting the parasite in the liver. Understanding the tissue-specific features of the immune response is emerging as a vital requirement for understanding protective immunity. The small parasite inoculum, the scarcity of infected cells and the tolerogenic properties of the liver represent hurdles for the establishment of protective immunity in endemic areas. In this review, we discuss recent advances on liver-specific features of immunity including innate recognition of malaria pre-erythrocytic stages, CD8 T cell interactions with infected hepatocytes, antigen presentation for effective CD8 T cell responses and generation of liver-resident memory CD8 T cells. A better understanding of the factors involved in the induction and maintenance of effector CD8 T cell immunity against malaria pre-erythrocytic stages is crucial for the development of an effective vaccine targeting the initial phase of malaria infection.
Topics: Animals; Erythrocytes; Humans; Immunity, Cellular; Liver; Malaria; Organ Specificity; Plasmodium; Sporozoites
PubMed: 29217460
DOI: 10.1016/j.mib.2017.12.001