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Pathogens (Basel, Switzerland) Oct 2023Human African trypanosomiasis (also known as sleeping sickness, with and as etiological agents), American trypanosomiasis (also known as Chagas disease, with as the...
Human African trypanosomiasis (also known as sleeping sickness, with and as etiological agents), American trypanosomiasis (also known as Chagas disease, with as the etiological agent), and leishmaniasis (including cutaneous, mucocutaneous, and visceral forms, with multiple species belonging to the genus as etiological agents) are recognized as neglected tropical diseases (NTDs) [...].
PubMed: 37887779
DOI: 10.3390/pathogens12101263 -
Science (New York, N.Y.) Jun 2023Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease and human African trypanosomiasis (HAT)....
Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease and human African trypanosomiasis (HAT). Improved HAT treatments are available, but Chagas disease therapies rely on two nitroheterocycles, which suffer from lengthy drug regimens and safety concerns that cause frequent treatment discontinuation. We performed phenotypic screening against trypanosomes and identified a class of cyanotriazoles (CTs) with potent trypanocidal activity both in vitro and in mouse models of Chagas disease and HAT. Cryo-electron microscopy approaches confirmed that CT compounds acted through selective, irreversible inhibition of trypanosomal topoisomerase II by stabilizing double-stranded DNA:enzyme cleavage complexes. These findings suggest a potential approach toward successful therapeutics for the treatment of Chagas disease.
Topics: Animals; Humans; Mice; Chagas Disease; Cryoelectron Microscopy; DNA Topoisomerases, Type II; Trypanosoma; Topoisomerase II Inhibitors; Triazoles; Trypanosomiasis, African; Drug Evaluation, Preclinical
PubMed: 37384702
DOI: 10.1126/science.adh0614 -
FEMS Microbiology Reviews Nov 2023Mitochondrial DNA replication is an essential process in most eukaryotes. Similar to the diversity in mitochondrial genome size and organization in the different... (Review)
Review
Mitochondrial DNA replication is an essential process in most eukaryotes. Similar to the diversity in mitochondrial genome size and organization in the different eukaryotic supergroups, there is considerable diversity in the replication process of the mitochondrial DNA. In this review, we summarize the current knowledge of mitochondrial DNA replication and the associated factors in trypanosomes with a focus on Trypanosoma brucei, and provide a new model of minicircle replication for this protozoan parasite. The model assumes the mitochondrial DNA (kinetoplast DNA, kDNA) of T. brucei to be loosely diploid in nature and the replication of the genome to occur at two replication centers at the opposing ends of the kDNA disc (also known as antipodal sites, APS). The new model is consistent with the localization of most replication factors and in contrast to the current model, it does not require the assumption of an unknown sorting and transport complex moving freshly replicated DNA to the APS. In combination with the previously proposed sexual stages of the parasite in the insect vector, the new model provides a mechanism for maintenance of the mitochondrial genetic diversity.
Topics: DNA, Kinetoplast; Genome, Mitochondrial; DNA Replication; DNA, Mitochondrial; Mitochondria; Protozoan Proteins
PubMed: 36449697
DOI: 10.1093/femsre/fuac047 -
Tropical Medicine and Infectious Disease Dec 2023Chagas disease is currently present in many non-endemic countries and remains a neglected tropical disease globally. A review of the literature identified significant... (Review)
Review
Chagas disease is currently present in many non-endemic countries and remains a neglected tropical disease globally. A review of the literature identified significant gaps and scarcity of updated information from European countries, with most studies reporting data from Spain and Italy. The index of underdiagnosis may be as high as 70%, affecting mainly females of child-bearing age. Standardized screening of fertile, non-pregnant, women from endemic countries and subsequent treatment is considered an essential strategy to control transmission and prevent new cases, yet no uniform legislation for screening risk groups exists. There is heterogeneity in Europe in terms of preventive strategies to avoid transfusion-related transmission of Chagas disease, not necessarily in line with the European directives, with some countries conducting systematic screening for infection in blood donors, whilst others rely on pre-transfusion questionnaires. The growing burden of the infection in resource-rich areas may provide an opportunity for progress in certain aspects of control and prevention. Options for improving screening strategies, management and linkage to care are reviewed.
PubMed: 38133445
DOI: 10.3390/tropicalmed8120513 -
Revista Da Sociedade Brasileira de... 2023
Topics: Humans; Trypanosoma cruzi; Coinfection; HIV Infections
PubMed: 38088667
DOI: 10.1590/0037-8682-0549-2023 -
Tropical Medicine and Infectious Disease Aug 2023Chagas disease is an emerging and neglected tropical disease caused by the protozoan parasite estimated to infect 8 to 10 million people worldwide, according to the...
Chagas disease is an emerging and neglected tropical disease caused by the protozoan parasite estimated to infect 8 to 10 million people worldwide, according to the World Health Organization [...].
PubMed: 37624333
DOI: 10.3390/tropicalmed8080395 -
Frontiers in Molecular Biosciences 2023Telomere maintenance is essential for genome integrity and chromosome stability in eukaryotic cells harboring linear chromosomes, as telomere forms a specialized... (Review)
Review
Telomere maintenance is essential for genome integrity and chromosome stability in eukaryotic cells harboring linear chromosomes, as telomere forms a specialized structure to mask the natural chromosome ends from DNA damage repair machineries and to prevent nucleolytic degradation of the telomeric DNA. In and several other microbial pathogens, virulence genes involved in antigenic variation, a key pathogenesis mechanism essential for host immune evasion and long-term infections, are located at subtelomeres, and expression and switching of these major surface antigens are regulated by telomere proteins and the telomere structure. Therefore, understanding telomere maintenance mechanisms and how these pathogens achieve a balance between stability and plasticity at telomere/subtelomere will help develop better means to eradicate human diseases caused by these pathogens. Telomere replication faces several challenges, and the "end replication problem" is a key obstacle that can cause progressive telomere shortening in proliferating cells. To overcome this challenge, most eukaryotes use telomerase to extend the G-rich telomere strand. In addition, a number of telomere proteins use sophisticated mechanisms to coordinate the telomerase-mediated telomere G-strand synthesis and the telomere C-strand fill-in, which has been extensively studied in mammalian cells. However, we recently discovered that trypanosomes lack many telomere proteins identified in its mammalian host that are critical for telomere end processing. Rather, uses a unique DNA polymerase, PolIE that belongs to the DNA polymerase A family ( DNA PolI family), to coordinate the telomere G- and C-strand syntheses. In this review, I will first briefly summarize current understanding of telomere end processing in mammals. Subsequently, I will describe PolIE-mediated coordination of telomere G- and C-strand synthesis in and implication of this recent discovery.
PubMed: 38074093
DOI: 10.3389/fmolb.2023.1302557