Article
Microbiology
Emilia Jane McLaughlin, Karinna Rubio-Pena, Annick Dujeancourt-Henry, Lucy Glover
Summary: This study aimed to disrupt monoallelic VSG expression and found that the DNA sequence of the ectopic VSG is lost in a transcription-dependent manner following DSB-triggered VSG switching. The loss of the ectopic VSG does not disrupt the number or variety of templates used for BES DSB repair, revealing strict mechanisms within the cell to reinforce monoallelic expression during antigenic variation.
Article
Cell Biology
Eliane Tihon, Karinna Rubio-Pena, Annick Dujeancourt-Henry, Aline Crouzols, Brice Rotureau, Lucy Glover
Summary: The life cycle of Trypanosoma brucei alternates between the tsetse fly vector and the mammalian host, and the infectivity to the host depends on the expression of metacyclic variant surface glycoprotein genes. This study reveals the role of VEX1 in the metacyclic differentiation process and its impact on the infectivity of T. brucei to mammalian hosts.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Biology
Desislava P. Staneva, Stefan Bresson, Tatsiana Auchynnikava, Christos Spanos, Juri Rappsilber, A. Arockia Jeyaprakash, David Tollervey, Keith R. Matthews, Robin C. Allshire
Summary: This study reveals the unique gene expression regulation mechanism in kinetoplastids, a highly divergent lineage of eukaryotes. The researchers identified a complex called SPARC, which consists of SET27 and CRD1, among other components, that is involved in establishing accurate promoter position and directionality.
Article
Biochemistry & Molecular Biology
Isabella E. Maudlin, Steve Kelly, Angela Schwede, Mark Carrington
Summary: The bloodstream form of Trypanosoma brucei relies on antigenic variation of a cell surface coat composed of variant surface glycoprotein (VSG) for survival in mammalian hosts, with the integrity of the VSG coat being crucial for its persistence. Investigation into the regulation of VSG mRNA levels revealed that the copy number varies with the identity of the VSG and that a pathway detects synthesis of non-functional VSG protein, leading to an increase in VSG mRNA levels.
MOLECULAR AND BIOCHEMICAL PARASITOLOGY
(2021)
Article
Multidisciplinary Sciences
Franziskla K. Geis, Yosef Sabo, Xiao Chen, Yinglu Li, Chao Lu, Stephen P. Goff
Summary: This study identifies CHAF1A and CHAF1B as factors involved specifically in silencing of HIV-1 DNAs early in infection, and these two proteins mediate the silencing of newly synthesized HIV-1 DNAs through noncanonical pathways.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Cell Biology
Kyung Yong Lee, Anindya Dutta
Summary: The cell-cycle phase plays a crucial role in determining repair pathway choice at DNA double-strand breaks, with Chk1 promoting non-homologous end joining (NHEJ) repair in the G1 phase. ASF1A, a histone chaperone, also promotes NHEJ independently of its chaperone activity. Chk1 phosphorylates ASF1A at Ser-166 in G1, enhancing its interaction with the repair protein MDC1 and promoting NHEJ repair.
Review
Microbiology
Bibo Li, Yanxiang Zhao
Summary: Trypanosoma brucei regularly switches its major surface antigen to evade host immune response, with telomere and subtelomere structure integrity being crucial for its survival and pathogenesis. Telomere proteins TRF and RAP1, with unique nucleic acid binding activities, play key roles in VSG expression and switching. Targeting TbTRF and TbRAP1's nucleic acid binding activities may serve as a potential therapeutic strategy against T. brucei.
Article
Cell Biology
Hee-Sook Kim
Summary: In Trypanosoma brucei, genes are arranged in polycistronic transcription units, with transcription termination sites being crucial for controlling mRNA production. Three chromatin factors, H3v, H4v, and base J, contribute to the regulation of transcription termination sites in a coordinated manner, with H4v playing a major role in this process.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Virology
Shirin Sultana, Fauzia Zarreen, Supriya Chakraborty
Summary: Histone chaperones play a crucial role in nucleosome assembly and disassembly on virus genomes. The interaction between viral proteins and histone chaperones is implicated in the integration of virus genomes into host genomes. Understanding the role of histone chaperones in viruses with DNA or RNA genomes is essential for governing viral pathogenesis.
Article
Biochemistry & Molecular Biology
Miebaka Jamabo, Stephen John Bentley, Paula Macucule-Tinga, Praise Tembo, Adrienne Lesley Edkins, Aileen Boshoff
Summary: This study provides an in silico overview of HSP90 and its co-chaperones in African trypanosomes. Structural and phylogenetic analysis revealed differences in HSP90 proteins between different trypanosome species. The study also identified putative HSP90 genes and co-chaperones, providing an updated framework for drug target research in African trypanosomes.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Review
Parasitology
Joana R. C. Faria
Summary: African trypanosomes are early divergent protozoan parasites responsible for high mortality and morbidity as well as a great economic burden among the world's poorest populations. Understanding the mechanisms underpinning antigen as well as general gene expression control is crucial for designing effective control strategies against these organisms. Recent technological developments have advanced our understanding of nuclear organization and gene expression control in trypanosomes, opening novel research avenues.
Article
Biochemistry & Molecular Biology
Anna Trenaman, Lucy Glover, Sebastian Hutchinson, David Horn
NUCLEIC ACIDS RESEARCH
(2019)
Article
Biochemistry & Molecular Biology
Martin Zoltner, Gustavo D. Campagnaro, Gergana Taleva, Alana Burrell, Michela Cerone, Ka-Fai Leung, Fiona Achcar, David Horn, Sue Vaughan, Catarina Gadelha, Alena Zikova, Michael P. Barrett, Harry P. de Koning, Mark C. Field
JOURNAL OF BIOLOGICAL CHEMISTRY
(2020)
Article
Microbiology
Joana Faria, Vanessa Luzak, Laura S. M. Muller, Benedikt G. Brink, Sebastian Hutchinson, Lucy Glover, David Horn, T. Nicolai Siegel
Summary: The study reveals a mechanism in Trypanosoma brucei where a single expressed antigen-coding gene interacts with a major messenger RNA splicing locus in a specific nuclear compartment, ensuring monogenic expression. Specific proteins VEX1 and VEX2 are associated with an antigen exclusion complex, playing a role in this process of antigen transcription and mRNA splicing. Depletion of VEX2 results in loss of monogenic antigen expression and increased interactions between previously silent antigen genes and the splicing locus.
NATURE MICROBIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Carys Davies, Cher-Pheng Ooi, Georgios Sioutas, Belinda S. Hall, Haneesh Sidhu, Falk Butter, Sam Alsford, Bill Wickstead, Gloria Rudenko
Summary: The African trypanosome Trypanosoma brucei relies on a protective VSG coat for survival in mammalian hosts. A whole genome RNAi library screen identified a novel DNA binding protein TbSAP, which plays an important role in silencing the extensive VSG repertoire in bloodstream form T. brucei.
NUCLEIC ACIDS RESEARCH
(2021)
Review
Parasitology
David Horn
Summary: Genome-scale genetic screens have played a crucial role in African trypanosomes by uncovering mechanisms related to drug resistance, metabolism, and gene expression control. They have also been effective in identifying potential antitrypanosomal drug targets.
TRENDS IN PARASITOLOGY
(2022)
Article
Multidisciplinary Sciences
Yanika Borg, Sam Alsford, Vasos Pavlika, Alexei Zaikin, Darren N. Nesbeth
Summary: Kinetoplastid protozoa, with unique properties, have been shown to hold bioengineering potential. This study successfully constructed an oscillatory gene network in Trypanosoma brucei for the first time, laying the foundation for future synthetic biology research.
Article
Biochemistry & Molecular Biology
Simone Altmann, Eva Rico, Sandra Carvalho, Melanie Ridgway, Anna Trenaman, Hannah Donnelly, Michele Tinti, Susan Wyllie, David Horn
Summary: This study reports a simple method for rapid and precise editing of priority drug targets in trypanosomatids. By targeting and editing drug targets, combined with sequencing technology, potential impacts on drug efficacy can be assessed quickly.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Microbiology
Gustavo Bravo Ruiz, Michele Tinti, Melanie Ridgway, David Horn
Summary: VSG expression plays a crucial role in parasite virulence and is a fascinating subject in extreme biology. This study identified three candidate VSG regulators and demonstrated the role of CFB2 in controlling VSG expression through the VSG 3' UTR. Additionally, insights into the connections between VSG expression control, ribosomal protein expression, and cytokinesis were revealed.
Correction
Microbiology
Manu De Rycker, Susan Wyllie, David Horn, Kevin D. Read, Ian H. Gilbert
NATURE REVIEWS MICROBIOLOGY
(2022)
Review
Microbiology
Manu De Rycker, Susan Wyllie, David Horn, Kevin D. Read, Ian H. Gilbert
Summary: Leishmaniasis, Chagas disease, and human African trypanosomiasis are major causes of death and illness, particularly in low- and middle-income countries. The development of new medicines for leishmaniasis and Chagas disease is urgently needed, with limited progress in the clinical pipeline for Chagas disease. This review provides an overview of recent advances in understanding the biology of these pathogens, with a focus on drug discovery, as well as the development of new drug candidates and potential solutions to overcome challenges in clinical development.
NATURE REVIEWS MICROBIOLOGY
(2023)
Article
Multidisciplinary Sciences
Catarina A. Marques, Melanie Ridgway, Michele Tinti, Andrew Cassidy, David Horn
Summary: In this study, a genome-wide RNA-interference library screen was used to investigate the cell cycle defects in Trypanosoma brucei. The results provide comprehensive functional genomic evidence for the known and novel machineries, pathways, and regulators that coordinate trypanosome cell cycle progression.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Medicinal
Livio Racane, Lucija Pticek, Sanja Kostrun, Silvana Raic-Malic, Martin Craig Taylor, Michael Delves, Sam Alsford, Francisco Olmo, Amanda Fortes Francisco, John M. Kelly
Summary: We designed and synthesized a series of symmetric benzothiazole derivatives and evaluated their efficacy against Trypanosoma brucei and Plasmodium falciparum. One compound showed high selectivity and trypanocidal activity, curing mice infected with trypanosomiasis. It also exhibited activity against the malaria parasite.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Microbiology
Douglas Escrivani, Viktor Scheidt, Michele Tinti, Joana Faria, David Horn
Summary: Some pathogens use antigenic variation to evade mammalian host adaptive immune responses. African trypanosomes employ variant surface glycoproteins (VSGs) to continually switch their active VSGs and avoid immune recognition. Switched trypanosomes compete in a predictable manner that is dependent on the activated VSG, and the population of cells that activates minichromosome derived VSGs has a competitive advantage.
Article
Microbiology
Anna Trenaman, Michele Tinti, Abdelmadjid Atrih, David Horn
Summary: Nucleoside analogs are widely used as anti-infective agents, but their potential as anti-parasitic agents has not been fully explored. This study identified two proteins, Tb927.6.2800 and HD82, associated with purine analog resistance in African trypanosomes. The findings also validated two nucleoside kinases involved in pro-drug activation. HD82, related to the mammalian nuclear viral restriction factor SAMHD1, sensitized trypanosomes to nucleoside analogs by reducing native nucleotide pools. This study provides insights into nucleoside/nucleotide metabolism and nucleoside analog resistance in trypanosomatids.
Review
Microbiology
Manu De Rycker, Susan Wyllie, David Horn, Kevin D. Read, Ian H. Gilbert
Summary: Leishmaniasis, Chagas disease, and human African trypanosomiasis are causing significant death and morbidity, especially in low- and middle-income countries. There is a critical need for new medications for leishmaniasis and Chagas disease, while the clinical development pipeline for Chagas disease remains sparse. This review discusses recent advancements in understanding the biology of these pathogens, with a focus on drug discovery, and explores progress in developing new drug candidates and identifying potential molecular targets. The challenges in developing new clinical candidates are also discussed, along with potential solutions to overcome these hurdles.
NATURE REVIEWS MICROBIOLOGY
(2023)