Review
Biochemistry & Molecular Biology
Bibo Li
Summary: Telomere maintenance is crucial for genome stability and regulation of antigenic variation in microbial pathogens. Trypanosomes, such as T. brucei, use a unique DNA polymerase, PolIE, to coordinate the synthesis of telomere G- and C-strands, in contrast to mammalian cells that rely on telomere proteins. Understanding these mechanisms can aid in the development of treatments for diseases caused by these pathogens.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2023)
Article
Biochemical Research Methods
David Feldman, Luke Funk, Anna Le, Rebecca J. Carlson, Michael D. Leiken, FuNien Tsai, Brian Soong, Avtar Singh, Paul C. Blainey
Summary: The combination of efficient genetic engineering and high-resolution phenotypic readouts has greatly accelerated the discovery of genetic components underlying fundamental and disease-related processes. Optical pooled screens using in situ sequencing provide a scalable integration of barcoded lentiviral libraries with high-content imaging assays, enabling single-cell resolution and accurate sequence reads for large-scale genetic screens.
Article
Entomology
Xiangzhao Yue, Yongkang Liang, Zhishuang Wei, Jun Lv, Yongjin Cai, Xiaobin Fan, Wenqing Zhang, Jie Chen
Summary: This study identified potential kkv transcriptional regulators through comprehensive RNA interference analyses and validated their roles in vivo using transgenic Drosophila lines. Fer3 was shown to be crucial for activating kkv transcription and regulating genes involved in chitin synthesis. The study also revealed a potential complex mechanism of kkv transcription regulation involving an interaction network with bithorax complex components.
Article
Biochemical Research Methods
Saba Parvez, Zachary J. J. Brandt, Randall T. T. Peterson
Summary: MIC-Drop is a method for large-scale CRISPR screening in zebrafish, using microfluidics to create droplets containing Cas9, multiplexed single-guide RNAs, and corresponding DNA barcodes. This method allows genetic screens to be performed in F0 zebrafish, targeting tens to hundreds of genes simultaneously during injection. MIC-Drop is valuable for developmental biologists, zebrafish geneticists, and researchers interested in in vivo functional genetic screens in a vertebrate model system. It is also useful for chemical biologists seeking to identify targets of small molecules causing phenotype changes in zebrafish. Using MIC-Drop, a typical screen of 100 genes can be completed within 2-3 weeks by a single user.
Article
Multidisciplinary Sciences
Nicola M. Moloney, Konstantin Barylyuk, Eelco Tromer, Oliver M. Crook, Lisa M. Breckels, Kathryn S. Lilley, Ross F. Waller, Paula MacGregor
Summary: This study maps the spatial proteomes of two African trypanosome species, Trypanosoma brucei and Trypanosoma congolense, providing insights into the molecular basis for diversity within and between these pathogen species. Comparative analysis reveals key routes of parasitic adaptation to different biological niches.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Fabien Guegan, K. Shanmugha Rajan, Fabio Bento, Daniel Pinto-Neves, Mariana Sequeira, Natalia Guminska, Seweryn Mroczek, Andrzej Dziembowski, Smadar Cohen-Chalamish, Tirza Doniger, Beathrice Galili, Antonio M. Estevez, Cedric Notredame, Shulamit Michaeli, Luisa M. Figueiredo
Summary: This study identified 1428 previously uncharacterized lncRNA genes in the T. brucei genome. The key regulator, grumpy lncRNA, was found to promote parasite differentiation into the quiescent stumpy form, with this function being promoted by the encoded small nucleolar RNA. Overexpression of grumpy reduced parasitemia in infected mice.
Article
Biotechnology & Applied Microbiology
Chloe E. Jones, Wenfang S. Tan, Finn Grey, David J. Hughes
Summary: Viral infections activate the interferon response, inducing the expression of hundreds of interferon-stimulated genes to limit virus replication and spread. However, this response is characterized by redundancy, often requiring a combination of ISGs to limit infection.
JOURNAL OF GENERAL VIROLOGY
(2021)
Article
Oncology
Sigve Nakken, Sveinung Gundersen, Fabian L. M. Bernal, Dimitris Polychronopoulos, Eivind Hovig, Jorgen Wesche
Summary: oncoEnrichR is a flexible bioinformatics tool that helps cancer researchers comprehensively investigate a given gene list in multiple facets of cancer relevance. It integrates prior knowledge specifically relevant to cancer, producing a structured and user-friendly analysis report. The usefulness of oncoEnrichR is demonstrated through the interrogation of candidate gene lists from proteomic and CRISPR screens.
INTERNATIONAL JOURNAL OF CANCER
(2023)
Article
Multidisciplinary Sciences
Danielle E. Anderson, Jin Cui, Qian Ye, Baoying Huang, Ya Tan, Chao Jiang, Wenhong Zu, Jing Gong, Weiqiang Liu, So Young Kim, Biao Guo Yan, Kristmundur Sigmundsson, Xiao Fang Lim, Fei Ye, Peihua Niu, Aaron T. Irving, Haoyu Zhang, Yefeng Tang, Xuming Zhou, Yu Wang, Wenjie Tan, Lin-Fa Wang, Xu Tan
Summary: Bats are found to play a crucial role in the zoonotic transmission of major viral diseases, and they exhibit unique innate immune characteristics that are essential for viral replication. The gene MTHFD1 is identified as a key player in the viral tolerance of both bat and human cells, presenting a potential target for developing broad-spectrum antiviral therapy. Research on bats provides valuable insights into understanding genetic factors influencing viral interactions and responses.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
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
Biology
Yan Ruan, Jiaqi Wang, Meng Yu, Fengsheng Wang, Jiangjun Wang, Yixiao Xu, Lianlian Liu, Yuda Cheng, Ran Yang, Chen Zhang, Yi Yang, JiaLi Wang, Wei Wu, Yi Huang, Yanping Tian, Guangxing Chen, Junlei Zhang, Rui Jian
Summary: An extended pluripotency gene regulatory network in mouse embryonic stem cells was proposed through integrative analysis of CRISPR/Cas9-based functional genomics screens and multi-omics data. By integrating various types of data, a new pluripotency gene regulatory network with six functionally independent transcriptional modules was constructed. The activity pattern of these modules was found to be shared by both mouse ESCs and pluripotent cells of early embryos, as well as human ESCs and cancers. These findings provide novel insights into the molecular basis of ESC pluripotency.
COMMUNICATIONS BIOLOGY
(2023)
Review
Parasitology
Sara Silva Pereira, Andrew P. Jackson, Luisa M. Figueiredo
Summary: An intriguing and remarkable feature of African trypanosomes is their antigenic variation system, mediated by the variant surface glycoprotein (VSG) family. Recent studies have revealed that the VSG repertoire has a complex evolutionary history and plays a key role in immune evasion and disease epidemiology. The diversity in sequence, genomic organization, and expression patterns within the VSG family may explain variations in parasite virulence and disease pathology, indicating a need for further exploration of their functional roles.
TRENDS IN PARASITOLOGY
(2022)
Article
Multidisciplinary Sciences
Sebastian Shaw, Sebastian Knuesel, Daniel Abbuehl, Arunasalam Naguleswaran, Ruth Etzensperger, Mattias Benninger, Isabel Roditi
Summary: African trypanosomes exhibit social motility on semi-solid surfaces. The authors found that procyclic forms acidify their environment due to glucose metabolism, generating pH gradients that are sensed via cyclic AMP signaling. Parasite mutants defective in cAMP signaling are inhibited in fly infection.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Laura Smithson, Pearl Ihuoma Akazue, Lucy Findlater, Theresa Manful Gwira, Sue Vaughan, Jack D. Sunter
Summary: The parasites Trypanosoma brucei, T. congolense, and T. vivax, which are closely related, cause neglected tropical diseases known as African Trypanosomiasis. This study identified 13 proteins that localize to the flagellar groove, with three of these proteins shown to play a key role in the attachment of the new flagellum tip. Interestingly, T. congolense and T. vivax did not assemble a canonical groove around the new flagellum tip. This suggests rapid evolution of membrane-cytoskeleton structures and reflects the niche specialization of each species.
MOLECULAR MICROBIOLOGY
(2022)
Article
Immunology
Mariame Camara, Alseny M'mah Soumah, Hamidou Ilboudo, Christelle Travaille, Caroline Clucas, Anneli Cooper, Nono-Raymond Kuispond Swar, Oumou Camara, Ibrahim Sadissou, Estefania Calvo Alvarez, Aline Crouzols, Jean-Mathieu Bart, Vincent Jamonneau, Mamadou Camara, Annette MacLeod, Bruno Bucheton, Brice Rotureau
Summary: In the study of gambiense human African trypanosomiasis, it was found that live parasites may remain undetected in the blood of some seropositive individuals but are present in their skin. The skin may serve as a potential reservoir for African trypanosomes.
CLINICAL INFECTIOUS DISEASES
(2021)
Article
Chemistry, Medicinal
Victoriano Corpas-Lopez, Sonia Moniz, Michael Thomas, Richard J. Wall, Leah S. Torrie, Dorothea Zander-Dinse, Michele Tinti, Stephen Brand, Laste Stojanovski, Sujatha Manthri, Irene Hallyburton, Fabio Zuccotto, Paul G. Wyatt, Manu De Rycker, David Horn, Michael A. J. Ferguson, Joachim Clos, Kevin D. Read, Alan H. Fairlamb, Ian H. Gilbert, Susan Wyllie
ACS INFECTIOUS DISEASES
(2019)
Article
Biochemistry & Molecular Biology
Anna Trenaman, Lucy Glover, Sebastian Hutchinson, David Horn
NUCLEIC ACIDS RESEARCH
(2019)
Article
Multidisciplinary Sciences
Susan Wyllie, Stephen Brand, Michael Thomas, Manu De Rycker, Chun-wa Chung, Imanol Pena, Ryan P. Bingham, Juan A. Bueren-Calabuig, Juan Cantizani, David Cebrian, Peter D. Craggs, Liam Ferguson, Panchali Goswami, Judith Hobrath, Jonathan Howe, Laura Jeacock, Eun-Jung Ko, Justyna Korczynska, Lorna MacLean, Sujatha Manthri, Maria S. Martinez, Lydia Mata-Cantero, Sonia Moniz, Andrea Nuhs, Maria Osuna-Cabello, Erika Pinto, Jennifer Riley, Sharon Robinson, Paul Rowland, Frederick R. C. Simeons, Yoko Shishikura, Daniel Spinks, Laste Stojanovski, John Thomas, Stephen Thompson, Elisabet Viayna Gaza, Richard J. Wall, Fabio Zuccotto, David Horn, Michael A. J. Ferguson, Alan H. Fairlamb, Jose M. Fiandor, Julio Martin, David W. Gray, Timothy J. Miles, Ian H. Gilbert, Kevin D. Read, Maria Marco, Paul G. Wyatt
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2019)
Article
Microbiology
Clare F. Collett, Carl Kitson, Nicola Baker, Heather B. Steele-Stallard, Marie-Victoire Santrot, Sebastian Hutchinson, David Horn, Sam Alsford
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(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
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
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)
