Trypanosomatids Are Much More Than Just Trypanosomes: Clues from The
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Novel Treatment of African Trypanosomiasis
From Department of Microbiology, Tumor and Cell Biology (MTC) Karolinska Institutet, Stockholm, Sweden NOVEL TREATMENT OF AFRICAN TRYPANOSOMIASIS Suman Kumar Vodnala Stockholm 2013 Published and printed by Larserics Digital Print AB, Sundbyberg. © Suman Kumar Vodnala, 2013 ISBN 978-91-7549-030-4 ABSTRACT Human African Trypanosomiasis (HAT) or Sleeping Sickness is fatal if untreated. Current drugs used for the treatment of HAT have difficult treatment regimens and unacceptable toxicity related issues. The effective drugs are few and with no alternatives available, there is an urgent need for the development of new medicines, which are safe, affordable and have no toxic effects. Here we describe different series of lead compounds that can be used for the development of drugs to treat HAT. In vivo imaging provides a fast non-invasive method to evaluate parasite distribution and therapeutic efficacy of drugs in real time. We generated monomorphic and pleomorphic recombinant Trypanosoma brucei parasites expressing the Renilla luciferase. Interestingly, a preferential testis tropism was observed with both the monomorphic and pleomorphic recombinants. Our data indicate that preferential testis tropism must be considered during drug development, since parasites might be protected from many drugs by the blood-testis barrier (Paper I). In contrast to most mammalian cells, trypanosomes cannot synthesize purines de novo. Instead they depend on the host to salvage purines from the body fluids. The inability of trypanosomes to engage in de novo purine synthesis has been exploited as a therapeutic target by using nucleoside analogues. We showed that adenosine analogue, cordycepin in combination with deoxycoformycin cures murine late stage models of African trypanosomiasis (Paper II). -
Short Communication Tandem Affinity Purification of Exosome And
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by St Andrews Research Repository 1 Short communication 2 3 Tandem affinity purification of exosome and replication factor C 4 complexes from the non-human infectious kinetoplastid parasite 5 Crithidia fasciculata 6 7 Wakisa Kipandula a, b, Terry K. Smith a and Stuart A. MacNeill a, * 8 9 a Biomedical Sciences Research Complex, University of St Andrews, North 10 Haugh, St Andrews, Fife KY16 9ST, UK. 11 b Department of Biomedical Sciences, College of Medicine, University of Malawi, 12 Private Bag 360, Chichiri, Blantyre 3, Malawi. 13 14 * Corresponding author: 15 Email: [email protected] 16 Tel. (+44) 1334 467268 17 18 19 20 1 21 Abstract 22 23 Kinetoplastid parasites are responsible for a range of diseases with significant 24 global impact. Trypanosoma brucei and Trypanosoma cruzi cause human African 25 trypanosomiasis and Chagas disease, respectively, while various Leishmania 26 species are responsible for cutaneous, mucocutaneous and visceral 27 leishmaniasis. Understanding the biology of these organisms is key for effective 28 diagnosis, prophylaxis and treatment. The insect parasite Crithidia fasciculata 29 offers a safe and low-cost alternative for studies of kinetoplastid biology. C. 30 fasciculata does not infect humans, can be cultured to high yields in inexpensive 31 serum-free medium in a standard laboratory, and has a completely sequenced 32 publically available genome. Taking advantage of these features, however, 33 requires the adaptation of existing methods of analysis to C. fasciculata. Tandem 34 affinity purification is a widely used method that allows for the rapid purification of 35 intact protein complexes under native conditions. -
Non-Leishmania Parasite in Fatal Visceral Leishmaniasis–Like Disease, Brazil
DISPATCHES Non-Leishmania Parasite in Fatal Visceral Leishmaniasis–Like Disease, Brazil Sandra R. Maruyama,1 Alynne K.M. de Santana,1,2 performed whole-genome sequencing of 2 clinical isolates Nayore T. Takamiya, Talita Y. Takahashi, from a patient with a fatal illness with clinical characteris- Luana A. Rogerio, Caio A.B. Oliveira, tics similar to those of VL. Cristiane M. Milanezi, Viviane A. Trombela, Angela K. Cruz, Amélia R. Jesus, The Study Aline S. Barreto, Angela M. da Silva, During 2011–2012, we characterized 2 parasite strains, LVH60 Roque P. Almeida,3 José M. Ribeiro,3 João S. Silva3 and LVH60a, isolated from an HIV-negative man when he was 64 years old and 65 years old (Table; Appendix, https:// Through whole-genome sequencing analysis, we identified wwwnc.cdc.gov/EID/article/25/11/18-1548-App1.pdf). non-Leishmania parasites isolated from a man with a fatal Treatment-refractory VL-like disease developed in the man; visceral leishmaniasis–like illness in Brazil. The parasites signs and symptoms consisted of weight loss, fever, anemia, infected mice and reproduced the patient’s clinical mani- festations. Molecular epidemiologic studies are needed to low leukocyte and platelet counts, and severe liver and spleen ascertain whether a new infectious disease is emerging that enlargements. VL was confirmed by light microscopic exami- can be confused with leishmaniasis. nation of amastigotes in bone marrow aspirates and promas- tigotes in culture upon parasite isolation and by positive rK39 serologic test results. Three courses of liposomal amphotericin eishmaniases are caused by ≈20 Leishmania species B resulted in no response. -
Recent Advances in Trypanosomatid Research: Genome Organization, Expression, Metabolism, Taxonomy and Evolution
Parasitology Recent advances in trypanosomatid research: genome organization, expression, metabolism, cambridge.org/par taxonomy and evolution 1 2 3,4 5,6 Review Dmitri A. Maslov , Fred R. Opperdoes , Alexei Y. Kostygov , Hassan Hashimi , Julius Lukeš5,6 and Vyacheslav Yurchenko3,5,7 Cite this article: Maslov DA, Opperdoes FR, Kostygov AY, Hashimi H, Lukeš J, Yurchenko V 1Department of Molecular, Cell and Systems Biology, University of California – Riverside, Riverside, California, USA; (2018). Recent advances in trypanosomatid 2de Duve Institute, Université Catholique de Louvain, Brussels, Belgium; 3Life Science Research Centre, Faculty of research: genome organization, expression, 4 metabolism, taxonomy and evolution. Science, University of Ostrava, Ostrava, Czech Republic; Zoological Institute of the Russian Academy of Sciences, 5 Parasitology 1–27. https://doi.org/10.1017/ St. Petersburg, Russia; Biology Centre, Institute of Parasitology, Czech Academy of Sciences, České Budejovice 6 S0031182018000951 (Budweis), Czech Republic; University of South Bohemia, Faculty of Sciences, České Budejovice (Budweis), Czech Republic and 7Martsinovsky Institute of Medical Parasitology, Tropical and Vector Borne Diseases, Sechenov Received: 30 January 2018 University, Moscow, Russia Revised: 23 April 2018 Accepted: 23 April 2018 Abstract Key words: Unicellular flagellates of the family Trypanosomatidae are obligatory parasites of inverte- Gene exchange; kinetoplast; metabolism; molecular and cell biology; taxonomy; brates, vertebrates and plants. Dixenous species are aetiological agents of a number of diseases trypanosomatidae in humans, domestic animals and plants. Their monoxenous relatives are restricted to insects. Because of the high biological diversity, adaptability to dramatically different environmental Author for correspondence: conditions, and omnipresence, these protists have major impact on all biotic communities Vyacheslav Yurchenko, E-mail: vyacheslav. -
Modeled Structure of Trypanothione Reductase of Leishmania Infantum
BMB reports Modeled structure of trypanothione reductase of Leishmania infantum Bishal K. Singh1, Nandini Sarkar1, M.V. Jagannadham2 & Vikash K. Dubey1,* 1Department of Biotechnology, Indian Institute of Technology Guwahati, Assam-781039, India, 2Molecular Biology Unit, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005, India Trypanothione reductase is an important target enzyme for malian GR share approximately 40% sequence identity and structure-based drug design against Leishmania. We used ho- are mutually exclusive with respect to disulfide substrate spe- mology modeling to construct a three-dimensional structure of cificity (1), indicating a difference in substrate binding pocket the trypanothione reductase (TR) of Leishmania infantum. The geometry. structure shows acceptable Ramachandran statistics and a re- The trypanothione system is necessary for protozoan surviv- markably different active site from glutathione reductase(GR). al because the dithiol trypanothione is required for the syn- Thus, a specific inhibitor against TR can be designed without thesis of DNA precursors, the homeostasis of ascorbate, the interfering with host (human) GR activity. [BMB reports 2008; detoxification of hydroperoxides, and the sequestration/export 41(6): 444-447] of thiol conjugates. Moreover, the majority of peroxidases that eliminate the reactive oxygen species (ROS) generated in the aerobic metabolism are trypanothione dependent (5). In addi- INTRODUCTION tion, the absence of this pathway from the mammalian host and the sensitivity of trypanosomatids to oxidative stress make Trypanothione reductase (E.C. 1.6.4.8) is a member of the di- it an attractive target for structure-based drug design. sulfide oxidoreductase family of enzymes (1) that presents an The leishmaniasis are caused by 20 species pathogenic for attractive target for the development of new drugs by rational humans belonging to the genus Leishmania, a protozoa trans- inhibitor design. -
Pathogenomics of Trypanosomatid Parasites
White Paper 8/12/07 Pathogenomics of Trypanosomatid parasites Greg Buck (Virginia Commonwealth University) Matt Berriman (Wellcome Trust Sanger Institute) John Donelson (University of Iowa) Najib El-Sayed (University of Maryland) Jessica Kissinger (University of Georgia) Larry Simpson (University of California, Los Angeles) Andy Tait (University of Glasgow) Marta Teixeira (University of Sao Paulo, Brasil) Stephen Beverley (Washington University, St. Louis) Executive Summary. The family Trypanosomatidae of the protistan order Kinetoplastida includes three major lineages of human pathogens – the Leishmania and the African and American trypanosomes – that each rank within the top 10 in terms of global impact. The combined impact measured by DALY of these three parasites approaches 5 million. There are currently five ‘completed’ genomes of kinetoplastids: one African trypanosome, three Leishmania, and one American trypanosome, the latter being effectively a preliminary draft sequence due to assembly problems caused by its hybrid nature and extensive repetitive sequences. Perhaps unlike the situation found in other groups of eukaryotic pathogens, trypanosomatids present two unique challenges. First is the fact that within each of the three major lineages, a wide range of disease pathologies is found. Thus, we are probing multiple diseases. Second is the fact that the trypanosomatids are relatively ancient, with divergences amongst the major lineages ranging from 200-500 million years ago. Thus, there is a wide range of evolutionary and pathological ‘space’ yet to be explored by genomic methods, accompanied by great opportunities for new insights and discovery. The goals of this sequencing effort include improvement of: 1) our understanding of the mechanisms by which these pathogens cause disease; 2) our ability to influence the severity of these diseases through chemo- or immuno- prophylaxis and treatment; and, 3) our understanding of the biology that led these organisms to evolve into such successful pathogens. -
Genomics of Trypanosomatidae: Where We Stand and What Needs to Be Done?
pathogens Review Genomics of Trypanosomatidae: Where We Stand and What Needs to Be Done? Vyacheslav Yurchenko 1,2,* , Anzhelika Butenko 1,3 and Alexei Y. Kostygov 1,4,* 1 Life Science Research Centre, Faculty of Science, University of Ostrava, 710 00 Ostrava, Czech Republic; [email protected] 2 Martsinovsky Institute of Medical Parasitology, Tropical and Vector Borne Diseases, Sechenov University, 119435 Moscow, Russia 3 Institute of Parasitology, Biology Centre, Czech Academy of Sciences, 370 05 Ceskˇ é Budˇejovice, Czech Republic 4 Zoological Institute of the Russian Academy of Sciences, 190121 St. Petersburg, Russia * Correspondence: [email protected] (V.Y.); [email protected] (A.Y.K.) Abstract: Trypanosomatids are easy to cultivate and they are (in many cases) amenable to genetic manipulation. Genome sequencing has become a standard tool routinely used in the study of these flagellates. In this review, we summarize the current state of the field and our vision of what needs to be done in order to achieve a more comprehensive picture of trypanosomatid evolution. This will also help to illuminate the lineage-specific proteins and pathways, which can be used as potential targets in treating diseases caused by these parasites. Keywords: trypanosomatids; next-generation sequencing; genomics Citation: Yurchenko, V.; Butenko, A.; Kostygov, A.Y. Genomics of 1. Introduction Trypanosomatidae: Where We Stand The flagellates of the family Trypanosomatidae represent one of the most evolu- and What Needs to Be tionarily successful groups of parasitic protists, adapted to an extremely wide range of Done? Pathogens 2021, 10, 1124. hosts—from various animals (mainly insects and vertebrates) to flowering plants and even https://doi.org/10.3390/pathogens ciliates. -
Trypanosomatids Are Much More Than Just Trypanosomes: Clues from the Expanded Family Tree
UC Riverside UC Riverside Previously Published Works Title Trypanosomatids Are Much More than Just Trypanosomes: Clues from the Expanded Family Tree. Permalink https://escholarship.org/uc/item/89h481p3 Journal Trends in parasitology, 34(6) ISSN 1471-4922 Authors Lukeš, Julius Butenko, Anzhelika Hashimi, Hassan et al. Publication Date 2018-06-01 DOI 10.1016/j.pt.2018.03.002 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Review Trypanosomatids Are Much More than Just Trypanosomes: Clues from the Expanded Family Tree 1,2, 1,3 1,2 4 1,5 Julius Lukeš, * Anzhelika Butenko, Hassan Hashimi, Dmitri A. Maslov, Jan Votýpka, and 1,3 Vyacheslav Yurchenko Trypanosomes and leishmanias are widely known parasites of humans. How- Highlights ever, they are just two out of several phylogenetic lineages that constitute the Dixenous trypanosomatids, such as the human Trypanosoma parasites, family Trypanosomatidae. Although dixeny – the ability to infect two hosts – is a infect both insects and vertebrates. derived trait of vertebrate-infecting parasites, the majority of trypanosomatids Yet phylogenetic analyses have revealed that these are the exception, are monoxenous. Like their common ancestor, the monoxenous Trypanoso- and that insect-infecting monoxenous matidae are mostly parasites or commensals of insects. This review covers lineages are both abundant and recent advances in the study of insect trypanosomatids, highlighting their diverse. diversity as well as genetic, morphological and biochemical complexity, which, Globally, over 10% of true bugs and until recently, was underappreciated. The investigation of insect trypanoso- flies are infected with monoxenous try- matids is providing an important foundation for understanding the origin and panosomatids, whereas other insect groups are infected much less fre- evolution of parasitism, including colonization of vertebrates and the appear- quently. -
Juliana Isabel Giuli Da Silva Ferreira
JULIANA ISABEL GIULI DA SILVA FERREIRA Descrição morfológica e Filogenia de parasitas do gênero Trypanosoma em pequenos mamíferos silvestres do Brasil São Paulo 2020 JULIANA ISABEL GIULI DA SILVA FERREIRA Descrição morfológica e Filogenia de parasitas do gênero Trypanosoma em pequenos mamíferos silvestres do Brasil Tese apresentada ao Programa de Pós- Graduação em Epidemiologia Experimental Aplicada às Zoonoses da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo para obtenção do título de Doutor em Ciências. Departamento: Medicina Veterinária Preventiva e Saúde Animal Área de concentração: Epidemiologia Experimental Aplicada às Zoonoses Orientador: Prof. Dr. Arlei Marcili De acordo: Orientador Coorientadora: Profa. Dra. Andréa Pereira da Costa São Paulo 2020 Obs.: A versão original encontra-se disponível na Biblioteca da FMVZ/USP. Autorizo a reprodução parcial ou total desta obra, para fins acadêmicos, desde que citada a fonte. DADOS INTERNACIONAIS DE CATALOGAÇÃO NA PUBLICAÇÃO (Biblioteca Virginie Buff D’Ápice da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo) T. 3964 Ferreira, Juliana Isabel Giuli da Silva FMVZ Descrição morfológica e Filogenia de parasitas do gênero Trypanosoma em pequenos mamíferos silvestres do Brasil / Juliana Isabel Giuli da Silva Ferreira. – 2020. 64 f. : il. Tese (Doutorado) – Universidade de São Paulo. Faculdade de Medicina Veterinária e Zootecnia. Departamento de Medicina Veterinária Preventiva e Saúde Animal, São Paulo, 2020. Programa de Pós-Graduação: Epidemiologia Experimental Aplicada às Zoonoses. Área de concentração: Epidemiologia Experimental Aplicada às Zoonoses. Orientador: Prof. Dr. Arlei Marcili. Coorientadora: Profa. Dra. Andréa Pereira da Costa 1. Trypanosoma. 2. Filogenia. 3. Marsupiais. 4. Roedores. I. Título. Ficha catalográfica elaborada pela bibliotecária Maria Aparecida Laet, CRB 5673-8, da FMVZ/USP. -
Substrates for the Enzyme Trypanothione Disulfide Reductase
Proc. Nati. Acad. Sci. USA Vol. 85, pp. 5374-5378, August 1988 Biochemistry "Subversive" substrates for the enzyme trypanothione disulfide reductase: Alternative approach to chemotherapy of Chagas disease (Trypanosoma cruzi/leishmaniasis/naphthoquinone/nitrofuran) GRAEME B. HENDERSON*t, PETER ULRICH*, ALAN H. FAIRLAMBt, IAN ROSENBERG§, MIERCIO PEREIRA§, MICHAEL SELA¶1, AND ANTHONY CERAMI* *Laboratory of Medical Biochemistry, The Rockefeller University, New York, NY 10021; *Department of Medical Protozoology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom; §Department of Medicine, New England Medical Center Hospitals, Boston, MA 02111; and $Weizmann Institute of Science, Rehovot, Israel 76100 Contributed by Michael Sela, March 2, 1988 ABSTRACT The trypanosomatid flavoprotein disulfide unusual NADPH-dependent flavoprotein disulfide reductase reductase, trypanothione reductase, is shown to catalyze one- (trypanothione reductase) (8), which maintains trypanothione electron reduction of suitably substituted naphthoquinone and in the dithiol form [Try(SH)2] within the cell. In addition, nitrofuran derivatives. A number of such compounds have trypanosomatids also possess trypanothione-dependent per- been chemically synthesized, and a structure-activity relation- oxidase activity (9, 10). Given that the antioxidant defenses of ship has been established; the enzyme is most active with trypanosomatids are based upon trypanothione, inhibition of compounds that contain basic functional groups in side-chain trypanothione reductase or subversion of its antioxidant role residues. The reduced products are readily reoxidized by within the cell represents an attractive target for the design of molecular oxygen and thus undergo classical enzyme-catalyzed drugs to treat trypanosomatid infections. redox cycling. In addition to their ability to act as substrates for Trypanothione disulfide reductase has been purified from trypanothione reductase, the compounds are also shown to Crithidia fasciculata and T. -
Aerobic Kinetoplastid Flagellate Phytomonas Does Not Require Heme
Aerobic kinetoplastid flagellate Phytomonas does not require heme for viability Ludekˇ Korenýˇ a,b, Roman Sobotkab,c, Julie Kovárovᡠa,b, Anna Gnipováa,d, Pavel Flegontova,b, Anton Horváthd, Miroslav Oborníka,b,c, Francisco J. Ayalae,1, and Julius Lukesˇa,b,1 aBiology Centre, Institute of Parasitology, Czech Academy of Sciences and bFaculty of Science, University of South Bohemia, 370 05 Ceské Budejovice, Czech Republic; cInstitute of Microbiology, Czech Academy of Sciences, 379 81 Trebon, Czech Republic; dFaculty of Natural Sciences, Comenius University, 842 15 Bratislava, Slovakia; and eDepartment of Ecology and Evolutionary Biology, University of California, Irvine, CA 92697 Contributed by Francisco J. Ayala, January 19, 2012 (sent for review December 8, 2011) Heme is an iron-coordinated porphyrin that is universally essential aerobic environment (8). In soluble guanylyl cyclase, heme serves as a protein cofactor for fundamental cellular processes, such as as the nitric oxide sensor, and thus plays an important role in electron transport in the respiratory chain, oxidative stress re- signal transduction. Heme is also an important regulatory mol- sponse, or redox reactions in various metabolic pathways. Parasitic ecule because it reversibly binds to certain proteins, such as fl kinetoplastid agellates represent a rare example of organisms transcription factors and ion channels, and thus modulates their that depend on oxidative metabolism but are heme auxotrophs. functions (9). Here, we show that heme is fully dispensable for the survival of The central position of heme in a variety of cellular functions Phytomonas serpens, a plant parasite. Seeking to understand the makes it essential for the viability of virtually all living systems. -
Dramatic Changes in Gene Expression in Different Forms of Crithidia Fasciculata Reveal Potential Mechanisms for Insect- Specific Adhesion in Kinetoplastid Parasites
Washington University School of Medicine Digital Commons@Becker Open Access Publications 2019 Dramatic changes in gene expression in different forms of Crithidia fasciculata reveal potential mechanisms for insect- specific adhesion in kinetoplastid parasites John N. Filosa Corbett T. Berry Gordon Ruthel Stephen M. Beverley Wesley C. Warren See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Authors John N. Filosa, Corbett T. Berry, Gordon Ruthel, Stephen M. Beverley, Wesley C. Warren, Chad Tomlinson, Peter J. Myler, Elizabeth A. Dudkin, Megan L. Povelones, and Michael Povelones RESEARCH ARTICLE Dramatic changes in gene expression in different forms of Crithidia fasciculata reveal potential mechanisms for insect-specific adhesion in kinetoplastid parasites 1 1¤ 1 2 John N. Filosa , Corbett T. BerryID , Gordon Ruthel , Stephen M. Beverley , Wesley C. Warren3, Chad Tomlinson4, Peter J. Myler5,6,7, Elizabeth A. Dudkin8, Megan 8 1 L. PovelonesID *, Michael PovelonesID * a1111111111 1 Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, a1111111111 Pennsylvania, United States of America, 2 Department of Molecular Microbiology, Washington University a1111111111 School of Medicine, St. Louis, Missouri, United States of America, 3 University of Missouri, Bond Life a1111111111 Sciences Center, Columbia, Missouri, United States of America, 4 McDonnell Genome Institute, Washington a1111111111 University School of Medicine, St. Louis,