Davila, AM

Tyler, KM

Memórias do Instituto Oswaldo Cruz.

English

University of East Anglia digital repository

1Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 96: 000-000, 2001MEETING REPORTThe Net Closes in TrypanosomatidsAlberto MR DÆvila, Kevin M Tyler*Departamento de Bioquímica e Biologia Molecular, Instituto Oswaldo Cruz-Fiocruz, Av. Brasil 4365, 21045-900Rio de Janeiro, RJ, Brasil *Northwestern University, Chicago, IL, USAAt the turn of the last century, Africa faced anepidemic of sleeping sickness. For a while in the70’s, with the advent and targeted use of insecti-cides like DDT, it seemed the disease would beeradicated. Today, Africa faces another sleepingsickness epidemic, which it seems little betterequipped to respond to than it was a century agoand sleeping sickness looks to be a disease whichmay be with us for a long time to come. For thisreason, the Third Internet Conference on SalivarianTrypanosomes and Trypanosomatids was designedas a virtual world meeting specifically targeted atproviding a real world focus for basic scientistsworking with trypanosomes. The conference wasfree, spread over a two-week period and consistedof six sessions’ a focused debate and a poster ses-sion. The full proceedings are published in the In-ternational Journal for Parasitology 31(5-6), May,2001.In statesman like keynote addresses to confer-ence, two of the most senior figures in the field,George Cross and J Richard Seed reviewed the keyadvances and failures of the last century. Theirpresentations tackled the potential impact of cur-rent new technologies and the political, social andeconomic realities in which the pipeline from sci-ence to public health must operate in order to tacklesleeping sickness. They also went on to addressthe future of trypanosome research and integratedcontrol approaches in public health.BIOLOGY AND ULTRASTRUCTUREKeith Gull kicked off the scientific proceed-ings with a philosophical review of kinetoplastidcell biology. He asked and answered questionsabout how to utilize the vast amounts of informa-tion and new tools generated by current genomeprojects to pursue fundamental biological questionsassociated with the kinetoplastida in a post genomicera. The mechanisms by which the catenated massof minicircles and maxicircles composing the ki-netoplast is replicated and segregated with fidelityin each cell cycle has been on of the most intrigu-ing areas of research in kinetoplastid biology.James Morris and colleagues from the Englund labreviewed current thinking on kinetoplast replica-tion going on to propose a model in which the ki-netoplast actually spins to ensure a uniform distri-bution of minicircles in the periphery. MichelDollet discussed the extreme heterogeneity withinthe genus Phytomonas (plant trypanosomatids) anddescribed the characterization of a monophyleticgroup of phloem restricted trypanosomatids – the“phloemicola”. Peter Overath and colleagues dis-cussed the evolutionary significance of their ob-servation that the presence of highly immunogenicsurface proteins was peculiar to the salivaria, withnon-salivarian trypanosomes having weakly immu-nogenic mucin-like carbohydrate-rich glycopro-teins on their surface instead. Finally, one of us(KMT) presented an updated life cycle for Trypa-nosoma cruzi highlighting unresolved areas of in-terest.BIOCHEMISTRY AND DRUG DEVELOPMENTThe first presentation of the session by FredOpperdoes and Paul Michels reviewed the progressmade in developing glycolysis enzymes as drugtargets since the discovery that glycolysis is par-tially compartmentalized in the trypanosome’sglycosome. They then moved on to describing cur-rent work characterizing the enzymes of the pen-tose phosphate pathway. Thomas Seebeck pre-sented a digest of his labs recent work investigat-ing cAMP signalling in trypanosomes, highlight-ing, and the characterization new genes in thecAMP-signalling pathway including a new familyof phosphodiesterases as possible therapeutic tar-gets. A complimentary presentation from MeciaOliveira demonstrated that disruption of inositolmetabolism in T. cruzi was a valid target for che-motherapy. Together, these papers sparked con-siderable discussion as to the respective roles oninositol, calcium and cAMP signalling in trypano-some differentiation and proliferation. HerbTanowitz presented data on the activation of theE-mails: davila@gene.dbbm.fiocruz.br   k-tyler@northwestern.edu2 Net Closes in Trypanosomatids  AMR DÆvila, KM TylerERK 1/2, AP-1, ET-1 pathways by T. cruzi infec-tion in the myocardium. He suggested that the vas-culature plays a role in the pathogenesis of chagasiccardiomyopathy and discussed the implications forthe use of palliative therapeutics in treatment ofChagas heart disease. Closing the session, Harryde Koning provided a comprehensive review ofthe manner in which current and prospective drugsfor the treatment of sleeping sickness are believedto cross the parasite plasma membrane. In particu-lar, emphasizing the role of the P2 adenosine trans-porter in the development of drug resistance andthe difficulties which must be faced in order toovercome this resistance.MOLECULAR BIOLOGYPiet Borst and Sebastian Ulbert started this ses-sion by reviewing the field which has, more thanany other, popularized the study of T. brucei, themechanism by which the trypanosome evades thehost immune response-antigenic variation. His re-view focused on recent work on the mechanism ofexpression site switching and on the way inactiveexpression sites are kept silent. Expression siteswere the primary topic of a timely and comple-mentary review from Luc Vanhamme and col-leagues of the Pays lab which explained what isknown about the mechanism by which only onesite is expressed and possible reasons for the mul-tiplicity of expression sites. Wim Degrave providedan update on the current status of the try-panosomatid genome projects (Leishmania major‘Freidlin’, T. brucei TREU927/4, and T. cruzi CL-Brenner) helpful links for genome-related re-sources and key contacts. Diamar da Costa-Pintoand colleagues in the Traub-Cseko lab presentedwork in Leishmania utilizing GFP as a fluorescentmarker for the subcellular localization of con-structs. In particular trafficking to a lysosomal com-partment of a GFP/cysteine protease chimaericprotein was investigated. Hitherto the conferenceit has been widely speculated that no polymeraseII promoters existed in trypanosomatids. However,in the final talk of the session Anish Das and col-leagues from the Bellofatto lab were able to con-vincingly demonstrate that Spliced Leader RNAgene transcription (in Leptomonas seymori) isdriven from a polymerase II promoter. They alsoprovided a characterization of the promoter andits associated promoter binding proteins and de-tails of the promoter’s transcriptional activity.IMMUNOLOGY AND PATHOLOGYThe controversy over the mechanisms by whichChagas  heart disease pathogenesis occurs was re-visited by the first two talks of the session. It iswell established that both parasite directed immuneand autoimmune responses are elicited duringChagas heart disease. It is also believed by most,that cardiac pathology is immune mediated. Thecausal linking of these observations is, however,still poorly construed –, as are the relative amountsof cardiac damage each immune component con-tributes. In the first presentation by Rick Tarleton,Occam’s razor was invoked to argue that becauseparasites are persistent during heart disease, thereis no reason to invoke autoimmunity as a mecha-nism of pathogenesis. However, in the session’ssecond talk, Juan Leon and David Engman elo-quently argued that, given the weight of circum-stantial evidence that autoimmunity is present insome T. cruzi infected humans and mice it mayhave a role in pathogenesis. Indeed, they were ableto demonstrate that the level of cardiac myosinautoimmunity induced during acute T. cruzi infec-tion can be similar in character and magnitude tothat of an established model of autoimmune cardi-omyopathy. In another presentation addressing thepathogenesis of Chagas heart disease, PaolaMinoprio reviewed the mechanisms, effects andimplications of the polyclonal activation of lym-phocytes which is characteristic of the disease. SamBlack and colleagues presented a review of theinteresting and apparently novel mechanism of in-nate immunity of Cape buffalo to salivarian trypa-nosome infections in particular highlighting therespective roles of xanthine oxidase and serumcatalase in parasite killing. Patrick de Baetselierfrom the Beschin lab presented an extensive char-acterization of the effect that knocking out the try-panosome phospholipase C gene has on the im-mune response in a murine model. In essence, evi-dence was presented that the observed attenuationof disease caused by the knockout parasites resultedfrom a shift in the balance of the immune responsetowards a type II cytokine environment. Piscinecryptobiosis is a kinetoplastid disease of fish whichcauses significant damage to the annual catchworld-wide, Patrick Woo’s presentation reviewedthe progress made in exploiting vaccines, drugs andtransgenic fish to counteract the disease and high-lighted parallels between cryptobiosis and thekinetoplastid diseases of mammals.EPIDEMIOLOGYMichel Tibayrenc provided the rationale behindthe creation of a centralized agency to counteremerging and re-emerging infectious diseases inEurope and set forth a triple mission for The Euro-pean Center for Infectious Diseases: to providesurveillance and control, advanced research, train-ing and teaching. Peter van den Bosche reviewedthe epidemiological status of bovine trypano-somosis in Southern Africa, emphasizing that con-3Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 96, 2001trol options vary in accordance with four differentepidemiological situations that can be readily dis-tinguished. Notably, control of tsetse with insecti-cide treated cattle is effective only when a largeproportion of feeds are taken from cattle over alarge area and when tsetse invasion can be suffi-ciently reduced. Discussion of the use oftrypanosomosis vs trypanosomiasis took place af-ter this presentation, an issue which has proveddivisive between veterinary and medical fields –in keeping with the theme of increased communi-cations between related disciplines, reconciliationwas proposed by simply treating both terms asvalid. Geoff Hide and Aimee Tilley described theuse of mobile genetic elements (MGE) PCR forthe molecular typing of T. brucei strains. MGEmarkers like RIME have the advantage that theyare specific to trypanosomes, usually unlinked andhave what can be approximated to a random dis-tribution throughout the trypanosome genome.These advantages have potentiated a rapid, sensi-tive tool for discriminating between strains andinvestigating the epidemiology of sleeping sick-ness even in clinical isolates. Some discussion onthe occurrence of mixed infections and selectivepressure of field isolates in the lab took place withWendy Gibson. John McDermott and PaulColeman reviewed the current control strategiesfor tsetse-transmitted trypanosomosis in cattle indifferent geographic regions of sub-Saharan Af-rica. According to their comparison, the rankingsof the effect of control strategies on reducing dis-ease prevalence were vector control, vaccination,and drug use, in that order. Finally, MarcDesquesnes and one of us (AMRD) described theusefulness of a PCR-based assay to differentiateamong trypanosomatid species using only one pairof primers.VECTORSIn this session, Chris Schofield and Ian Maud-lin called attention to the control of African trypa-nosomiasis. Referring to the declaration on thecontrol of African trypanosomiasis, signed in the36th session of the Organization for African Unity(OAU), they compared the operational challengesof that concerted effort with the Southern Coneinitiative against Chagas disease. Charles Beardreviewed recent progress in a promising new areaof control, the use of genetically modified endo-symbiotic bacteria of the triatomine intestinal tractto make triatomine bugs refractory to infection byT. cruzi and hence break the life-cycle. A pointabout plasmid stability under field conditions andthe possibility of recombination was raised in dis-cussion which led to debate on the desirability offixing such genes in the wild population since themore stable the genetic transformation, the greaterthe potential efficiency and permanence of the ap-proach. Complementary work on manipulating themicroflora of the tsetse fly was presented by ColinDale and Sue Welburn in which the endosymbiont“Sodalis” strain was engineered to avoid potenti-ating trypanosome susceptibility in tsetse. FrancisOloo reviewed the status and prospects for tsetsecontrol in Eastern Africa. Discussion focussed onsimple, cost-effective and user-friendly tactics thatcould be adopted by local communities, and high-lighted the problems in maintaining such programsand the risk of reinvasion when if programs lapse.Priscilla Machado and colleagues from theEdmundo Grisard’s lab presented data on thesusceptibility of Rhodnius species to different T.rangeli strains, suggesting the existence of highadaptation between strain and local vector. The lastpresentation of this session was the one fromAlexandre Peixoto and colleagues describing newmolecular markers for phlebotomine sand flies.PHYLOGENY AND EVOLUTIONHooman Momen opened this session review-ing some current problems in the systematics oftrypanosomatids. His suggestion to include Leish-mania, Sauroleishmania and Endotrypanum withina single genus because of their genetic affinity pro-voked considerable discussion. Wendy Gibsonhighlighted recent research on genetic exchangein T. brucei and called attention to the position ofT. brucei in a molecular phylogenetic tree basedon 18S ribosomal sequence, noting that the treeprovided no clues to the likely existence of geneticexchange in trypanosome species other thanSalivaria. The ensuing discussion focussed onmolecular techniques for “trapping” the sexualstages of T. brucei as well as reports suggestingsexual process in several other trypanosomatids.Finally, Sergei Podlipaev offered us a review fo-cussed on the diversity of insect trypanosomatids,which raised discussion on the lack of referencestrains for detailed studies, the presence of endo-symbionts, and the lack presence of trypano-somatids in early insects as Paleoptora.POSTER SESSIONNotable among the posters was a phylogeneticcomparison of elongation factor genes by EricLeblanc and colleagues. Two reports by BradMcGwire first (with KP Chang) that loss of GP63adversely affects Leishmania survival in macroph-ages and second (with DM Engman) that themechanism of flagellar targeting for the flagellarcalcium binding protein FCaBP is conserved be-tween Leishmania and trypanosomes. A poster byJeroen Saeij and Geert Wiegertjes showed evidence4 Net Closes in Trypanosomatids  AMR DÆvila, KM Tylerof a role for NO in fish immunity to trypanoplas-mas. Our pick for best poster, however, went toEdith Authié and colleagues which showed con-vincingly that vaccination with the cysteine pro-tease of T. congolense (congopain) attenuatedpathogenesis by neutralizing the enzymes activitywithout actually affecting the development of theinfection.CONCLUSIONS AND NEW INITIATIVESThe meeting was a great success with a goodlevel of discussion. Transcending geographic bar-riers was one of our aims and conference presentedresearch from 17 countries and from every conti-nent. The level of attendance was beyond our ex-pectations. In the first week alone we logged over20,000 hits from about 1,500 machines (individualIP addresses) with 400-500 registering at the site.This kind of attendance is much higher than a spe-cialist conference of this kind could ever realisti-cally expect to field in the real world and was in-dicative of the huge amount of interest the confer-ence generated. Detailed technical conclusions andrecommendations are published in the proceedings.The currency of science is information, and inrecent years the internet has revolutionized the rateand scale at which information can be transferred.This is just as well since vastly more, pertinent in-formation is now being generated and processedthan ever before. The internet has a huge potentialto provide for enhanced communications betweengroups of scientists, between science and publichealth and between science and the public at large.For those interested in kinetoplastid disease theinternet offers the prospect of an utopian visionfor universally accessible, free, single site accessto all kinetoplastid related internet resources. Thesecould include textbooks, lecture series, genomicand proteogenomic databases, links to bio-informatics tools, conferences and symposia, spe-cialist listings, discussion groups and even chatrooms. The conference was launched fromTrypanosome.com and we are hopeful that we willbe able to use this site in the future as a stagingpoint from which to unify and rationalize existinginternet resources whilst adding more as the needarises. Our next step in realizing this aim will be tosituate a new e-journal (Kinetoplastid Biology andDisease) at the site. This should allow the report-ing on current projects and advances and shouldencourage debate of topical issues throughout thesite. As for future conferences, the next will be heldin 2002 but we will aim to hold at least one fo-cussed symposium before then – the proceedingsof which to be published in the new e-journal. Inwriting this article for Memórias do InstitutoOswaldo Cruz what we aim to report is not a faitaccompli but rather the initiation of a project tofacilitating the use of the web to take aim atkinetoplastid diseases.

The net closes on trypanosomiasis

Alberto MR Dávila

Kevin M Tyler

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Memórias do Instituto Oswaldo Cruz

The net closes on trypanosomatids

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The net closes on trypanosomiasis

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