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  Previous issue date: 2015Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa do Timo. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Ciências Biomédicas. Programa de Pós-Graduação em Biologia Celular e do Desenvolvimento. Rio de Janeiro, RJ, Brasil.School of Medicine and Health Sciences. Research Center for Neglected Diseases of Poverty. Department of Microbiology, Immunology and Tropical Medicine. Washington, DC, USA

Brindley, Paul J.

Jurberg, Arnon D.

Frontiers in Genetics

PubMed

Jurburg, Arnon D.

George Washington University: Health Sciences Research Commons (HSRC)

Himmelfarb Health Sciences Library, The George Washington UniversityHealth Sciences Research CommonsMicrobiology, Immunology, and Tropical MedicineFaculty Publications Microbiology, Immunology, and Tropical Medicine2015Gene function in schistosomes: recent advancestoward a cureArnon D. JurburgPaul J. BrindleyGeorge Washington UniversityFollow this and additional works at: http://hsrc.himmelfarb.gwu.edu/smhs_microbio_facpubsPart of the Genetics and Genomics Commons, Medical Immunology Commons, MedicalMicrobiology Commons, and the Parasitology CommonsThis Journal Article is brought to you for free and open access by the Microbiology, Immunology, and Tropical Medicine at Health Sciences ResearchCommons. It has been accepted for inclusion in Microbiology, Immunology, and Tropical Medicine Faculty Publications by an authorizedadministrator of Health Sciences Research Commons. For more information, please contact hsrc@gwu.edu.APA CitationJurburg, A. D., & Brindley, P. J. (2015). Gene function in schistosomes: recent advances toward a cure. Frontiers in Genetics, 6 ().http://dx.doi.org/10.3389/fgene.2015.00144EDITORIALpublished: 15 April 2015doi: 10.3389/fgene.2015.00144Frontiers in Genetics | www.frontiersin.org 1 April 2015 | Volume 6 | Article 144Edited and reviewed by:John R. Battista,Louisiana State University and A & MCollege, USA*Correspondence:Arnon D. Jurberg,ajurberg@ioc.fiocruz.br;ajurberg@gmail.com;Paul J. Brindley,pbrindley@gwu.eduSpecialty section:This article was submitted toEvolutionary and GenomicMicrobiology,a section of the journalFrontiers in GeneticsReceived: 16 February 2015Accepted: 26 March 2015Published: 15 April 2015Citation:Jurberg AD and Brindley PJ (2015)Gene function in schistosomes: recentadvances toward a cure.Front. Genet. 6:144.doi: 10.3389/fgene.2015.00144Gene function in schistosomes:recent advances toward a cureArnon D. Jurberg 1, 2* and Paul J. Brindley 3*1 Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation/Fiocruz, Rio de Janeiro, Brazil,2Graduate Program in Cell and Developmental Biology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro,Rio de Janeiro, Brazil, 3Department of Microbiology, Immunology, and Tropical Medicine, Research Center for NeglectedDiseases of Poverty, School of Medicine and Health Sciences, Washington, DC, USAKeywords: schistosomiasis, economical impact, poverty, treatment, gene functionNeglected Tropical Diseases (NTDs) drive poverty and social inequality; indeed NTDs are mani-festations of these problems (Bardosh, 2014). Poverty is a major detriment to human development.Measuring poverty by estimating poverty lines has led the World Bank to initially set the incomevalue of US$1 a day and later update it to US$1.25 a day at 2005 purchasing power parity as therevised international poverty line (Ravallion et al., 1991, 2009). This meant that in 2005 peopleearning less than US$37.5 a month lived in poverty—about 1.4 billion people worldwide (Chen andRavallion, 2008). Despite considerable efforts and highly uneven temporal and regional improve-ments since that point (Chen and Ravallion, 2008; United Nations, 2013), each one of these impov-erished persons is potentially exposed to infectious diseases due to precarious conditions, such ascontaminated drinking water, malnutrition, lack of sanitation or shelter, and inadequate basic ser-vices including education, health and security (WHO-World Health Organization, 2012; UnitedNations, 2013).However, because they mostly impact populations of lower-income countries, the NTDs receiverelatively little attention and funding from the international community. For example, whereashelminth infections are estimated to affect more than one billion people in sub-Saharan Africa,Asia and the Americas (Hotez et al., 2007), the global expenditures on helminth infection targetedresearch and development (R&D) was a mere US$66.8 million in 2008, with uneven distributionacross diverse diseases and focus mainly for basic research (Institute of Medicine, 2011). In com-parison, Kanavos et al. (2010) have estimated a global investment of more than US$17 billion oncancer R&D in 2007, with estimates for 2008 of more than 12.7 million new cases and∼7.6 milliondeaths (Ferlay et al., 2010). Although, deaths due to helminth infection, estimated to be around300,000 deaths a year, are not as imposing as for some other infectious diseases associated mor-tality, helminth infection-induced burden of disease results in premature and ongoing disabilityand impediments throughout life, and impacts negatively and largely on the economy of endemicregions (Hotez et al., 2006). Hence, these characteristics led to the grouping of 17 parasitic, bacterialand viral diseases as NTDs by the World Health Organization (Salaam-Blyther, 2014).Schistosomiasis is one of these NTDs, and moreover is considered the most important of thehelminth diseases in terms of morbidity and mortality (Hotez et al., 2008; King, 2015). Amongthe most problematic of the NTDs due to its extensive geographical distribution and publichealth impact, schistosomiasis is caused by infection with trematode worms of the genus Schis-tosoma. Infection occurs in contaminated freshwater through skin penetration of a larval formof the worm known as the cercaria. Cercariae are produced by clonal expansion of germinalcells in the intermediate snail host following infection of the snail by a ciliated larva termed themiracidium (Pan, 1965; Cheng and Bier, 1972; Jurberg et al., 2008). There are species-specific,geographical constraints among the schistosome and the intermediate host. Schistosoma man-soni infects snails of the genus Biomphalaria, whereas S. japonicum and S. haematobium infectthe genera Oncomelania and Bulinus, respectively. In these snails, the invading miracidium firstJurberg and Brindley Gene function in schistosomestransforms into mother-sporocyst then into daughter-sporocystsprior to generation of cercariae, which escape from the snail backto the freshwater. Cercariae actively swim toward a human hostwhere they penetrate the skin directly (Pan, 1965). Within thehuman skin, the cercaria sheds its tail, transforms into a bloodvessel inhabiting form termed the schistosomulum, which devel-ops within the bloodstream or to a lesser extent the lymphaticsystem (Miller and Wilson, 1978). These schistosomula circu-late with the blood as they develop to sexually mature bloodflukes, sometimes completing two or three systemic circuits untilthey establish residency in the portal hepatic tract (S. mansoniand S. japonicum) or the pelvic organs (S. haematobium) (Wil-son, 2009). Unlike other platyhelminths, schistosomes evolveddioecism—separate sexes—and need to mate for producing eggs.Eggs are released into the bloodstream and many embolize insmaller blood vessels and capillaries of diverse organs, inducingthe characteristic granulomatous reaction of schistosomiasis (seeHams et al., 2013). Eggs reaching the intestines (S. mansoni andS. japonicum) or the bladder (S. haematobium) induce inflam-matory responses that facilitate passage of the schistosome eggthrough the wall of bowel or bladder, respectively, to the lumenfrom where the eggs exit to the external environment in feces orurine (Lenzi et al., 1987 for S. mansoni). On the reaching fresh-water, the egg hatches to release the motile, ciliated miracidium,thereby completing the developmental cycle of the pathogen, asdepicted in Figure 1. Eggs that fail to be eliminatedmay cause dif-ferent symptoms depending on the schistosome species, but fre-quently cause chronic inflammation and fibrosis (Gryseels et al.,2006; Hams et al., 2013; Colley and Secor, 2014).In spite of the information on schistosome biology atpresent, with 14,933 published papers from 1980 to 2014 (using“Schistosoma” as the query at PubMed)—which accounts for78% of all the retrieved schistosome literature at this database—a definitive cure for schistosomiasis still faces daunting chal-lenges and may be far from being achieved. In particular, 71%of the research funds for schistosomiasis in 2008 (approx-imately US$14 million) were designed to basic instead ofapplied investigation (Institute of Medicine, 2011). Yet, con-current presence of schistosomes at different stages of devel-opment floods the infected person with a battery of diverseantigens, which induce conflicting immune responses (Colleyand Secor, 2014). Moreover, naturally occurring re-infectionsraise the possibility that immunization against schistosomia-sis may not work (Colley and Secor, 2014). Another aspect ofcontrolling schistosome infection regards education and san-itation, once informed endemic populations still insist on,and/or frequently have no alternative but using the contam-inated watercourses for bathing, laundry and other house-hold activities, recreation, and so forth (Enk et al., 2010)(Supplementary Figure 1). Indeed, the sustained and repeateduse of praziquantel in endemic regions raises the justifiableworry for the appearance of drug resistance (Cioli et al., 2014).To raise hopes for fighting schistosomiasis, game-changingadvances and tools from other fields of research are beingadapted and implemented for research on schistosomes, espe-cially the strategies related to the study of gene function (Hoff-mann et al., 2014). For example, deployment of the clusteredFIGURE 1 | Developmental cycle of the schistosome. Schistosomes areobligate parasites that evolved a complex developmental cycle using twohosts, a snail and a human (or other mammal). In the human (or laboratorymouse, or other permissive mammalian host), the worms reside within theblood and reproduce sexually. Eggs released by the female schistosome exitto the external environment with the feces or urine. The egg hatches infreshwater, releasing the miracidium larva that infected the aquatic snail. Theparasite undergoes asexual reproduction in the snail, producing cercariae thatare shed from the snail into the water. Cercariae penetrate the skin of thehuman in contact with contaminated water, to complete the developmentalcycle of the pathogen (we acknowledge Figure 1 of Gryseels et al. (2006) forinspiration for this schematic).regulatory interspaced short palindromic repeats (CRISPR)/Cassystem for genome editing (see Doudna and Charpentier, 2014)and/or schistosome transgenesis for gain-of-function manipu-lation (Mann et al., 2014) extends the range of experimen-tal approaches to interrogate the host-parasite relationship andto test novel vaccines and other interventions. It is now thetime for research on schistosomiasis to evolve from -omics tofunction.Our new research topic includes 15 papers, both primaryresearch articles and reviews from a representative cadre of theleading experts in the field of research on schistosomes and schis-tosomiasis, and neglected tropical diseases. The themes spanmolecular genetics including chromosomal evolution, epigeneticcontrol of schistosome genes, vaccine studies including targetingproteolysis and enzyme inhibitors central to the physiology of theparasites, and how infection with this NTD pathogen inducesbladder cancer. The reports also address signaling pathways,including insulin receptors in these pathogens, kinomes, andkinases, glycogenome, molecular studies on sex differentiationFrontiers in Genetics | www.frontiersin.org 2 April 2015 | Volume 6 | Article 144Jurberg and Brindley Gene function in schistosomesand host-parasite interactions including the snail-schistosomerelationship. The 91 authors are from 14 countries, includingfrom regions where schistosomiasis is endemic such as Angola,Egypt, Brazil, and China. We hope you will be informed by thisseries, as well as enjoy the authors’ scholarly contributions, thatthe work and ideas presented advance the field toward better con-trol or even a cure for schistosomiasis, and that this ResearchTopic elevates investigation in schistosomiasis and related NTDsinto the more newsworthy areas of emerging and infectiousdisease research.AcknowledgmentsWe thank Paulo Marcos Zech Coelho and Áureo Almeidafor kindly providing the photographs and Meredith E. Brind-ley for expert assistance with the artwork and figures.AJ received support from awards 400408/2013-9, ConselhoNacional de Desenvolvimento Científico e Tecnológico (CNPq)and E-26/111.086/2014, Fundação Carlos Chagas Filho deAmparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ).PB received support from awards CA155297 and CA164719,National Cancer Institute, US National Institutes of Health.Supplementary MaterialThe Supplementary Material for this article can be foundonline at: http://www.frontiersin.org/journal/10.3389/fgene.2015.00144/fullSupplementary Figure 1 | A representative endemic region forschistosomiasis, in this example in rural Minas Gerais state, Brazil. Thetriptych illustrates the role of sub-standard sanitation and of human activities incontaminated watercourses that also are ecosystems that include the snailintermediate hosts of schistosomiasis (Photographs kindly provided by ÁureoAlmeida and Paulo Marcos Coelho, René Rachou Research Center/Fiocruz-MG,Brazil).ReferencesBardosh, K. (2014). Global aspirations, local realities: the role of social scienceresearch in controlling neglected tropical diseases. Infect. Dis. Poverty. 3:35. doi:10.1186/2049-9957-3-35Chen, S., and Ravallion, M. (2008). The Developing World is Poorer Than WeThought, but no Less Successful in the Fight Against Poverty. Washington DC,World Bank.Cheng, T. C., and Bier, J. W. (1972). Studies on molluscan schistosomiasis: ananalysis of the development of the cercaria of Schistosoma mansoni. Parasitol-ogy 64, 129–141. doi: 10.1017/S003118200004470XCioli, D., Pica-Mattoccia, L., Basso, A., and Guidi, A. (2014). Schistosomiasiscontrol: praziquantel forever? Mol. Biochem. Parasitol. 195, 23–29. doi:10.1016/j.molbiopara.2014.06.002Colley, D. G., and Secor, W. E. (2014). Immunology of human schistosomiasis.Parasite Immunol. 36, 347–357. doi: 10.1111/pim.12087Doudna, J. A., and Charpentier, E. (2014). Genome editing. The new frontier ofgenome engineering with CRISPR-Cas9. Science 346:1258096. doi: 10.1126/sci-ence.1258096Enk, M. J., Lima, A. C., Barros Hda, S., Massara, C. L., Coelho, P. M., and Schall,V.T. (2010). Factors related to transmission of and infection with Schistosomamansoni in a village in the South-eastern Region of Brazil.Mem. Inst. OswaldoCruz. 105, 570–577. doi: 10.1590/S0074-02762010000400037Ferlay, J., Shin, H.-R., Bray, F., Forman, D., Mathers, C., and Parkin, D. M. (2010).Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J.Cancer 127, 2893–2917. doi: 10.1002/ijc.25516Gryseels, B., Polman, K., Clerinx, J., and Kestens, L. (2006). Human schistosomia-sis. Lancet 368, 1106–1118. doi: 10.1016/S0140-6736(06)69440-3Hams, E., Aviello, G., and Fallon, P. G. (2013). The Schistosoma granuloma: friendor foe? Front. Immunol. 4:89. doi: 10.3389/fimmu.2013.00089Hoffmann, K. F., Brindley, P. J., and Berriman, M. (2014). Halting harmfulhelminths. Science 346, 168–169. doi: 10.1126/science.1261139Hotez, P. J., Brindley, P. J., Bethony, J. M., King, C. H., Pearce, E. J., and Jacobson, J.(2008). Helminth infections: the great neglected tropical diseases. J. Clin. Invest.188, 1311–1321. doi: 10.1172/JCI34261Hotez, P. J., Bundy, D. A. P., Beegle, K., Brooker, S., Drake, L., de Silva, N., et al.(2006). “Helminth infections: soil-transmitted helminth infections and schisto-somiasis,” inDisease Control Priorities in Developing Countries, 2nd Edn., eds D.T. Jamison, J. G. Breman, A. R. Measham, G. Alleyne, M. Claeson, D. B. Evans,P. Jha, A. Mills, and P. Musgrove (Washington, DC: World Bank), 467–482.Hotez, P. J., Molyneux, D. H., Fenwick, A., Kumaresan, J., Sachs, S. E., Sachs, J.D., et al. (2007). Control of neglected tropical diseases. N. Engl. J. Med. 357,1018–1027. doi: 10.1056/NEJMra064142Institute of Medicine. (2011). The Causes and Impacts of Neglected Tropical andZoonotic Diseases: Opportunities for Integrated Intervention Strategies. Wash-ington, DC: The National Academies Press.Jurberg, A. D., Pascarelli, B. M., Pelajo-Machado, M., Maldonado, A. Jr., Mota,E. M., and Lenzi, H. L. (2008). Trematode embryology: a new method forwhole-egg analysis by confocal microscopy.Dev. Genes Evol. 218, 267–271. doi:10.1007/s00427-008-0209-0Kanavos, P., Sullivan, R., Lewison, G., Schurer, W., Eckhouse, S., and Vlachopi-oti, Z. (2010). The role of funding and policies on innovation in cancer drugdevelopment. Ecancermedicalscience 4:164. doi: 10.3332/ecancer.2010.164King, C. H. (2015). It’s time to dispel the myth of “asymptomatic” schis-tosomiasis. PLoS Negl. Trop. Med. 9:e0003504. doi: 10.1371/journal.pntd.0003504Lenzi, H. L., Lenzi, J. A., and Sobral, A. C. (1987). Eosinophils favor the passageof eggs to the intestinal lumen in schistosomiasis. Braz. J. Med. Biol. Res. 20,433–435.Mann, V. H., Suttiprapa, S., Skinner, D. E., Brindley, P. J., and Rinaldi, G. (2014).Pseudotyped murine leukemia virus for schistosome transgenesis: approaches,methods and perspectives. Transgenic Res. 23, 539–556. doi: 10.1007/s11248-013-9779-3Miller, P., and Wilson, R. A. (1978). Migration of the schistosomula of Schis-tosoma mansoni from the skin to lungs. Parasitology 77, 281–302. doi:10.1017/S0031182000050253Pan, S. C. (1965). The fine structure of the miracidium of Schistosomamansoni. J. Invertebr. Pathol. 36, 307–372. doi: 10.1016/0022-2011(80)90040-3Ravallion, M., Chen, S., and Sangraula, P. (2009). Dollar a day revisited. WorldBank Econ. Rev. 23, 163–184. doi: 10.1093/wber/lhp007Ravallion, M., Datt, G., and van de Walle, D. (1991). Quantifying absolute povertyin the developing world. Rev. Income Wealth 37, 345–361. doi: 10.1111/j.1475-4991.1991.tb00378.xSalaam-Blyther, T. (2014). Progress in Combating Neglected Tropical Diseases(NTDs): U.S. and Global Efforts from FY2006 to FY2015. Washington, DC:Congressional Research Service.United Nations. (2013). A New Global Partnership: Eradicate Poverty andTransform Economies through Sustainable Development. The Report ofthe High-Level Panel of Eminent Persons on the Post-2015 Develop-ment Agenda (New York, NY: UN Publications), 69. Available online at:http://www.un.org/sg/management/pdf/HLP_P2015_Report.pdfWHO-World Health Organization. (2012). Research Priorities for HelminthInfections: Technical Report of the TDR Disease Reference Group onHelminth Infections (Geneva: WHO Press), 174. Available online at:www.who.int/tdr/stewardship/global_report/en/index.htmlFrontiers in Genetics | www.frontiersin.org 3 April 2015 | Volume 6 | Article 144Jurberg and Brindley Gene function in schistosomesWilson, R. A. (2009). The saga of schistosome migration and attrition. Parasitology136, 1581–1592. doi: 10.1017/S0031182009005708Conflict of Interest Statement: The authors declare that the research was con-ducted in the absence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.Copyright © 2015 Jurberg and Brindley. This is an open-access article distributedunder the terms of the Creative Commons Attribution License (CC BY). The use,distribution or reproduction in other forums is permitted, provided the originalauthor(s) or licensor are credited and that the original publication in this jour-nal is cited, in accordance with accepted academic practice. No use, distribution orreproduction is permitted which does not comply with these terms.Frontiers in Genetics | www.frontiersin.org 4 April 2015 | Volume 6 | Article 144

English

Gene function in schistosomes: recent advances toward a cure

Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa do Timo. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Ciências Biomédicas. Programa de Pós-Graduação em Biologia Celular e do Desenvolvimento. Rio de Janeiro, RJ, Brasil.School of Medicine and Health Sciences. Research Center for Neglected Diseases of Poverty. Department of Microbiology, Immunology and Tropical Medicine. Washington, DC, USA

LAReferencia - Red Federada de Repositorios Institucionales de Publicaciones Científicas Latinoamericanas

Schistosomes are human parasites distributed worldwide in tropical and sub-tropical latitudes, especially in developing countries and impoverished regions. These neglected tropical disease (NTD) pathogens causes debilitating illnesses, which include hepatosplenomegaly, hepatic fibrosis, haemorrhagic necrotic ulcerations in the intestinal mucosa, urogenital tract diseases, in addition to cardiopulmonary, renal and neurologic lesions due to egg accumulation in the liver, intestines, uro-genital tissues and other sites. Urogenital schistosomiasis is a risk factor for bladder cancer and increases the risk of transmission of HIV infection. Despite extensive effort to control this NTD over the years, deployment on a considerable scale of commercially available drugs in endemic populations has induced the emergence of resistant isolates and raised the need to identify new targets for alternative therapies. Because of the availability of genomes of the three major species of human schistosomiasis, and through advances in functional genomics and live imaging, studies on schistosomes have now come into focus as models to investigate adaptations to parasitism and developmental biology of trematodes and cestodes, and indeed flatworms and Lophotrochozoans, at large. This Research Topic aims at gathering state-of-art essays on schistosome genetics, genetics, pathobiology and immunobiology. It also aims to highlight advances in understanding of the host-parasite relationship, in paradigms that address this NTD, and to discuss new perspectives and advances in chemotherapy and immunoprophylaxis

Dias Jurberg, Arnon

Expeditio Repositorio Institucional Universidad Jorge Tadeo Lozano

Gene function in schistosomes: recent advances towards a cure

Arnon Dias Jurberg

Paul J Brindley

Directory of Open Access Books (DOAB)

Arnon D. Jurberg

Paul J. Brindley

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EDITORIAL
published: 15 April 2015
doi: 10.3389/fgene.2015.00144
Frontiers in Genetics | www.frontiersin.org 1 April 2015 | Volume 6 | Article 144
Edited and reviewed by:
John R. Battista,
Louisiana State University and A & M
College, USA
*Correspondence:
Arnon D. Jurberg,
ajurberg@ioc.fiocruz.br;
ajurberg@gmail.com;
Paul J. Brindley,
pbrindley@gwu.edu
Specialty section:
This article was submitted to
Evolutionary and Genomic
Microbiology,
a section of the journal
Frontiers in Genetics
Received: 16 February 2015
Accepted: 26 March 2015
Published: 15 April 2015
Citation:
Jurberg AD and Brindley PJ (2015)
Gene function in schistosomes: recent
advances toward a cure.
Front. Genet. 6:144.
doi: 10.3389/fgene.2015.00144
Gene function in schistosomes:
recent advances toward a cure
Arnon D. Jurberg 1, 2* and Paul J. Brindley 3*
1 Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation/Fiocruz, Rio de Janeiro, Brazil,
2Graduate Program in Cell and Developmental Biology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro,
Rio de Janeiro, Brazil, 3Department of Microbiology, Immunology, and Tropical Medicine, Research Center for Neglected
Diseases of Poverty, School of Medicine and Health Sciences, Washington, DC, USA
Keywords: schistosomiasis, economical impact, poverty, treatment, gene function
Neglected Tropical Diseases (NTDs) drive poverty and social inequality; indeed NTDs are mani-
festations of these problems (Bardosh, 2014). Poverty is a major detriment to human development.
Measuring poverty by estimating poverty lines has led the World Bank to initially set the income
value of US$1 a day and later update it to US$1.25 a day at 2005 purchasing power parity as the
revised international poverty line (Ravallion et al., 1991, 2009). This meant that in 2005 people
earning less than US$37.5 a month lived in poverty—about 1.4 billion people worldwide (Chen and
Ravallion, 2008). Despite considerable efforts and highly uneven temporal and regional improve-
ments since that point (Chen and Ravallion, 2008; United Nations, 2013), each one of these impov-
erished persons is potentially exposed to infectious diseases due to precarious conditions, such as
contaminated drinking water, malnutrition, lack of sanitation or shelter, and inadequate basic ser-
vices including education, health and security (WHO-World Health Organization, 2012; United
Nations, 2013).
However, because they mostly impact populations of lower-income countries, the NTDs receive
relatively little attention and funding from the international community. For example, whereas
helminth infections are estimated to affect more than one billion people in sub-Saharan Africa,
Asia and the Americas (Hotez et al., 2007), the global expenditures on helminth infection targeted
research and development (R&D) was a mere US$66.8 million in 2008, with uneven distribution
across diverse diseases and focus mainly for basic research (Institute of Medicine, 2011). In com-
parison, Kanavos et al. (2010) have estimated a global investment of more than US$17 billion on
cancer R&D in 2007, with estimates for 2008 of more than 12.7 million new cases and∼7.6 million
deaths (Ferlay et al., 2010). Although, deaths due to helminth infection, estimated to be around
300,000 deaths a year, are not as imposing as for some other infectious diseases associated mor-
tality, helminth infection-induced burden of disease results in premature and ongoing disability
and impediments throughout life, and impacts negatively and largely on the economy of endemic
regions (Hotez et al., 2006). Hence, these characteristics led to the grouping of 17 parasitic, bacterial
and viral diseases as NTDs by the World Health Organization (Salaam-Blyther, 2014).
Schistosomiasis is one of these NTDs, and moreover is considered the most important of the
helminth diseases in terms of morbidity and mortality (Hotez et al., 2008; King, 2015). Among
the most problematic of the NTDs due to its extensive geographical distribution and public
health impact, schistosomiasis is caused by infection with trematode worms of the genus Schis-
tosoma. Infection occurs in contaminated freshwater through skin penetration of a larval form
of the worm known as the cercaria. Cercariae are produced by clonal expansion of germinal
cells in the intermediate snail host following infection of the snail by a ciliated larva termed the
miracidium (Pan, 1965; Cheng and Bier, 1972; Jurberg et al., 2008). There are species-specific,
geographical constraints among the schistosome and the intermediate host. Schistosoma man-
soni infects snails of the genus Biomphalaria, whereas S. japonicum and S. haematobium infect
the genera Oncomelania and Bulinus, respectively. In these snails, the invading miracidium first
Jurberg and Brindley Gene function in schistosomes
transforms into mother-sporocyst then into daughter-sporocysts
prior to generation of cercariae, which escape from the snail back
to the freshwater. Cercariae actively swim toward a human host
where they penetrate the skin directly (Pan, 1965). Within the
human skin, the cercaria sheds its tail, transforms into a blood
vessel inhabiting form termed the schistosomulum, which devel-
ops within the bloodstream or to a lesser extent the lymphatic
system (Miller and Wilson, 1978). These schistosomula circu-
late with the blood as they develop to sexually mature blood
flukes, sometimes completing two or three systemic circuits until
they establish residency in the portal hepatic tract (S. mansoni
and S. japonicum) or the pelvic organs (S. haematobium) (Wil-
son, 2009). Unlike other platyhelminths, schistosomes evolved
dioecism—separate sexes—and need to mate for producing eggs.
Eggs are released into the bloodstream and many embolize in
smaller blood vessels and capillaries of diverse organs, inducing
the characteristic granulomatous reaction of schistosomiasis (see
Hams et al., 2013). Eggs reaching the intestines (S. mansoni and
S. japonicum) or the bladder (S. haematobium) induce inflam-
matory responses that facilitate passage of the schistosome egg
through the wall of bowel or bladder, respectively, to the lumen
from where the eggs exit to the external environment in feces or
urine (Lenzi et al., 1987 for S. mansoni). On the reaching fresh-
water, the egg hatches to release the motile, ciliated miracidium,
thereby completing the developmental cycle of the pathogen, as
depicted in Figure 1. Eggs that fail to be eliminatedmay cause dif-
ferent symptoms depending on the schistosome species, but fre-
quently cause chronic inflammation and fibrosis (Gryseels et al.,
2006; Hams et al., 2013; Colley and Secor, 2014).
In spite of the information on schistosome biology at
present, with 14,933 published papers from 1980 to 2014 (using
“Schistosoma” as the query at PubMed)—which accounts for
78% of all the retrieved schistosome literature at this database—
a definitive cure for schistosomiasis still faces daunting chal-
lenges and may be far from being achieved. In particular, 71%
of the research funds for schistosomiasis in 2008 (approx-
imately US$14 million) were designed to basic instead of
applied investigation (Institute of Medicine, 2011). Yet, con-
current presence of schistosomes at different stages of devel-
opment floods the infected person with a battery of diverse
antigens, which induce conflicting immune responses (Colley
and Secor, 2014). Moreover, naturally occurring re-infections
raise the possibility that immunization against schistosomia-
sis may not work (Colley and Secor, 2014). Another aspect of
controlling schistosome infection regards education and san-
itation, once informed endemic populations still insist on,
and/or frequently have no alternative but using the contam-
inated watercourses for bathing, laundry and other house-
hold activities, recreation, and so forth (Enk et al., 2010)
(Supplementary Figure 1). Indeed, the sustained and repeated
use of praziquantel in endemic regions raises the justifiable
worry for the appearance of drug resistance (Cioli et al., 2014).
To raise hopes for fighting schistosomiasis, game-changing
advances and tools from other fields of research are being
adapted and implemented for research on schistosomes, espe-
cially the strategies related to the study of gene function (Hoff-
mann et al., 2014). For example, deployment of the clustered
FIGURE 1 | Developmental cycle of the schistosome. Schistosomes are
obligate parasites that evolved a complex developmental cycle using two
hosts, a snail and a human (or other mammal). In the human (or laboratory
mouse, or other permissive mammalian host), the worms reside within the
blood and reproduce sexually. Eggs released by the female schistosome exit
to the external environment with the feces or urine. The egg hatches in
freshwater, releasing the miracidium larva that infected the aquatic snail. The
parasite undergoes asexual reproduction in the snail, producing cercariae that
are shed from the snail into the water. Cercariae penetrate the skin of the
human in contact with contaminated water, to complete the developmental
cycle of the pathogen (we acknowledge Figure 1 of Gryseels et al. (2006) for
inspiration for this schematic).
regulatory interspaced short palindromic repeats (CRISPR)/Cas
system for genome editing (see Doudna and Charpentier, 2014)
and/or schistosome transgenesis for gain-of-function manipu-
lation (Mann et al., 2014) extends the range of experimen-
tal approaches to interrogate the host-parasite relationship and
to test novel vaccines and other interventions. It is now the
time for research on schistosomiasis to evolve from -omics to
function.
Our new research topic includes 15 papers, both primary
research articles and reviews from a representative cadre of the
leading experts in the field of research on schistosomes and schis-
tosomiasis, and neglected tropical diseases. The themes span
molecular genetics including chromosomal evolution, epigenetic
control of schistosome genes, vaccine studies including targeting
proteolysis and enzyme inhibitors central to the physiology of the
parasites, and how infection with this NTD pathogen induces
bladder cancer. The reports also address signaling pathways,
including insulin receptors in these pathogens, kinomes, and
kinases, glycogenome, molecular studies on sex differentiation
Frontiers in Genetics | www.frontiersin.org 2 April 2015 | Volume 6 | Article 144
Jurberg and Brindley Gene function in schistosomes
and host-parasite interactions including the snail-schistosome
relationship. The 91 authors are from 14 countries, including
from regions where schistosomiasis is endemic such as Angola,
Egypt, Brazil, and China. We hope you will be informed by this
series, as well as enjoy the authors’ scholarly contributions, that
the work and ideas presented advance the field toward better con-
trol or even a cure for schistosomiasis, and that this Research
Topic elevates investigation in schistosomiasis and related NTDs
into the more newsworthy areas of emerging and infectious
disease research.
Acknowledgments
We thank Paulo Marcos Zech Coelho and Áureo Almeida
for kindly providing the photographs and Meredith E. Brind-
ley for expert assistance with the artwork and figures.
AJ received support from awards 400408/2013-9, Conselho
Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
and E-26/111.086/2014, Fundação Carlos Chagas Filho de
Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ).
PB received support from awards CA155297 and CA164719,
National Cancer Institute, US National Institutes of Health.
Supplementary Material
The Supplementary Material for this article can be found
online at: http://www.frontiersin.org/journal/10.3389/fgene.
2015.00144/full
Supplementary Figure 1 | A representative endemic region for
schistosomiasis, in this example in rural Minas Gerais state, Brazil. The
triptych illustrates the role of sub-standard sanitation and of human activities in
contaminated watercourses that also are ecosystems that include the snail
intermediate hosts of schistosomiasis (Photographs kindly provided by Áureo
Almeida and Paulo Marcos Coelho, René Rachou Research Center/Fiocruz-MG,
Brazil).
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Conflict of Interest Statement: The authors declare that the research was con-
ducted in the absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Copyright © 2015 Jurberg and Brindley. This is an open-access article distributed
under the terms of the Creative Commons Attribution License (CC BY). The use,
distribution or reproduction in other forums is permitted, provided the original
author(s) or licensor are credited and that the original publication in this jour-
nal is cited, in accordance with accepted academic practice. No use, distribution or
reproduction is permitted which does not comply with these terms.
Frontiers in Genetics | www.frontiersin.org 4 April 2015 | Volume 6 | Article 144


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