Break Out: Urogenital Schistosomiasis and Schistosoma Haematobium Infection in the Post- Genomic Era Paul J

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3-2013 Break out: Urogenital schistosomiasis and Schistosoma haematobium infection in the post- genomic era Paul J. Brindley George Washington University

Peter J. Hotez George Washington University

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Recommended Citation Brindley, P.J. & Hotez, P.J. (2013). Break out: Urogenital schistosomiasis and Schistosoma haematobium infection in the post-genomic era. PLoS Neglected Tropical Diseases, 7(3), article number e1961.

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Paul J. Brindley1*, Peter J. Hotez2,3* 1 Department of Microbiology, Immunology, and Tropical Medicine, George Washington University School of Medicine and Health Sciences, Washington DC, United States of America, 2 Departments of Pediatrics and Molecular Virology and Microbiology, National School of Tropical Medicine at Baylor College of Medicine, Houston, Texas, United States of America, 3 Sabin Vaccine Institute and Texas Children’s Hospital Center for Vaccine Development, Houston, Texas, United States of America

The newly completed whole genome sequence of resulting female genital schistosomiasis and other chronic morbidities that use Schistosoma haematobium, the leading cause (FGS) is associated with contact bleeding, disability-adjusted life years (DALYs) as a of human schistosomiasis and an emerging co- discharge, pain on intercourse, and sec- metric suggests that chronic urogenital factor in Africa’s AIDS and cancer epidemics, ondary infections and diminished fertility; schistosomiasis may equal or even exceed together with rapidly advancing genetic manipula- it is also a source of shame and stigma malaria or other better-known conditions tion technologies, is providing new insights that [6,7]. FGS is not a rare condition—one in terms of its disease burden in Africa [4]. could lead to the development of a new generation estimate suggested that of the estimated 70 Despite its overwhelming public health of tools for eliminating this ancient scourge. million children currently infected with S. importance and its well-established links to Today, more than 90% of the roughly haematobium, approximately 19 million girls HIV/AIDS and cancer, S. haematobium has 200 million cases of schistosomiasis occur and women will eventually develop FGS been labeled ‘‘the neglected schistosome’’ in Africa [1,2], of which approximately in the coming decade [8]. However, these [10,11]. Indeed, as shown in Table 1, a two-thirds are caused by Schistosoma haema- numbers are likely conservative estimates, search of the literature named in PubMed tobium [3], the etiologic agent of urogenital such that FGS may represent one of the (the online database of the US National schistosomiasis. More recently, Charles most common gynecological conditions in Library of Medicine) supports this asser- King and his colleagues have suggested Africa. tion. Over the last five years, there have that the number of cases of S. haematobium In addition to the pathologies outlined been 644 papers listed in PubMed per may be much greater than previously above, the effects of chronic S. haematobium million cases of Asian schistosomiasis believed, even possibly double or triple infection in children have been linked to caused by Schistosoma japonicum and 25 that of earlier prevalence estimates [4]. If chronic inflammation and pain, as well as papers per million cases of S. mansoni confirmed, urogenital schistosomiasis may growth stunting and cognitive deficits infection, Africa’s other major schisto- represent the most common infection or among tens of millions of children [4]. some. In contrast, only three papers per even adverse health condition in sub- FGS has also been identified as a co-factor million cases of S. haematobium infection Saharan Africa. in Africa’s AIDS epidemic, especially in have appeared in PubMed over the last Urogenital schistosomiasis results when Zimbabwe and Tanzania, where it was five years. (The 342 publications over the adult female S. haematobium worm pairs linked to a 3–4 times increased risk in past five years investigating S. haematobium living in the veins draining key pelvic acquiring HIV infection [6–8]. S. haemato- and schistosomiasis haematobia represent organs, including the bladder, uterus, and bium eggs have now been further identified challenging research; and much effort cervix, release terminal-spine eggs that as a Group 1 carcinogen responsible for a went into studies on this organism during penetrate the tissues and are excreted in in unique squamous cell carcinoma, which is the several decades before that. Much of the urine to allow propagation of the parasite life cycle. However, many schis- widespread in S. haematobium–endemic this work was undertaken with humans as tosome eggs fail to exit the body, and areas [5,9]. S. haematobium also exerts the host, compounding the challenges for come to embolize within the capillary beds important host endocrine effects based in the research and encumbering progress. of pelvic end-organs, especially the tissues part on its ability to synthesize and release Although a review of this literature is of the bladder, ureters, and female and estradiol [9]. A full consideration of these beyond the aim of our editorial, studies male genital organs. Here they induce granulomas and ultimately small fibrotic Citation: Brindley PJ, Hotez PJ (2013) Break Out: Urogenital Schistosomiasis and Schistosoma haematobium nodules known as ‘‘sandy patches’’ [5]. Infection in the Post-Genomic Era. PLoS Negl Trop Dis 7(3): e1961. doi:10.1371/journal.pntd.0001961 Numerous granulomas and sandy patches Published March 28, 2013 cause bladder and ureteral inflammation Copyright: ß 2013 Hotez, Brindley. This is an open-access article distributed under the terms of the Creative associated with hematuria in more than Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, 50% of the cases [3], in addition to organ provided the original author and source are credited. deformities associated with ureteric ob- Funding: No specific funding was received for this work. struction, secondary urinary tract and Competing Interests: The authors have declared that no competing interests exist. renal infections, hydronephrosis, and ulti- * E-mail: [email protected] (PJB); [email protected] (PJH) mately renal failure in millions of people living in Africa [5]. Paul J. Brindley, PhD, is a Deputy Editor of PLOS Neglected Tropical Diseases. He is a professor in the Department of Microbiology, Immunology and Tropical Medicine, School of Medicine & Health Sciences, The George Up to 75% of girls and women with Washington University, Washington, DC. He is also the Scientific Director of the Research Center for Neglected chronic S. haematobium infection will also Diseases of Poverty at George Washington University. Peter J. Hotez, MD, PhD, is Co-Editor-in-Chief of PLOS experience deposition of eggs with granu- Neglected Tropical Diseases. He is President of the Sabin Vaccine Institute, Professor and Head of the Section of Pediatric Tropical Medicine in the Department of Pediatrics at Texas Children’s Hospital and Baylor College of lomas and sandy patches on their uterus, Medicine, and Dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, cervix, and lower genital tract [6,7]. The Texas, United States of America.

PLOS Neglected Tropical Diseases | www.plosntds.org 1 March 2013 | Volume 7 | Issue 3 | e1961 Table 1. Number of citations in PubMed over the last five years, 2008–2012.

Number of PubMed Approximate Number of Citations over the Last PubMed Citations per Parasite Species Human Cases Five Yearsb Millions of Human Cases References

Schistosoma japonicum 1 million 644 644 Steinmann et al. 2006 [1] Schistosoma mansoni 54 milliona 1,371 25 Van der Werf et al. 2003 [3] Schistosoma haematobium 112 milliona 342 3 Van der Werf et al. 2003 [3]

aSub-Saharan Africa only. bSearch conducted on July 14, 2012. doi:10.1371/journal.pntd.0001961.t001 such as those by Agnew, Cheever, and japonicum infections has stimulated at neocarcinogenesis of eggs in situ, and Doenhoff on rodent models of infection least two generations of molecular and molecules with immunomodulatory [12,13]; Capron and co-workers on vac- cellular immunologists to undertake functions. cines [14]; Feldmeier, Kjetland, Shiff, and groundbreaking studies on these two others on female genital schistosomiasis helminthiases and to unravel the com- It is particularly promising and of great and bladder cancer [7,9,15]; Brooker, plexities of schistosome-mediated im- importance that the development of Deelder, Hamburger, Mutapi, Sturrock, munopathogenesis [21–23]. Within the mouse models for S. haematobium infections and others on epidemiology, co-infections, last two years (2011–2012), key studies is maturing roughly in parallel with the and diagnostics [3,16–18]; and Kitron, have been conducted in genetically development of in vitro technologies for Loker, and Rollinson on intermediate host modified knock-out mice to also iden- parasite gene manipulation together with snails, ecology, and evolutionary aspects tify co-factors, leading to improved the completion of whole genome sequenc- [10,19,20] have provided crucial scaffolds, understanding of S. haematobium carci- ing for S. haematobium. Assuming additional the ‘‘shoulders of giants’’ as it were. nogenesis [24], while microinjection of proteomic and metabolomics projects for Investigators accessing the newly available S. haematobium eggs in the bladder of S. haematobium move forward, together with genetic tools can now gaze from these mice has been shown to reproduce epigenetic studies and advances with in shoulders and hopefully move rapidly to urinary tract fibrosis and other bladder vitro methods linked to RNAi and trans- new interventions for S. haematobium infec- histopathologic changes typically found genesis, the next few years could become a tion. [We apologize to investigators we did in human urogenital schistosomiasis watershed for S. haematobium research. In not have space to mention.]) [25]. Expansion of such studies, in- so doing, we can anticipate striking new Nonetheless, the field of S. haematobium cluding work in humanized mouse insights into parasite-induced carcinogen- research, in contrast to studies for the models, will undoubtedly produce esis and HIV/AIDS co-infections that other schistosomes, has largely remained new insights into parasite-induced im- result from urogenital schistosomiasis. ‘‘on the outside looking in’’ with respect to munopathogenesis, carcinogenesis, Breakthroughs in S. haematobium studies breakthroughs in the areas of omics, high FGS, and HIV/AIDS co-infections. will require international cooperation and throughput drug screening, reverse vacci- a new level of support. The community of 2. In vitro systems. The first report of the S. haematobium researchers is not numeri- nology, molecular imaging, bioengineer- genetic manipulation of S. haematobium ing, structural biology, and molecular cally large, but could easily embrace by short interfering ribonucleic acids scientists working on other schistosomes immunology. Whereas some of the dearth (siRNAs) into parasite eggs, and subse- in scientific activity and productivity for as well as those involved in cancer and quent culturing of eggs, miracidia, urogenital schistosomiasis can be ascribed AIDS research. One way to proceed is to schistosomula, and adult schistosomes to the fact simply that it is a neglected establish a consortium of S. haematobium [11], portend enormous promise for tropical disease, this observation cannot investigators and projects, possibly analyzing novel S. haematobium genes. explain why research on S. japonicum and through joint funding from the US Such in vitro studies would comple- Schistosoma mansoni has been more active National Cancer Institute, National Insti- ment ongoing in vivo projects in mice and fruitful. It is plausible that the tute of Allergy and Infectious Disease as outlined above. Simultaneously, following factors are responsible for this (NIAID) and/or other institutes or centers work in mammalian cell lines and situation: 1) the absence of mouse animal of the National Institutes of Health (NIH), transgenic schistosomes will provide models; 2) the absence of in vitro systems; the Wellcome Trust, European Union and additional insights into parasite-medi- and 3) the absence of a completed genome government support, and possibly private ated carcinogenesis [26,27]. projects and related omics projects. donors such as the Bill & Melinda Gates The good news is that studies conducted 3. Omics. In 2012, the 385-Mb genome of Foundation. We believe that no one within the past two years suggest that S. haematobium was completed at 74-fold agency will likely do it all in terms of many of these barriers have now been coverage [28–30]. While there was a significantly advancing the S. haematobium surmounted either completely or partially high synteny between the roughly research and development agenda. We and that there is a path forward to 13,000 genes of S. haematobium and the also note that, with taxpayer-funded facilitate a new era of S. haematobium other two schistosomes, a number of support from the NIAID-NIH, an Egyp- research. unique S. haematobium genes were tian strain of S. haematobium and its identified, including genes encoding intermediate host snail Bulinus truncatus 1. Animal models of infection. The availability novel drug targets, estrogen-synthesiz- reagents are available to interested inves- of mouse models for S. mansoni and S. ing enzymes that might be involved in tigators anywhere in the world from the

PLOS Neglected Tropical Diseases | www.plosntds.org 2 March 2013 | Volume 7 | Issue 3 | e1961 BEI Resources catalog of the American [33]. While the drug donations and a in place an aggressive program of research Type Culture Collection [31]. subsequent 26 May 2012 World Health and development that includes fundamen- In 2012, the global community respond- Assembly resolution calling for schistoso- tal studies and translational approaches ed to the call that ‘‘Africa is desperate for miasis elimination [34] are essential, we toward development of new diagnostics, praziquantel’’ [32], with an unprecedent- feel that alone such measures will not drugs, and vaccines. Basic research con- ed commitment of praziquantel donations address Africa’s burden of S. haematobium– ducted within the last two years has now from Merck KgaA and a London Decla- induced cancer nor the stealth role of S. set the stage to go that extra mile. ration as a first step for the elimination of haematobium in promoting Africa’s AIDS schistosomiasis as a public health problem epidemic. In parallel, there needs to be put

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PLOS Neglected Tropical Diseases | www.plosntds.org 3 March 2013 | Volume 7 | Issue 3 | e1961