The Michael Hsieh Lab IN THE DEPARTMENT OF UROLOGY

My Personal Holy Grail

Posted 5:01 PM, February 4, 2013, by Michael Harrison Hsieh

A recent News Focus article in Science has highlighted the need for continued and expanded funding for development of schistosomiasis vaccines [1]. Miriam Tendler, a Brazilian parasitologist, has long labored over Sm14, a vaccine candidate for Schistosoma mansoni, the major worldwide cause of hepatoenteric schistosomiasis (see Dr. Tendler's picture below). Another vaccine candidate, Bilhvax, is based on the 28 kiloDalton glutathione S-transferase of Schistosoma haematobium, the etiologic agent of urogenital schistosomiasis[2]. I applaud these efforts, given that urogenital schistosomiasis is the most common form of schistosomiasis worldwide[3].
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However, the preclinical testing of the Bilhvax vaccine was based on two studies using patas monkeys[4,5]. Research of non-human primates such as patas monkeys is expensive, and to many people, ethically objectionable. Moreover, non-human primates suffer from a lack of species-specific reagents, at least relative to mice and other “workhorse” research species.

Accordingly, one of my personal holy grails has been the development of a rodent model of S. haematobium worm-based, urogenital oviposition. This model would be a low-cost alternative to non-human primate-based urogenital schistosomiasis research, and would likely be more amenable to scientific interrogation using rodent-specific reagents. Currently, natural transdermal infection (the mode of infection in humans) of rodents with S. haematobium leads to hepatoenteric rather than urogenital disease. Although this permits propagation of the S. haematobium life cycle, it does not facilitate studies of the important urogenital aspects of S. haematobium infection.

Indeed, Van der Werf et al. calculated that in a 2 week period in 2000, 70 and 32 million individuals in sub-Saharan Africa experienced hematuria and dysuria associated with S. haematobium infection, respectively [3]. Major S. haematobium-triggered bladder wall pathology and severe hydronephrosis (urinary tract dilatation, in this case due to obstruction) were predicted to afflict 18 and 10 million people, respectively. Urogenital schistosomiasis appears to predispose individuals to earlier onset and more aggressive bladder cancers [6,7]. Finally, 150,000 people die annually due to urogenital schistosomiasis-induced obstructive renal failure. Much of these sequelae, particularly in advanced infections, are not reversible by praziquantel, currently the only WHO-approved drug for schistosomiasis.

The lack of alternative treatments for advanced schistosomiasis led us, in large part, to develop the first tractable mouse model of urogenital schistosomiasis. In this model, we microinject S. haematobium eggs into the mouse bladder wall, which bypasses the problematic natural life cycle in mice. Egg injection results in many of the signs and symptoms seen in human urogenital schistosomiasis, including hematuria (bloody urine), urinary frequency, and the development of egg granulomata and urothelial hyperplasia and squamous metaplasia, two potential precursor lesions of bladder cancer[8,9].

Although this egg-based model has enormous potential for learning more about how S. haematobium eggs trigger bladder pathology in the mammalian host, ultimately it lacks worm-based oviposition. This is a flaw from the perspective of schistosomiasis-specific drugs, vaccines, and diagnostics, since many approaches are focused on worm-related biology. Establishing a rodent model wherein adult S. haematobium worms lay eggs in the pelvic organs of its host would open up tremendous opportunities for the development of schistosomiasis-specific drugs, vaccines, and diagnostics. I hope to be able to develop such a model soon; an efficacious schistosomiasis vaccine is indeed overdue.

1. Kupferschmidt, K. (2013). A Worm Vaccine, Coming at a Snail's Pace Science, 339 (6119), 502-503 DOI: 10.1126/science.339.6119.502
2. Riveau G, Poulain-Godefroy OP, Dupré L, Remoué F, Mielcarek N, et al. (1998) Glutathione S-transferases of 28kDa as major vaccine candidates against schistosomiasis. Memórias do Instituto Oswaldo Cruz 93 Suppl 1: 87–94. Available:http://www.ncbi.nlm.nih.gov/pubmed/9921328. Accessed 5 February 2013.
3. Van der Werf MJ, De Vlas SJ, Brooker S, Looman CW, Nagelkerke NJ, et al. (2003) Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa. Acta Trop 86: 125–139. Available:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12745133. Accessed 18 August 2011.
4. Boulanger D, Warter A, Trottein F, Mauny F, Brémond P, et al. (1995) Vaccination of patas monkeys experimentally infected with Schistosoma haematobium using a recombinant glutathione S-transferase cloned from S. mansoni. Parasite immunology 17: 361–369. Available:http://www.ncbi.nlm.nih.gov/pubmed/8552409. Accessed 5 February 2013.
5. Boulanger D, Warter A, Sellin B, Lindner V, Pierce RJ, et al. (1999) Vaccine potential of a recombinant glutathione S-transferase cloned from Schistosoma haematobium in primates experimentally infected with an homologous challenge. Vaccine 17: 319–326. Available:http://www.ncbi.nlm.nih.gov/pubmed/9987169. Accessed 5 February 2013.
6. Group W (2011) Schistosoma haematobium. In: International Agency for Research on Cancer WHO, editor. A Review of Human Carcinogens: Biological Agents. Geneva: World Health Organization, Vol. 100B. pp. 377–390.
7. Bedwani R, Renganathan E, El Kwhsky F, Braga C, Abu Seif HH, et al. (1998) Schistosomiasis and the risk of bladder cancer in Alexandria, Egypt. British journal of cancer 77: 1186–1189. Available:http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2150141&tool=pmcentrez&rendertype=abstract.
8. Ray D, Nelson TA, Fu C-L, Patel S, Gong DN, et al. (2012) Transcriptional Profiling of the Bladder in Urogenital Schistosomiasis Reveals Pathways of Inflammatory Fibrosis and Urothelial Compromise. PLoS Negl Trop Dis 6: e1912. Available:http://dx.plos.org/10.1371/journal.pntd.0001912. Accessed 30 November 2012.
9. Fu C-L, Odegaard JI, Herbert DR, Hsieh MH (2012) A Novel Mouse Model of Schistosoma haematobium Egg-Induced Immunopathology. PLoS Pathog 8: e1002605. Available:http://dx.plos.org/10.1371/journal.ppat.1002605. Accessed 30 March 2012.

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