inthedark

Reading PubMed Abstracts in the Dark

Within PubMed, users can configure literature searches of interest to be run automatically at regular intervals and have e-mail alerts sent when new publications are annotated in PubMed. As someone who studies Schistosoma haematobium, the parasitic worm that causes urogenital schistosomiasis, I naturally have an automatic search configured for “haematobium”. I have a terrible habit each morning, after my wake-up alarm goes off, of checking my iPhone for any e-mail alerts of new PubMed articles on S. haematobium. Typically my bedroom is still dark and my mind groggy when I do this. Imagine this, then, when I recently saw an e-mail alert that raised my eyebrows and woke me instantly.

The e-mail alert contained the abstract for an in press Vaccine article entitled “Cross-species protection: Schistosoma mansoni Sm-p80 vaccine confers protection against Schistosoma haematobium in hamsters and baboons”. This abstract caught my attention for a number of reasons. First, although I am not currently engaged in schistosome vaccine research, I would love to be so. Second, I am keenly interested in the potential applications and limitations of various animal models of urogenital schistosomiasis. Despite hamsters being suitable hosts for S. haematobium infection, they tend to develop hepatoenteric schistosomiasis, rather than urogenital disease like S. haematobium-infected humans. This greatly limits the value of hamsters for urogenital schistosomiasis research.

Indeed, the authors of this Vaccine article noted no urogenital pathology in any of their 7 vehicle- and 10 vaccine-treated hamsters, all of which had been infected with S. haematobium. Remarkably, this was true even after 28 weeks of infection. As the authors stated, “in this study no eggs were detected in the urinary bladder of hamsters either in the control or the experimental group. This drawback limits the suitability of hamsters as a model to study S. haematobium-associated pathogenesis to the fullest.” The authors then go on to note that “the lack of an experimentally tractable small animal model has significantly limited our knowledge of vaccine efficacy and mechanistic aspects related to the urogenital schistosomiasis pathogen, S. haematobium”. This statement, which echoes my sentiments exactly, is followed by a citation of our 2012 PLOS Pathogens paper describing the first tractable animal (mouse) model of S. haematobium egg-induced bladder pathology. Like hamsters, mice that are naturally infected through the skin with S. haematobium cercariae, the larval stage infective for humans, develop hepatoenteric rather than urogenital disease. In our PLOS Pathogens paper we bypassed this problematic life cycle by directly microinjecting S. haematobium eggs into the mouse bladder wall, thereby delivering the parasite life stage of interest into the host tissues of interest.

The authors of the Vaccine paper remarked that “even though statistically significant data were obtained from the hamster model on prophylactic efficacy, the absence of eggs in the urinary bladder indicated a better model was needed and led us to develop and optimize a S. haematobium model in baboons”. I applaud the authors for their determination to develop and test their vaccine in a higher fidelity experimental model of urogenital schistosomiasis. It has long been known that baboons are suitable hosts for S. haematobium infection, but non-human primate studies, including those using baboons, suffer from a lack of species-specific reagents, logistical difficulties (due to costs and housing needs), and are ethically contentious. Accordingly, the authors were only able to test a total of four baboons – 2 receiving vehicle injections, and 2 receiving the candidate vaccine. Fortunately the authors were able to obtain favorable data on egg counts in the bladder and urine of these baboons, but their findings are statistically limited by the small sample size.

One of the authors’ interesting findings is that the candidate vaccine seemed to induce gamma-interferon and IL-17-secreting peripheral blood mononuclear cells:

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This suggests that the vaccine induced antigen-specific cytokine secretion. Overall I was thrilled by this paper and I hope the vaccine succeeds. However, the manuscript perfectly highlighted some major shortcomings of my group’s work and the urogenital schistosomiasis research community more broadly. In short, we lack a tractable animal model of reliable, worm-based oviposition in host pelvic organs. Although my lab’s PLOS Pathogens paper was a contribution to the field, ultimately an egg-based mouse model of urogenital schistosomiasis is merely that. The vast majority of candidate diagnostics, drugs, and vaccines for urogenital schistosomiasis target adult S. haematobium worm-derived molecules. Baboons can be used for translational urogenital schistosomiasis research, but in the final analysis they are experimentally unwieldy. What we really need, and what my group continues to strive for, is a mouse model of worm-based egg laying in pelvic organs. The field needs a clever and reliable means to coax S. haematobium worms to lay eggs in the pelvic rather than digestive organs of the mouse. Success in this regard would open up urogenital schistosomiasis to high throughput diagnostic, drug, and vaccine testing.

I’m optimistic that we will eventually develop such a model. In the meantime, I’ll keep rolling over each morning and checking my iPhone for the latest updates.