The Michael Hsieh Lab IN THE DEPARTMENT OF UROLOGY

As Mouse-Like as Humanly Possible

Posted 7:42 PM, February 12, 2013, by Michael Harrison Hsieh

Professor Ron Davis, a fellow faculty member at Stanford, recently co-authored a Proceedings of the National Academy of Sciences (PNAS) paper reporting that a number of long-accepted mouse models of inflammatory diseases do not recapitulate the human versions of these ailments[1]. The poor correlation between transcriptional responses in mouse versus human infections, burns, and trauma is perhaps best demonstrated in this figure from the PNAS article:

PNAS figure.jpg

The red and blue letter symbols represent human and mouse inflammatory diseases, respectively. The x- and y-axes denote fold-changes in gene expression and the proportions of genes changed in the same direction (increased or decreased expression), respectively. A perfect mouse model would overlap completely with its human counterpart on the figure. Note that none of the mouse models come even close to overlapping their human versions!

Based on these and other findings outlined in the paper, the authors strongly caution against over-reliance on mouse models of inflammatory diseases. In other words, perhaps we have inadvertently rendered some disciplines of immunology as mouse-like as humanly possible. The movement towards so-called “human immunology” is also reflected elsewhere on the Stanford campus. Professor Mark Davis has championed a transition from mouse- to human-based immunology studies to better understand the human immune system. This is exemplified by Professor Davis’ recent publication in Immunity studying the virus-specific T cell repertoire of humans[2].

While these calls for clinical material-based research are warranted, ultimately many disorders are difficult to study directly in humans, either due to ethical and/or logistical obstacles. This applies to schistosomiasis, chronic infection with parasitic Schistosoma worms. Although it is feasible to study the systemic immune response to chronic schistosomiasis by performing assays on the peripheral blood of infected patients, it is challenging to catch patients during the acute phases when they are first infected. Most patients with schistosomiasis are infected as young children in endemic regions lacking the research infrastructure necessary for well-designed clinical studies. Thus, it is uncertain when many of these patients became first infected with schistosomiasis, and examining such patient cohorts in general is difficult in resource-poor endemic regions. Even studying newly Schistosoma-infected visitors to an endemic region is difficult; this patient cohort is small and sporadic, especially compared to the indigenous populations living in schistosomiasis-rampant areas.

There are additional challenges to completely human-based immunological studies in schistosomiasis. Much of the sequelae of infection are driven by the deposition of highly immunogenic eggs in the urogenital or hepatoenteric tracts. The resulting inflammation triggers granuloma formation and fibrosis. This can lead to obstructive kidney failure in the case of Schistosoma haematobium, the etiologic agent of urogenital schistosomiasis, or liver failure, in the case of Schistosoma mansoni and Schistosoma japonicum, which cause hepatoenteric schistosomiasis. Although end-stage schistosomiasis-induced tissue immune responses can be studied using cystectomy, hepatectomy, and bladder and liver biopsies, these tissues are not normally sampled in early schistosomiasis infections. Hence, it is ethically and logistically difficult to secure and study these infected tissues during acute infection. Understanding the acute tissue responses to schistosomiasis is likely key to preventing the development of chronic sequelae.

In large part, these issues led us to develop the first experimentally tractable mouse model of urogenital schistosomiasis[3,4]. Historically, natural transdermal infection of mice (the route of infection for humans) with S. haematobium results in hepatoenteric rather than urogenital schistosomiasis. To overcome the problematic life cycle in mice, we microinjected purified S. haematobium eggs into the bladder walls of mice. This approach recapitulates many of the sequelae seen in human urogenital schistosomiasis, including hematuria, urinary frequency, bladder granuloma formation, urothelial abnormalities, and profound fibrosis. The synchronous nature of granuloma induction by egg injection allows us to precisely study the temporal kinetics of the early host response in urogenital schistosomiasis. Moreover, our models facilitate the study of bladder tissue-based immune responses to infection. We suggest that carefully designed and validated mouse models of human inflammation will continue to have an important and complementary role to clinical sample-based human immunology. Certainly, we should persist in making mouse models as human as humanly possible.

1. Seok, J., Warren, H., Cuenca, A., Mindrinos, M., Baker, H., Xu, W., Richards, D., McDonald-Smith, G., Gao, H., Hennessy, L., Finnerty, C., Lopez, C., Honari, S., Moore, E., Minei, J., Cuschieri, J., Bankey, P., Johnson, J., Sperry, J., Nathens, A., Billiar, T., West, M., Jeschke, M., Klein, M., Gamelli, R., Gibran, N., Brownstein, B., Miller-Graziano, C., Calvano, S., Mason, P., Cobb, J., Rahme, L., Lowry, S., Maier, R., Moldawer, L., Herndon, D., Davis, R., Xiao, W., Tompkins, R., , ., Abouhamze, A., Balis, U., Camp, D., De, A., Harbrecht, B., Hayden, D., Kaushal, A., O'Keefe, G., Kotz, K., Qian, W., Schoenfeld, D., Shapiro, M., Silver, G., Smith, R., Storey, J., Tibshirani, R., Toner, M., Wilhelmy, J., Wispelwey, B., & Wong, W. (2013). Genomic responses in mouse models poorly mimic human inflammatory diseases Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1222878110
2. Su LF, Kidd BA, Han A, Kotzin JJ, Davis MM (2013) Virus-Specific CD4+ Memory-Phenotype T Cells Are Abundant in Unexposed Adults. Immunity. Available:http://www.ncbi.nlm.nih.gov/pubmed/23395677. Accessed 10 February 2013.
3. 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.
4. 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.

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