Dr. Christopher Dwight Huston
Host-Pathogen Interactions of Intestinal Protozoa
In our laboratory we study two waterborne intestinal protozoa that infect humans: Entamoeba histolytica and Cryptosporidium parvum. Both of these parasites are major public health problems in the developing world. They predominantly affect young children and, in the case of Cryptosporidium, immunocompromised individuals such as those with AIDS. Recently, both have garnered increased interest in the United States due to concern that they could be intentionally introduced into the water supply in an act of bioterrorism.</br>
Cryptosporidium species are apicomplexan parasites that cause severe diarrhea in both immunocompetent and immunocompromised individuals. The infectious oocysts are resistant to standard water treatment methods and Cryptosporidium has been associated with numerous waterborne epidemics including one involving more than 400,000 Milwaukee residents in 1993. Nitazoxanide is the only available treatment for cryptosporidiosis, but it only has modest efficacy in children and is equivalent to a placebo in immunocompromised people. Although new drugs are badly needed, drug development has been impeded by an inability to continuously culture the parasite in vitro, and by lack of economic incentive to develop new drugs for treatment of cryptosporidiosis, which predominantly affects people in low income countries. In order to address the clinical need for better anti-Cryptosporidium drugs while acknowledging the economic reality of who this disease affects, we are taking a drug-repurposing approach. That is, we have focused our efforts on identification of drugs that are already approved or for which a substantial economic investment has already been made for treatment of other diseases. To enable this approach, we developed and optimized a high-throughput cell-based assay for in vitro growth of Cryptosporidium parvum within intestinal epithelial cells that utilizes automated liquid handling, microscopy and image analysis. We have used this assay to screen several small molecule libraries and identify novel inhibitors of C. parvum growth, several of which we are now developing as potential treatments for humans with cryptosporidiosis. Students in my laboratory are also conducting studies to determine the mechanism of action for the most promising drug screening hits. Since genetic tools to study Cryptosporidium parasites are currently very limited, we believe that this chemical genetics approach has the potential to provide important new insights into the biology of Cryptosporidium species and related parasites.
E. histolytica calreticulin (green) is present on the cell surface and functions as a phagocytosis receptor.
Cryptosporidium parvum infection of the human intestinal epithelial cell line HCT-8. C. parvum (green); DNA (blue); scale bar is 5 microns.
Biopsy specimen showing the histopathology of human amebic colitis due to E. histolytica infection. The acute inflammation, hemorrhage, and amebic trophozoites with ingested human cells seen here are typical. Hematoxylin and eosin stain; original image 400x magnification.
302 Stafford Hall
Heron BT, Sateriale A, Teixeira JE, Huston CD. Evidence for a novel Entamoeba histolytica lectin activity that recognizes carbohydrates present on ovalbumin. International Journal for Parasitology. 2011. 41:137-44. PMID: 20807536
Teixeira JE, Sateriale A, Bessoff KE, Huston CD. Control of Entamoeba histolytica adherence involves EhMSP-1, a M8 family surface metalloprotease with homology to leishmanolysin. Infection and Immunity. 2012. 80:2165-76. PMID: 22451519.
Vaithilingam A, Teixeira JE, Miller PJ, Heron BT, Huston CD. Entamoeba histolytica cell surface calreticulin binds human C1q and functions in amebic phagocytosis of host cells. Infection and Immunity. 2012. 80:2008-2018. PMID: 22473608.
Sateriale A, Vaithilingam A, Donnelly L, Miller P, Huston CD. Feed forward regulation of phagocytosis by Entamoeba histolytica. Infection and Immunity. 2012. 80:4456-4462. PMID: 23045476.
Bessoff K, Sateriale A, Lee KK, Huston CD. Drug repurposing screen reveals FDA-approved inhibitors of human HMG-CoA reductase and isoprenoid synthesis that block Cryptosporidium parvum growth. Antimicrobial Agents and Chemotherapy. 2013. Feb 4 [ePub ahead of print]. PMID: 23380723.