Host-Pathogen Interactions of Intestinal Protozoa

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.



Profile

Chris received his M.D. degree in 1994 from Cornell University Medical College. He then served as an intern, resident, and chief resident in internal medicine at the University of Vermont. From 1998 to 2000, he was a fellow in infectious diseases at the University of Virginia, after which he received a Howard Hughes Postdoctoral Fellowship to continue his training. He joined UVM�s infectious diseases faculty in 2003 where he is now an Associate Professor. He is an adjunct faculty member in the Department of Microbiology and Molecular Genetics.

Research Description

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.



Entamoeba histolytica, the cause of amebic dysentery and liver abscess, infects an estimated 50 million people annually. We study two aspects of Entamoeba biology that correlate with virulence. E. histolytica phagocytosis of host cells, which is a prominent histologic feature of invasive amebiasis, is the first aspect. Studies from our lab and others have shown that there is tremendous redundancy in amebic phagocytosis receptors and the ligands that they bind. Nevertheless, non-clonal populations of E. histolytica trophozoites with variable phagocytic ability are evident in human pathologic samples and in vitro. We have taken a systems-based approach to begin understanding the differences between these phagocytic and non-phagocytic populations by sorting the populations and examining global gene expression. We find significant differences in expression of genes implicated in the phagocytic process, and, interestingly, the act of phagocytosis itself alters amebic gene expression in a manner that results in increased phagocytic ability. The data are consistent with a feed-forward regulatory mechanism. We are currently working to determine the molecular basis for this gene regulatory program and how it affects virulence. Our second Entamoeba project focuses on regulation of E. histolytica adherence by an amebic cell surface metalloprotease, EhMSP-1. EhMSP-1 deficient amebae are hyper-adherent and have reduced motility. Our working hypothesis is that EhMSP-1 controls amebic adherence by cleaving amebic adhesins and/or host ligands, thereby affecting both the number of adhesin-ligand interactions and outside-to-in cell signaling in E. histolytica. We are employing a combination of proteomics and cell biological methods to test this hypothesis.

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.

<i>E. histolytica</i> calreticulin (green) is present on the cell surface and functions as a phagocytosis receptor.” ></center></p>
<p><font size=E. histolytica calreticulin (green) is present on the cell surface and functions as a phagocytosis receptor.

<i>Cryptosporidium parvum</i> infection of the human intestinal epithelial cell line HCT-8.  <i>C. parvum</i> (green); DNA (blue); scale bar is 5 microns.” ></center></p>
<p><font size=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 <i>E. histolytica</i> infection.  The acute inflammation, hemorrhage, and amebic trophozoites with ingested human cells seen here are typical.   Hematoxylin and eosin stain; original image 400x magnification.” ></center></p>
<p><font size=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.

Highlighted Publications

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.

View all Huston publications here.

* indicates equal contribution

Recent Publications

Roncolato EC, Teixeira JE, Barbosa JE, Zambelli Ramalho LN, Huston CD (2014) Immunization with the Entamoeba histolytica surface metalloprotease EhMSP-1 protects hamsters from amebic liver abscess. Infect Immun in press.

Checkley W, White AC Jr, Jaganath D, Arrowood MJ, Chalmers RM, Chen XM, Fayer R, Griffiths JK, Guerrant RL, Hedstrom L, Huston CD, Kotloff KL, Kang G, Mead JR, Miller M, Petri WA Jr, Priest JW, Roos DS, Striepen B, Thompson RC, Ward HD, Van Voorhis WA, Xiao L, Zhu G, Houpt ER (2014) A review of the global burden, novel diagnostics, therapeutics, and vaccine targets for cryptosporidium. Lancet Infect Dis in press.

Bessoff K, Spangenberg T, Foderaro JE, Jumani RS, Ward GE, Huston CD (2014) Identification of Cryptosporidium parvum active chemical series by Repurposing the open access malaria box. Antimicrob Agents Chemother 58(5): 2731-9.

Sateriale A, Roy NH, Huston CD (2013) SNAP-tag technology optimized for use in Entamoeba histolytica. PLoS One 8(12): e83997.

Sateriale A, Bessoff K, Sarkar IN, Huston CD (2014) Drug repurposing: mining protozoan proteomes for targets of known bioactive compounds. J Am Med Inform Assoc 21(2): 238-44.

Bessoff K, Sateriale A, Lee KK, Huston CD (2013) Drug repurposing screen reveals FDA-approved inhibitors of human HMG-CoA reductase and isoprenoid synthesis that block Cryptosporidium parvum growth. Antimicrob Agents Chemother 57(4): 1804-14.

Sateriale A, Vaithilingam A, Donnelly L, Miller P, Huston CD (2012) Feed-forward regulation of phagocytosis by Entamoeba histolytica. Infect Immun 80(12): 4456-62.

View all Huston publications here.

Selected Awards

Alpha Omega Alpha-Cornell University Medical College (1993)

Good Physician Award-Cornell University Medical College Given by class vote to the member of the graduating class who best exemplifies the intangible qualities of the “good physician”. (1994)

Frank L. Babbott, M.D. Memorial Award-Dept. of Medicine, University of Vermont College of Medicine (1997)

American Society forTropical Medicine and Hygiene Young Investigator Award (1999)

Howard Hughes Postdoctoral Fellowship for Physicians Project title: Characterization of the mechanism of apoptotic killing by Entamoeba histolytica (Howard Hughes Postdoctoral Fellowship for Physicians)

American Society for Clinical Investigation Young Investigator Award (2007)


Christopher Huston, M.D.

Christopher
Huston, M.D.

Associate Professor
Department of Medicine

 

802-656-1388
Office: 302B Stafford
Lab: 302 Stafford Hall

Lab Members

   Rajiv Jumani, CMB Student

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