John C. Samuelson
Professor, Department of Molecular & Cell Biology
72 East Concord Street
Boston, MA 02118-2394 USA
MD and PhD, Harvard University, 1984
Post-doctoral training: Harvard University, 1984–1989
Entamoeba histolytica, Giardia lamblia, and Trichomonas are simple eukaryotes, which cause dysentery, diarrhea, and vaginitis, respectively. Our laboratory uses molecular biological methods to study the biochemistry, cell biology, pathogenesis, and evolution of these important human pathogens.
One project attempts to determine the composition of the walls of Entamoeba cysts, which are the infectious and diagnostic form. Chitin in cyst wall is made by stage-specific chitin synthases and is modified by endogenous chitin deacetylases and chitinases. Chitin fibrils in the wall are held together unique lectins, which have multiple chitin-binding domains. Post-translation modifications of the cyst wall lectins include addition of unusual O-phosphodiester-linked sugars and cleavages between chitin-binding domains. Identification of these cyst wall-associated lectins may lead to better diagnostic reagents for distinguishing pathogenic from non-pathogenic amebae.
A second project, which is performed in collaboration with my colleague Phillips Robbins, attempts to understand Asn-linked glycosylation in Entamoeba, Giardia, and other protists. In particular, we use bioinformatics to predict lipid-linked N-glycan precursors, as well as N-glycan associated proteins involved in quality control in the ER lumen. We test our predictions using biochemical methods, which include determinations of carbohydrate structures and purification of glycoproteins by lectin columns. These studies suggest 1) the present diversity of N-glycans derives in part from secondary loss of genes encoding enzyme involved in N-glycan precursor synthesis, 2) protists with short N-glycans lack N-glycan-dependent quality control, and 3) there is Darwinian selection for sites of N-glycans in secreted proteins of diverse eukaryotes and viruses. Unique parasite sugars may be novel vaccine candidates or targets for anti-microbial lectins.
A third project is concerned with how Entamoeba, Giardia, and Trichomonas adapt to the anaerobic environment in the intestinal lumen. We have identified an atrophic mitochondrion-derived organelle, which lacks enzymes of oxidative phosphorylation in Entamoeba. We have also identified numerous bacterium-like fermentation enzymes in these protists, which appear to have been obtained by lateral gene transfer (LGT). Although LGT is frequent between bacteria, it is unusual between bacteria and eukaryotes. Two of the bacterial genes acquired by LGT appear to be important for activating and inactivating metronidazole, the best drug against these organisms.
Chatterjee, A., Carpentieri, A., Ratner, D. M., Bullitt, E., Costello, C. E., Robbins, P. W., Samuelson, J. Giardia cyst wall protein 1 is a lectin that binds curled fibrils of the GalNAc homopolymer. PLoS Pathogens 2010; 6:e1001059.
Ghosh, S. K., Van Dellen, K. L., Chatterjee, A., Dey, T., Haque, R., Robbins, P. W., Samuelson, J. The Jacob2 lectin of the Entamoeba histolytica cyst wall binds chitin and is polymorphic. PLoS Negl Trop Dis 2010: 4:e750.
Bushkin, G. G., Ratner, D. M., Cui, J., Banerjee, S., Duraisingh, M. T., Jennings, C. V., Dvorin, J. D., Gubbels, M-J, Robertson, S. D., Steffen, M., O’Keefe, B. R., Robbins, P. W., Samuelson, J. Suggestive evidence for Darwinian selection against asparagine-linked glycans of Plasmodium and Toxoplasma. Eukaryotic Cell 2010; 9:228–41.
Chatterjee, A., Banerjee, S., Steffen, M., Moore, L. L., O’Connor, R. M., Ward, H. D., Robbins, P. W., Samuelson, J. Evidence for mucin-like glycoproteins that tether sporozoites of Cryptosporidium parvum to the inner surface of the oocyst wall. Eukaryotic Cell 2010; 9:84–96.
Cui, J., Smith, T., Robbins, P. W., Samuelson, J. Darwinian selection for sites of Asn-liked glycosylation in phylogenetically disparate eukaryotes and viruses. Proc. Natl. Acad. Sci. USA 2009; 106:13421–6.
Chatterjee, A., Ghosh, S. K., Jang, K., Bullitt, E., Moore, L. L., Robbins, P. W., Samuelson, J. Evidence for a “wattle and daub” model of the cyst wall of Entamoeba. PloS Pathogens 2009; 5:e1000498.
Pal, D., Banerjee, S., Cui, J., Schwartz, A., Ghosh, S. K., Samuelson, J. Giardia, Entamoeba, and Trichomonas enzymes activate metronidazole (nitroreductases) and inactivate metronidazole (NIMs). Antimicrobial Agents Chemotherapy 2009; 53:458–64.
Banerjee, S., Robbins, P. W., Samuelson, J. Molecular characterization of nucleocytosolic O-GlcNAc transferases of Giardia lamblia and Cryptosporidium parvum. Glycobiology 2009; 19:331–336. PubMed PMID:18948359; PubMed Central PMCID: PMC2733775.
Ratner, D. M., Cui, J., Steffen, M., Moore, L. L., Robbins, P. W., Samuelson, J. Changes in the N-glycome (glycoproteins with Asn-linked glycans) of Giardia lamblia with differentiation from trophozoites to cysts. Eukaryotic Cell 2008; 7:1930–40.
Magnelli, P., Cipollo, J. F., Ratner, D. M., Cui, J., Kelleher, D., Gilmore, R., Costello, C. E., Robbins, P. W., Samuelson, J. Unique Asn-linked oligosaccharides of the human pathogen Entamoeba histolytica. J. Biol. Chem. 2008; 283:18355–64.