Raffi V. Aroian
e-mail: raroian@ucsd.edu |
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Our laboratory researches the basic biology of infectious diseases and is actively seeking new cures for them. We study infectious diseases using the free-living nematode, Caenorhabditis elegans, and the mouse parasitic nematode, Heligmosomoides polygyrus bakeri.
Our research is currently focused on three areas; 1) pore-forming toxins; 2) anthelmintics; and 3) resistance to crystal proteins. Summaries are given below, and you can access more information on our lab website: http://aroianlab.ucsd.edu.
Pore-forming toxins: Pore-forming toxins (or PFTs) are the most common toxin made by pathogenic bacteria and are associated with some of the most important bacterial pathogens, such as Staphylococcus aureus and Streptococcus pyogenes. Despite their importance, very little is known about how these toxins work and how cells respond to this form of pathogenic attack.
Our laboratory is the first to study these toxins by using a molecular genetic model of pathogenesis, namely the interaction of C. elegans with the PFTs made by Bacillus thuringiensis (Bt). We are discovering the intracellular pathways that enable C. elegans cells to counteract intoxication by PFTs, how these pathways are interconnected, and their protective functions during PFT attack.
Anthelmintics: Soil-transmitted helminths (STH), including hookworm, whipworm, and Ascaris, are the most common infections in humans, affecting in excess of 2 billion. Children and pregnant women suffer the most from these intestinal worms. STH infections are one of the grea
t neglected diseases of our time. Despite the availability of a two classes of compounds (anthelmintics) to treat these diseases, there are urgent cries for new anthelmintics due to the threat of parasite resistance and decreasing efficacy of current therapies.
Our laboratory has discovered that Crystal (Cry) proteins made by Bt are effective anthelmintics. We have shown that Cry proteins can cure two different worm infections in two different rodents. We are currently using the mouse parasite H. polygyrus to study basic and applied research questions of how optimize Cry protein anthelmintic therapies and how to bring Cry proteins to human clinical trial.
Cry protein resistance: Bt Cry proteins have been used for decades as safe and natural insecticides to kill insects that eat crops and that transmit human disease. They are the most important and widely used biologically based pesticide. As with anthelmintics (see above), there is increasing concern that pests will develop resistance to Cry proteins.
Our laboratory is using C. elegans to study the genes and pathways that can mutate to Cry protein resistance and published a series of papers uncovering the fact that one of the receptors for Cry proteins is an invertebrate-specific glycolipid. We are currently exploring intracellular signaling pathways that, when mutated, lead to resistance. As with our studies on pore-forming toxins (above), these studies are revealing new insights into how cellular pathways are interconnected and how these pathways can be either protective against or co-opted by bacterial toxins.
Publications
Topic: Crystal proteins as anti-nematode compounds
Li, X.Q., Tan, A., Voegtline, M., Bekele, S., Chen, C.S., and Aroian, R.V. (2008) Expression of Cry5B Protein from Bacillus thuringiensis in Plant Roots Confers Resistance to Root-Knot Nematode, Biological Control, in press.
Li, X.Q., Wei, J.Z., Tan, A., and Aroian, R.V., (2007) Resistance to root-knot nematode in tomato roots expressing a nematicidal Bacillus thuringiensis crystal protein, Plant Biotechnology Journal 5: pp. 455–464.
Cappello, M., Bungiro, R.D., Harrison, L.M., Bischof, L.J., Griffitts, J.S., Barrows, B.D., and Aroian, R.V. (2006) A purified Bacillus thuringiensis crystal protein with therapeutic activity against the hookworm parasite Ancylostoma ceylanicum. Proc. Natl. Acad. Sci. 103(41): 15154-15159.
Wei* J.Z., Hale* K., Carta L., Platzer E., Wong C., Fang S.C., and Aroian R.V. (2003). Bacillus thuringiensis Crystal proteins that target nematodes, Proc. Natl. Acad. Sci. 100: 2760-2765.
Topic: Development of Resistance to Crystal proteins
Barrows, B.D., Haslam, S.M., Bischof, L.J., Morris, H.R., Dell, A., and Aroian, R.V. (2007) Resistance to Bt toxin in Caenorhabditis elegans from loss of fucose. J. Biol. Chem. 282: 3302-3311 .
Griffitts J.S., Haslam, S.M., Yang, T., Garczynski, S.F., Mulloy, B., Morris, H., Cremer, P.S., Dell, A., Adang, M.J., and Aroian, R.V. (2005). Glycolipids as receptors for Bacillus thuringiensis crystal toxin. Science 307: 922-925.
Griffitts J.S., Huffman D.L., Whitacre J.L., Barrows B.D., Marroquin L.D., Müller R., Brown J.R., Hennet T., Esko J.D., and Aroian R.V. (2003). Resistance to a bacterial toxin is mediated by removal of a conserved glycosylation pathway required for toxin - host interactions, J. Biol. Chem., 278(46): 45594-45602.
Griffitts J.S., Whitacre J.L., Stevens D.E., and Aroian R.V. (2001). Bt toxin resistance from loss of a putative carbohydrate-modifying enzyme, Science, 293:860-864.
Marroquin* L.D., Elyassnia* D., Griffitts J.S., Feitelson J.S. and Aroian R.V. (2000). Bacillus thuringiensis (Bt) toxin susceptibility and isolation of resistance mutants in the nematode Caenorhabditis elegans, Genetics, 155: 1693-1699.
Topic: Cellular defenses against pore-forming toxins
Huffman D.L., Abrami* L., Sasik* R., Corbeil J., van der Goot F.G., and Aroian R.V. (2004). Mitogen-activated protein kinase pathways defend against bacterial pore-forming toxins. Proc. Natl. Acad. Sci. 101(30): 10995-11000.
Topic: Reviews and Methods publications
Aroian R. V. and van der Goot, F.G., (2007) Pore-forming toxins and cellular non-immune defenses (CNIDs).
Curr. Opin. Microbiol. 10:57-61.
Barrows, B.D., Griffitts, J.S., and Aroian, R.V. (2007) Resistance is non-futile: Resistance to Crystal Toxin in the nematode Caenorhabditis elegans, J. Invert. Path. 95(3):198-200.
Bischof, L.J., Huffman, D.L., and Aroian, R.V. (2006) Assays for toxicity studies in C. elegans with Bt crystal proteins. Methods in Molecular Biology 351: 139-154.
Barrows, B.D., Griffitts, J.S., and Aroian, R.V. (2006). Caenorhabditis elegans Carbohydrates in Bacterial Toxin Resistance. Methods in Enzymology 417: 340-358.
Griffitts, J.S. and Aroian, R.V. (2005) Many roads to resistance: How invertebrates adapt to Bt toxins. Bioessays 27: 614-624.
Huffman D.L., Bischof L.J., Griffitts J.S., and Aroian R.V. (2004). Pore worms: Using Caenorhabditis elegans to study how bacterial toxins interact with their target hosts. Int. J. Med. Microbiol., 293: 599-607.
Raffi Aroian received his Ph.D. from the California Institute of Technology. His postdoctoral studies were carried out at UCSF, where he was a Helen Hayes Whitney Fellow and a Senior Postdoctoral Fellow of the American Cancer Society. He is the recipient of a New Investigators Award in Toxicological Sciences from the Burroughs-Wellcome Foundation and a Beckman Foundation Young Investigator.
