Abstract

Schistosomiasis is one of the world's greatest health problems, afflicting over 200 million people. We have been studying the biochemical and molecular mechanisms by which invasive larvae of Schistosoma mansoni initiate infection of the human host. We have determined which macromolecules are degraded as larvae invade skin and have purified the principal proteolytic enzyme that facilitates this invasion. We now will complete studies defining the structure of the active site of this proteinase using different peptide substrates. We will label the active site serine and purify its peptide for sequencing. We will also continue sequencing the protein from its amino-terminus. Having isolated several cDNA clones for the proteinase, we will sequence insert DNA from these clones and compare to amino acid sequences obtained from the purified protein. We can also use cDNA clones to study, by in situ hybridization, temporal expression of proteinase mRNA during development of cercariae in the snail host. Finally, having shown there is a host immune response to the proteinase, we will determine the onset, peak, and diminution of this response over the course of infection in two animal models.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Unknown (R22)
Project #
2R22AI020452-04A1
Application #
3444655
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1983-07-01
Project End
1989-12-31
Budget Start
1987-01-01
Budget End
1987-12-31
Support Year
4
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Britton, C; Redmond, D L; Knox, D P et al. (1999) Identification of promoter elements of parasite nematode genes in transgenic Caenorhabditis elegans. Mol Biochem Parasitol 103:171-81
Lim, K C; Sun, E; Bahgat, M et al. (1999) Blockage of skin invasion by schistosome cercariae by serine protease inhibitors. Am J Trop Med Hyg 60:487-92
Britton, C; McKerrow, J H; Johnstone, I L (1998) Regulation of the Caenorhabditis elegans gut cysteine protease gene cpr-1: requirement for GATA motifs. J Mol Biol 283:15-27
Hagen, H E; Klager, S L; McKerrow, J H et al. (1997) A simple assay for the detection of native and recombinant protease activity. Anal Biochem 251:121-2
Ramzy, R M; Faris, R; Bahgat, M et al. (1997) Evaluation of a stage-specific proteolytic enzyme of Schistosoma mansoni as a marker of exposure. Am J Trop Med Hyg 56:668-73
Ring, C S; Sun, E; McKerrow, J H et al. (1993) Structure-based inhibitor design by using protein models for the development of antiparasitic agents. Proc Natl Acad Sci U S A 90:3583-7
Fishelson, Z; Amiri, P; Friend, D S et al. (1992) Schistosoma mansoni: cell-specific expression and secretion of a serine protease during development of cercariae. Exp Parasitol 75:87-98
McKerrow, J H; Newport, G; Fishelson, Z (1991) Recent insights into the structure and function of a larval proteinase involved in host infection by a multicellular parasite. Proc Soc Exp Biol Med 197:119-24
Cohen, F E; Gregoret, L M; Amiri, P et al. (1991) Arresting tissue invasion of a parasite by protease inhibitors chosen with the aid of computer modeling. Biochemistry 30:11221-9
Resnick, S; Zimmer, B; Pappagianis, D et al. (1990) Purification and amino-terminal sequence analysis of the complement-fixing and precipitin antigens from Coccidioides immitis. J Clin Microbiol 28:385-8

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