Cryptosporidium is now a well-recognized cause of diarrhea in humans and animals throughout the world, and is associated with a substantial degree of morbidity and mortality in patients with the acquired immunodeficiency syndrome (AIDS). Molecular studies have identified two major genotypes of Cryptosporidium associated with human disease, Cryptosporidium hominis (human genotype 1 of C. parvum) and C. parvum (bovine genotype 2). Comparison of the complete genome sequences of C. parvum and C. hominis have not identified any differences in the complement of genes present, and the two genomes display >97% identity at the nucleotide level. However, these two species display significant differences in their host specificity and virulence. The overall hypothesis behind this proposal is that virulence and host specificity differences between C. hominis and C. parvum are the result of genetic differences that affect the developmental regulation and/or magnitude of parasite mRNA expression. The specific hypotheses that will be tested in this proposal are 1) C. parvum and C. hominis differ in their developmental regulation and/or magnitude of gene expression as they progress through their life cycles in human intestinal epithelial cells: and 2) C. parvum will display differences in its transcriptional profile depending on the species of host cell be parasitized (i.e. human vs. bovine). These hypotheses will be directly tested by: 1) comparing the complete transcriptional profile of C. hominis and C. parvum during in vitro infections in human intestinal cell culture models and during ex vivo infection of human intestinal explants; and 2) comparing the expression data obtained for C. parvum in human cells and tissues with those obtained from identical experiments performed in bovine intestinal cells and tissue explants. In addition, this complete dataset will provide valuable biological data to augment efforts to mine the Cryptosporidium genome sequences to identify transcriptional regulatory sequences and identify sequence variations between C. hominis and C. parvum that correlate with gene expression differences between C. hominis and C. parvum. These genetic variations may play a role in determining the differences in host specificity and virulence observed between these two human pathogens. In addition, as has been the case for Plasmodium, this dataset will be a valuable resource for the ongoing process of refining the annotation of the Cryptosporidium genome, in particular for those genes that display little or no similarity to previously characterized genes from any other organisms. ? ? ?
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