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Principles and practice of Clinical parasitology - Gillespie S.

Gillespie S. Principles and practice of Clinical parasitology - Wiley publishing , 2001. - 675 p.
ISBN 0-471-97729-2
Download (direct link): principlesandpracticeofclin2001.pdf
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factors and the intestinal response to the infection. However, despite the appreciation that C. parvum isolates are genetically diverse, there is as yet no delineation of specific virulence factors of C. parvum, nor genetic means to create defined mutants for pathogenetic analysis. Thus, insight into the pathogenesis of this infection currently arises from evaluation of the intestinal pathology of human and animal infections and from studies of in vitro and in vivo disease models (reviewed in Clark and Sears, 1996; Sears, 2000; Sears and Guerrant, 1994). Based on these data, Figure 6.3 proposes a model by which C. parvum infection may result in diarrheal disease.
Attachment of C. parvum sporozoites to intestinal epithelial and/or biliary cells appears to be a specific host-parasite interaction requiring both Gal/GalNAc epitopes on intestinal epithelial cell glycoproteins and on the sporozoite surface (Chen and LaRusso, 2000; Joe et al., 1994, 1998). Subsequent intestinal epithelial cell invasion by C. parvum sporozoites and merozoites has been shown to be dependent on remodeling of host cell actin (Chen and LaRusso, 2000; Elliot and Clark, 2000; Forney et al., 1999) but not tubulin, resulting in a plaquelike actin structure at the host-parasite interface. It is of interest that, in addition to actin and the
actin binding protein a-actinin (Elliott and Clark, 2000), a putative C. parvum transport protein termed CpABC localizes to the host cell-parasite boundary, where it is postulated to play a role in exporting molecules from the parasite to the cell or vice versa (Perkins et al., 1999). The exact mechanisms by which C. parvum cellular invasion results in actin rearrangement are unknown but current data suggest involvement of host cell kinase signaling pathways (Forney et al., 1999). C. parvum cellular invasion also appears to trigger new protein synthesis, including prostaglandin H synthase 2, proinflammatory cytokines/chemokines [tumor necrosis factor a (TNFa), interleukin-8 (IL-8), GRO-a and possibly interleukin-1p (IL-1 p)] and the mucosal antibiotic peptide, p-defensin, all potentially contributors to C. parvum disease pathogenesis, as outlined below (Laurent et al., 1997, 1998; Seydel et al., 1998; Tarver et al., 1998).
The histopathology resulting from invasion of the intestinal epithelium by C. parvum varies. Information on human intestinal pathology is primarily available from biopsies in AIDS patients with cryptosporidiosis and chronic diarrhea (Genta et al., 1993; Goodgame et al., 1993, 1995; Lumadue et al., 1998). In general, higher-intensity infections, as assessed by histo-pathology and number of stool oocysts, are accompanied by more severe gut injury, including villous atrophy and fusion, crypt hyperplasia and cellular submucosal infiltration (including both mononuclear cells and polymorphonuclear leukocytes), and are associated with evidence of carbohydrate, protein and vitamin (e.g. B12) malabsorption. Reduced activity of brush border enzymes (e.g. lactase, sucrase) occurs and is likely of clinical importance. However, no association between stool volume in AIDS patients and the intensity of infection by biopsy has been identified to date (Genta et al., 1993; Goodgame et al., 1995; Lumadue et al., 1998; Manabe et al., 1998). Furthermore, severe diarrhea is reported in some patients with low-intensity infections and normal duodenal histology. This latter observation could be due, for example, to severe infection in an unbiopsied site, unrecognized co-pathogens and/ or variations in the virulence of C. parvum strains.
In addition to malabsorption, several other potential mechanisms are postulated to contri-
bute to the development of intestinal symptoms (particularly diarrhea) in individuals with C. parvum infection. First, physiologic studies of C. parvum-infected intestinal tissue of mice and piglets and of human intestinal epithelial cell monolayers suggest that C. parvum infection may alter intestinal ion transport and/or increase gut permeability (Adams et al., 1994; Argenzio et al, 1990, 1993, 1994; Griffiths et al, 1994; Kapel et al., 1997; Moore et al., 1995). In the animal models, impaired absorption of sodium coupled to glucose occurs whether or not symptomatic disease results (Argenzio et al., 1990; Kapel et al., 1997; Moore et al., 1995). In contrast, glutamine-stimulated sodium absorption appears to remain largely intact, suggesting that glutamine-based oral rehydration solutions may be superior to glucose-based oral rehydration solutions in the treatment of C. parvum-induced diarrhea (Argenzio et al., 1990; Kapel et al., 1997; Levine et al., 1994). In more severe disease with diarrhea in piglets, prostanoid-dependent secretion may occur and it can be postulated that the kinases activated by cellular invasion by C. parvum may also act to stimulate intestinal secretion (Argenzio et al., 1990; Forney et al., 1999). Of note, consistent with the available in vitro results, studies of AIDS patients with C. parvum have also provided evidence of reduced intestinal barrier function (Goodgame et al., 1995; Lima et al., 1997). Second, elevated levels of the neuroactive prostaglandin, PGI2, are present in C. parvum-infected piglet intestinal tissue and inhibitor analyses suggest that the enteric nervous system contributes to secretion in C. parvum disease (Argenzio et al., 1996, 1997). Third, pro-inflammatory cytokines (e.g. TNFa, IL-8) are expected to stimulate mucosal recruitment of leukocytes, with production of inflammatory mediators such as prostaglandins (Kandil et al., 1994; Laurent et al., 1997, 1998; Seydel et al., 1998). These inflammatory mediators generated in response to C. parvum infection are known to stimulate intestinal secretion. Consistent with the potential importance of inflammation in the pathogenesis of diarrhea in C. parvum infection, up to 75% of symptomatic, but not asymptomatic, Brazilian children with C. parvum infection had evidence of fecal leukocytes in their stools (Newman et al., 1999). Fourth, cellular injury and apoptosis have been
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