Intestinal cryptosporidiosis: pathophysiologic alterations and specific cellular and humoral immune responses in rnu/+ and rnu/rnu (athymic) rats
Gardner, A.L.; Roche, J.K.; Weikel, C.S.; Guerrant, R.L.
American Journal of Tropical Medicine and Hygiene 44(1): 49-62
1991
ISSN/ISBN: 0002-9637 PMID: 1996741 Document Number: 385948
In order to develop an experimental model of symptomatic cryptosporidiosis in an immunosuppressed mammal, the pathophysiology of infection with Cryptosporidium and the humoral and cellular host responses in rnu/rnu (athymic) rats and their heterozygous (rnu/+) littermates was investigated by challenging suckling rats with >= 2.5 x 106 Cryptosporidium oocysts oro-gastrically. Normal and immunodeficient animals were followed for onset and duration of infection (faecal oocysts), physiological consequences (diarrhoea, impaired weight gain, brush-border enzyme activities), and immunologic response (both B- and T-lymphocyte-mediated). Homozygosity for the rnu gene was associated with protracted cryptosporidial infections; shedding for up to 52 days occurred, and delay in weight gain was noted in rnu/rnu-infected compared with rnu/rnu-uninfected rats. In contrast, cryptosporidial challenge of rnu/+ rats resulted in self-resolving infections, occasionally with transient diarrhoea lasting 4 days or less occurring 10-15 days after oro-gastric challenge. The latter animals mounted a cell-mediated immune response to Cryptosporidium: 3 months after challenge, 5 of 5 rnu/+ rats demonstrated positive skin test responses to a subcutaneous 3.5 micro g dose of cryptosporidial antigen. Further, sera from 6 rnu/+ rats 2 to 3 months after oro-gastric oocyst challenge exhibited specific anticryptosporidial immunoglobulin binding (A405 = 0.96), compared to that of 7 uninfected rnu/+ controls (A405 = 0.09). Macromolecules of MW 150 000, 105 000, and 88 000 in the Cryptosporidium antigen preparation were bound by serum immunoglobulin from previously infected, recovered rnu/+ rats. Two brush-border enzymes (lactase and alkaline phosphatase) were markedly reduced in the ileum 8-10 days after oro-gastric challenge in rats with diarrhoea and oocyst shedding. It was found that the rnu/rnu (athymic, nude) rat provides a useful model for study of prolonged cryptosporidial infection with impaired weight loss, brush-border enzyme alteration and intermittent diarrhoea. These studies further suggest that a T-lymphocyte population is involved in recovery from Cryptosporidium infection and that this recovery is associated with both cellular and humoral immune responses to specific cryptosporidial antigenic macromolecules. This mode should open further avenues for the study of the pathogenesis and protective immunity in cryptosporidial infection.