Liver and bile duct pathology followingCryptosporidium parvum infection of immunodeficient mice

Abstract

Cryptosporidium parvum (CP) is an apicomplexan parasite that causes trivial diarrhea in healthy subjects 1 and lifethreatening hepatobiliary, gastrointestinal, or respiratory tract infection in subjects with acquired immune deficiency syndrome 2-4 or CD154 deficiency (which causes X-linked immunodeficiency with hyper IgM [XHIM]). 5 The parasite is difficult to culture, and experimental studies have mostly used immunodeficient mice, particularly those with severe combined immunodeficiency (SCID), as models. 6-8 The infection in SCID mice is generally biphasic with gastrointestinal involvement for 4 to 6 weeks, followed by spread of the organism to the biliary tract. 9 SCID mice occasionally recover from CP infection spontaneously, a phenomenon linked with their intestinal flora. 10 Mice with intact immune systems eliminate cryptosporidia within 4 weeks of infection, and parasites are not generally found outside the small and large intestine. The transfer of spleen cells, and specifically CD4 cells, from immunologically intact mice to CP-infected SCID recipients is followed by clearing of the infection in 2 to 4 weeks. 11-13 Our previous studies indicated that mice with disrupted genes for CD154 and CD40 (the natural ligand of CD154, a member of the tumor necrosis factor family of cell surface receptors) are also unable to eliminate CP, 14 providing an animal model for this infection in boys with CD154 deficiency. Interferon gamma (IFN-␥) and interleukin-12 are also known to contribute to immunity to CP as shown by experiments in which these cytokines are neutralized by specific antibodies. 15,16 Recently, Theodos et al. 17 and Mead et al. 18 showed that CP infection can be rapidly fatal in mice with disrupted IFN-␥ genes. The interleukin-12, IFN-␥, CD40, and CD154 pathways interact at several levels, so it is unclear whether a single mechanism (such as IFN-␥ pathwaydependent apoptosis 19 ) accounts for the persistence or severity of CP infection in these immunodeficient strains or whether multiple pathways are involved.Although immunodeficient mice are established models for gastrointestinal infection by CP, less attention has been paid to the consequences of CP infection for the biliary tree. The fibrosis that develops around the portal tracts of AIDS patients with chronic cryptosporidial infections can mimic the histological changes seen in primary sclerosing cholangitis. 20 CP-infected XHIM patients also develop sclerosing cholangitis, and up to one third of these patients die from bile duct-related cancers. 5 CP infection has recently been reported to cause apoptosis of cultured human biliary epithelial cells (BEC), 21 raising the possibility that direct toxicity for BEC might be responsible for biliary tract damage in humans. The studies reported here were undertaken to determine whether apoptosis of CPinfected BEC would follow infection in vivo and whether mice with defective CD40/CD154 would also model the liver and biliary tree pathology associated with CP infection in humans. Our choice of immunodeficien...

Development of Cryptosporidium parvum-Induced Gastrointestinal Neoplasia in Severe Combined Immunodeficiency (SCID) Mice: Severity of Lesions Is Correlated with Infection Intensity

“…However, the presence of portal fibrosis, biliary sclerosis, and necrosis with dilation of ductlike structures lined by highly atypical biliary epithelial cells was found in IFN-γ knockout mice infected with Cryptosporidium . 25 These changes, classified as low-grade dysplasia, 25 are consistent with our results. Interestingly, similar histologic findings (especially Figure 3 in Mead and others 23 ) were associated with chronic C. parvum infection in NIH-III nu/nu mice.…”

“…24 Others authors have reported that liver involvement occurs later, in some cases 13-26 weeks PI. 25 However, we found that C. parvum parasites under Dex develop predominantly in the ileocaecal region and in the colon of SCID mice (Reference 6 and present work) ( Table 1 ).…”

Introducing Miltefosine as an Anti-cryptosporidial Agent in Immunocompromised Mice

“…In this study, liver section from five mice of group (IIa) showed inflammatory changes with no fibrosis, 30 days post-infection. Stephens et al [29] reported that chronic infections of the biliary tract with C. parvum in SCID mice developed triaditis, cholangitis and lobular hepatitis. Moreover dysplastic changes in the liver after C. parvum infection have been reported in SCID mice [30].…”

Nonmyeloablative Hematopoietic Stem Cell Transplant for X-Linked Hyper-Immunoglobulin M Syndrome With Cholangiopathy

“…18 There is also evidence that CD40-CD40L interactions between T cells and biliary epithelial cells infected with C parvum may be important in triggering apoptosis of infected cells and thereby promoting clearance of infection. 19 This immune defense would be restored in X-HIM patients after successful HSCT. Therefore, the favorable hepatic outcome that we observed in our patients after HSCT may reflect reconstitution of host defense with clearance of an underlying infectious process.…”