Cryptosporidium parvum, a potential cause of colic adenocarcinoma

Abstract

Background: Cryptosporidiosis represents a major public health problem. This infection has been reported worldwide as a frequent cause of diarrhoea. Particularly, it remains a clinically significant opportunistic infection among immunocompromised patients, causing potentially life-threatening diarrhoea in HIV-infected persons. However, the understanding about different aspects of this infection such as invasion, transmission and pathogenesis is problematic. Additionally, it has been difficult to find suitable animal models for propagation of this parasite. Efforts are needed to develop reproducible animal models allowing both the routine passage of different species and approaching unclear aspects of Cryptosporidium infection, especially in the pathophysiology field.

Results: We developed a model using adult severe combined immunodeficiency (SCID) mice inoculated with Cryptosporidium parvum or Cryptosporidium muris while treated or not with Dexamethasone (Dex) in order to investigate divergences in prepatent period, oocyst shedding or clinical and histopathological manifestations. C. muris-infected mice showed high levels of oocysts excretion, whatever the chemical immunosuppression status. Pre-patent periods were 11 days and 9.7 days in average in Dex treated and untreated mice, respectively. Parasite infection was restricted to the stomach, and had a clear preferential colonization for fundic area in both groups. Among C. parvum-infected mice, Dex-treated SCID mice became chronic shedders with a prepatent period of 6.2 days in average. C. parvum-inoculated mice treated with Dex developed glandular cystic polyps with areas of intraepithelial neoplasia, and also with the presence of intramucosal adenocarcinoma.

Conclusion: For the first time C. parvum is associated with the formation of polyps and adenocarcinoma lesions in the gut of Dex-treated SCID mice. Additionally, we have developed a model to compare chronic muris and parvum cryptosporidiosis using SCID mice treated with corticoids. This reproducible model has facilitated the evaluation of clinical signs, oocyst shedding, location of the infection, pathogenicity, and histopathological changes in the gastrointestinal tract, indicating divergent effects of Dex according to Cryptosporidium species causing infection.

Figure 1

Napierian logarithm of daily oocyst excretion (oocyst/mg faeces) in different groups of mice. Experimental groups were: P: C. parvum-infected SCID mice; PDex: C. parvum-infected Dex-treated SCID mice; M: C. muris-infected SCID mice; MDex: C. muris-infected Dex-treated SCID mice. Each box represents the middle half of data, the white line being the median. Whiskers represent the extreme values within 1.5 times the box height.

Figure 2

Experimental Cryptosporidium muris infection of SCID mice. (A) Stomach section from a Dex-untreated SCID mouse euthanatized at day 84 post-infection; (B) Stomach section from a Dex-treated SCID mouse euthanatized at day 46 post-infection. In both cases, gastric glands are filled with numerous parasites at different developmental stages (arrows). No signs of inflammation. Hematoxylin & Eosin staining.

Figure 3

Ileocaecal regions of mice from different groups. Normal caecum of (A) Uninfected mouse administered with dexamethasone (CDex group), (B) C. muris-infected Dex-treated mouse (MD group) and (C) C. parvum-infected mouse (P group). (D) Projection of polypoid structures with focal cystic dilation (arrows) developing inside the intestinal lumen of a C. parvum-infected Dex-treated SCID mouse. Hematoxylin & Eosin staining.

Figure 4

Experimental Cryptosporidium parvum infection of Dex-treated SCID mice: caecal region. (A) Polyp with areas of high-grade intraepithelial neoplasia (arrow 1) and intramucosal adenocarcinoma (arrow 2); (B) Abnormal nuclear changes consisting of prominent nucleoli and irregularly scattered chromatin; (C) Highly irregular glands, areas of loss of glandular differentiation. Presence of numerous parasites (arrow); (D) Presence of numerous parasites at different developmental stages in the intestinal epithelium (arrow). Hematoxylin & Eosin staining.

Figure 5

Experimental Cryptosporidium parvum infection of Dex-treated SCID mice. Low (A, D) and high magnification (B, C) of the caecal region showing the presence of abundant parasites (arrow), and high degree dysplasia (arrow). Hematoxylin & Eosin staining.