Persistent Cryptosporidium parvum Infection Leads to the Development of the Tumor Microenvironment in an Experimental Mouse Model: Results of a Microarray Approach.

Manasi Sawant,Pierre Gosset,Peggy Bouquet,Eric Viscogliosi,Anthony Mouray,Colette Creusy,Sadia Benamrouz-Vanneste,Nausicaa Gantois,Erika Duval,Adriana Mihalache,Magali Chabé,Gabriela Certad,David Hot

doi:10.3390/microorganisms9122569

Abstract

Cryptosporidium spp. are enteric protozoa parasites that infect a variety of vertebrate hosts. These parasites are capable of inducing life-threatening gastrointestinal disease in immunocompromised individuals. With the rising epidemiological evidence of the occurrence of Cryptosporidium infections in humans with digestive cancer, the tumorigenic potential of the parasite has been speculated. In this regard, Cryptosporidium parvum has been reported to induce digestive adenocarcinoma in a rodent model of chronic cryptosporidiosis. However, the processes by which the parasite could induce this carcinogenesis are still unknown. Therefore, the transcriptomes of C. parvum infected ileo-cecal regions of mice developing tumors were analyzed in the current study. For the first time, downregulation of the expression of α-defensin, an anti-microbial target of the parasite in response to C. parvum infection was observed in the transformed tissues. This phenomenon has been speculated to be the result of resistance of C. parvum to the host defense through the upregulated expression of interferon γ-stimulated genes. The inflammatory response generated as result of attenuated expression of anti-microbial peptides highlights the role of immune evasion in the C. parvum-induced tumorigenesis. The study has also succeeded in the characterization of the tumor microenvironment (TME) which is characterized by the presence of cancer associated fibroblasts, myeloid-derived suppressor cells, tumor-associated macrophages and extracellular matrix components. Identification of immune suppressor cells and accumulation of pro-inflammatory mediators speculates that chronic inflammation induced by persistent C. parvum infection assists in development of an immunosuppressive tumor microenvironment.

Highlights

The Apicomplexan parasite Cryptosporidium is recognized as one of the main waterborne agents causing diarrhea worldwide
Using the well-documented model of intestinal cryptosporidiosis (SCID mice treated with dexamethasone) through the oral administration of the oocysts, infection of C. parvum was detected by quantification of the oocyst shedding (Figure 1A)
The data collected strongly suggest that chronic inflammation associated with chronic infection plays an important role in C. parvum-induced digestive neoplasia

Summary

Introduction

The Apicomplexan parasite Cryptosporidium is recognized as one of the main waterborne agents causing diarrhea worldwide. This ubiquitous intracellular parasite is responsible of self-limited diarrhea in immunocompetent individuals but is capable of causing life-threatening disease in those who are immunocompromised [1]. Different cohort studies have reported that Cryptosporidium is one of the main pathogens responsible for severe diarrhea and mortality in children under 5 years old [2,3]. The low number of parasites required for an infection [7] coupled with the well-known resistance of Cryptosporidium oocysts to disinfection methods facilitates the waterborne transmission of cryptosporidiosis [8,9]. An ever-growing number of persons could be exposed to this parasite around the world. Despite its prevalence and impact on public health, neither treatment nor vaccine against Cryptosporidium, are yet available [10]

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