A Genetically Tractable, Natural Mouse Model of Cryptosporidiosis Offers Insights into Host Protective Immunity

Abstract

Summary Cryptosporidium is a leading cause of diarrheal disease and an important contributor to early childhood mortality, malnutrition, and growth faltering. Older children in high endemicity regions appear resistant to infection, while previously unexposed adults remain susceptible. Experimental studies in humans and animals support the development of disease resistance, but we do not understand the mechanisms that underlie protective immunity to Cryptosporidium . Here, we derive an in vivo model of Cryptosporidium infection in immunocompetent C57BL/6 mice by isolating parasites from naturally infected wild mice. Similar to human cryptosporidiosis, this infection causes intestinal pathology, and interferon-γ controls early infection while T cells are critical for clearance. Importantly, mice that controlled a live infection were resistant to secondary challenge and vaccination with attenuated parasites provided protection equal to live infection. Both parasite and host are genetically tractable and this in vivo model will facilitate mechanistic investigation and rational vaccine design.

A One Health Approach to Tackle Cryptosporidiosis

“…Understanding what drives immunity will aid development of much needed vaccines. Recent work by Sateriale et al [61] developed a new mouse model to dissect immunological responses to Cryptosporidium. They isolated a mouse-specific Cryptosporidium tyzzeri strain that infects the small intestine of immunologically competent mice, closely mimicking human infection.…”

Crypto-Currency: Investing in New Models to Advance the Study of Cryptosporidium Infection and Immunity

“…However, due to the inability to adequately further manipulate the genetics of these host organisms, and the high costs associated with their upkeep, researchers have been unable to explore mechanisms of the immune response to Cryptosporidium. In an effort to overcome these restrictions, Cryptosporidium tyzzeri, a species of the parasite that naturally infects mice, has recently been developed as a genetically tractable model of human infection (Sateriale et al, 2019).…”

“…In the murine model, mice lacking Tcells suffer from protracted and severe infections with C. tyzzeri. Mice lacking B-cells, however, show no protracted illness and clear the parasite just as well as wild-type mice (Sateriale et al, 2019). In humans, patients that produce insufficient amounts of the cytokine interferon gamma (IFNg) are documented to be highly susceptible to cryptosporidiosis (Morales et al, 1996).…”

Megasphaera in the stool microbiota is negatively associated with diarrheal cryptosporidiosis

“…Human polymorphisms are associated with an increased host susceptibility to cryptosporidiosis; however, these mutations do not completely explain the differences in infection outcomes [19,20]. Parasite genetics (within and across species) have been associated with differences in their host range [16,[21][22][23]. The role of the microbiome upon infection by Cryptosporidium has been examined in healthy adults [24] and animals [25,26]; but its role in differentiating diarrheal and subclinical infections is not known and nor is the impact of any differences in the microbiome composition occurring during infant cryptosporidiosis.…”