The Mucosal Innate Immune Response to Cryptosporidium parvum, a Global One Health Issue

Abstract

Cryptosporidium parvum is an apicomplexan parasite that infects the intestinal epithelium of humans and livestock animals worldwide. Cryptosporidiosis is a leading cause of diarrheal-related deaths in young children and a major cause of economic loss in cattle operations. The disease is especially dangerous to infants and immunocompromised individuals, for which there is no effective treatment or vaccination. As human-to-human, animal-to-animal and animal-to-human transmission play a role in cryptosporidiosis disease ecology, a holistic 'One Health' approach is required for disease control. Upon infection, the host's innate immune response restricts parasite growth and initiates the adaptive immune response, which is necessary for parasite clearance and recovery. The innate immune response involves a complex communicative interplay between epithelial and specialized innate immune cells. Traditional models have been used to study innate immune responses to C. parvum but cannot fully recapitulate natural host-pathogen interactions. Recent shifts to human and bovine organoid cultures are enabling deeper understanding of host-specific innate immunity response to infection. This review examines recent advances and highlights research gaps in our understanding of the host-specific innate immune response to C. parvum. Furthermore, we discuss evolving research models used in the field and potential developments on the horizon.

Keywords: Cryptosporidium parvum; One Health; innate immune response; intestinal epithelium; intestinal parasite.

Figure 1

Innate Immune Response to C. parvum. (A) C. parvum inhibits the release of the antimicrobial peptides β-defensin-1 and CCL20. (B) Activation of TLR receptors by C. parvum leads to the luminal secretion of antimicrobial peptides β-defensin-2 and LL-37 as well as the basolateral secretion of IL-8, TNFα, and GROα. (C) Inflammasome activation by C. parvum leads to the basolateral release of IL-18, which causes the luminal secretion of α -defensin-2 and LL-37. (D) C. parvum-mediated presentation of MICA and MICB lead to cytolysis of infected epithelial cells by NK cells. NK cells and macrophages both act as sources of IFN-γ during infection. (E) C. parvum trophozoites stimulate apoptosis, but merozoites inhibit apoptosis, mediated through survivin, osteoprotegerin, and BCL2. (F) In response to C. parvum, intestinal epithelial cells release numerous chemokines and cytokines including CCL2, CCL5, CXCL9, CXCL10, and IFN-λ3. (G) DCs respond to C. parvum by releasing IL-6, IL-1β, IL-12, IL-18, TNFα, and type I interferons. They can also migrate to lymph nodes following parasite exposure. Interferon (IFN), Interleukin (IL-), Tumor Necrosis Factor (TNF), C-C Chemokine Ligand (CCL), C-X-C Chemokine Ligand (CXCL), Growth Regulated Oncogene (GRO), Toll-Like Receptor (TLR), Nod-Like Receptor (NLR), MicroRNA 21 (miR21), Nuclear Factor (NF), Cathelicidin (LL-37), Major Histocompatibility Complex Class I Chain-Related Protein (MIC), B-Cell Lymphoma 2-Apoptosis Regulator (BCL2), Natural Killer Cell (NKC).

Figure 2

Intestinal Organoids. (A) graphical representation of an intestinal organoid. The inside of the organoid corresponds to the luminal side, and the outside of the organoid corresponds to the basolateral side. Blue: intestinal stem cells, Red: Paneth cells, Tan: enterocytes, Green: goblet cells, Yellow: enteroendocrine cells. (B) Bovine intestinal organoid 6 days post-plating. Numerous folds and budding structures are noted, indicating crypt and villi-like domains. (C) Sectioned ovine intestinal organoid illustrating nuclei (DAPI), apical junctional protein ZO-1 (green), and chromogranin-A (red) indicating enteroendocrine cell differentiation.