Innate immune cell response to host-parasite interaction in a human intestinal tissue microphysiological system

Abstract

Protozoan parasites that infect humans are widespread and lead to varied clinical manifestations, including life-threatening illnesses in immunocompromised individuals. Animal models have provided insight into innate immunity against parasitic infections; however, species-specific differences and complexity of innate immune responses make translation to humans challenging. Thus, there is a need for in vitro systems that can elucidate mechanisms of immune control and parasite dissemination. We have developed a human microphysiological system of intestinal tissue to evaluate parasite-immune–specific interactions during infection, which integrates primary intestinal epithelial cells and immune cells to investigate the role of innate immune cells during epithelial infection by the protozoan parasite, Toxoplasma gondii , which affects billions of people worldwide. Our data indicate that epithelial infection by parasites stimulates a broad range of effector functions in neutrophils and natural killer cell–mediated cytokine production that play immunomodulatory roles, demonstrating the potential of our system for advancing the study of human-parasite interactions.

Advances towards the complete in vitro life cycle of Toxoplasma gondii

“…This has also been achieved by generating collagen-supported epithelial sheets from intestinal organoids 94 . Immune cells and the microbiota are missing in these systems but can be added in co-culture approaches 95 , 96 . Several recent reviews have highlighted the great potential organoid-based systems will have as future cell culture models to either complement or, depending on the research question, even replace animal experiments in T. gondii and other Apicomplexa 97 – 100 .…”

New Avenues to Design Toxoplasma Vaccines Based on Oocysts and Cysts

“…Finally, a novel avenue that could help to improve the in vitro production of oocysts could be the recently described micro-physiological system of intestinal tissue described by Humayun et al. ( 55 ). By using a novel micromolding technique to generate hollow structures, artificial tubes of intestine can be engineered, recapitulating the lumen geometries of the gut ( 55 ).…”

“…( 55 ). By using a novel micromolding technique to generate hollow structures, artificial tubes of intestine can be engineered, recapitulating the lumen geometries of the gut ( 55 ). If this system were to be combined with either, or both, of the discoveries mentioned above, the culture of Toxoplasma intestinal stages in vitro mirroring natural conditions could be significantly improved.…”

“…( 54 ) and Humayun et al. ( 55 ) might lead to the in vitro production of oocysts from such a mutant strain without the need for using mice or cats. Finally, a better understanding of the genes involved in invasion and resistance of sporozoites present in the oocysts could lead to the discovery of valuable drug or vaccine targets that may prevent animals from getting infected and therefore spread the disease to other animals or humans.…”

Intestinal Microflora Vs Protozoan Parasites: From Interaction to Competition

“…Several studies examined the process of invasion at the cellular level and how parasite products contributes to the tissue injury, locally. In the very early phase of invasion, the Giardia enzyme, e.g., cysteine proteinases, break the affected epithelial barrier, and which further arouses the host's inflammatory and immunological responses.31 Host with normal immune armamentarium can easily recognize the protozoans [32]; but when the immune failed, the protozoan inhabitation that parasitizing mucosal facet may aoruse innate immune armamentarium, e.g., toll-like receptors (TLRs) [32,33]. T cells (particularly involving CD8+ cells), macrophages, neutrophils, and antibodies (e.g., IgM, IgG, and IgA) are major components of the acquired immune armamentarium necessary for the battle against giardiasis [34,35].…”