Cathelicidin and  Toxoplasmosis

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What is the role of cathelicidins in macrophages against intracellular microbes?

Toxoplasma gondii is a protozoan apicomplexan parasite, which can infect all warm-blooded humans and animals. Infection with T. gondii in immunocompromised individuals often leads to congenital toxoplasmosis, affecting the central nervous system. Clinical manifestations of toxoplasmosis include encephalitis, sepsis shock and retinochoroidal inflammation. In immunocompetent individuals, the development of toxoplasmosis is likely to course asymptomatically, highlighting the key role of immune defenses in controlling T. gondii infection.

 

The small intestine is critical in toxoplasmosis; this is the initial site for T. gondii invasion where immune defenses must counterattack. The ingested T. gondii cysts erupt in the small intestine, releasing bradyzoites, which transform to tachyzoites. When gut innate defenses fail, the tachyzoites invade and multiply in cells of the gut, travel to definitive locations (i.e., brain, retina, and muscles), and form cysts to establish long-term infections with eventual clinical signs.

 

This project in collaboration with Dr. Constance Finney (University of Calgary), investigates the early immune responses in host to fight T. gondii. Specifically, we study the mechanisms of action of cathelicidins secreted by white cells (neutrophils or macrophages) when exposed to T. gondii using cultured monocytes and in mice deficient in cathelicidins.

We hypothesize that cathelicidins produced by white cells are key in defenses against intracellular parasites by activating phagolysosomes and the release of mature pro-inflammatory cytokines. Thus, white cells patrolling in the bloodstream plus the production of cathelicidins contribute to suppress systemic propagation of parasites to vital organs (e.g., placenta) and prevent clinical signs (e.g., abortion).

 

Protective functions of cathelicidins that prevent the internalization of intracellular parasites (T. gondii ) are applied to the development of therapeutic applications against toxoplasmosis based on the utilization of cathelicidins. 

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