Host Cell Subversion and Immune Evasion by Apicomplexan Parasites

Toxoplasma gondii (Tg) is an important opportunistic pathogen causing neuropathology and a model for studying diseases by intracellular parasites.

Active invasion of immune cells is used by Tg for dissemination (Trojan horse).We will explore the hypothesis that Tg hijacks the migratory functions of immune cells using a novel motogenic GABA signaling axis in human phagocytes to reach restricted organs.

We will pursue our discovery that the neurotransmitter GABA has activation functions in immune cells, when subversed by intracellular pathogens.

Further, we will elucidate the cytoskeletal remodeling via the hijacking of MAP kinase signaling in parasitized cells and determine the role of extracellular vesicles in cell-cell communication, eg neurons.

Our finding that Tg can modulate GABAergic signaling is particularly interesting given the psycho-behavioral impact of chronic Tg infection and associations to mental diseases.Based on our recent in vivo findings of passage by Tg across the blood-brain barrier (BBB) and determinants of dissemination, we will perform a CRISPR/Cas9-based genome-wide T. gondii screening in human BBB organoid systems to unravel the molecular basis of BBB passage.

Jointly, elucidation of these basic processes should lead to a better understanding of the pathophysiology of infections by apicomplexan parasites.

The undertaken integrated approach aims at a further understanding of complex host-pathogen interactions with an impact on the outcome of disease.