The unicellular eukaryotic parasite Toxoplasma gondii hijacks the migration machinery of mononuclear phagocytes to promote its dissemination

Abstract

Toxoplasma gondii is an obligate intracellular protozoan with the ability to infect virtually any type of nucleated cell in warm‐blooded vertebrates including humans. Toxoplasma gondii invades immune cells, which the parasite employs as shuttles for dissemination by a Trojan horse mechanism. Recent findings are starting to unveil how this parasite orchestrates the subversion of the migratory functions of parasitised mononuclear phagocytes, especially dendritic cells (DCs) and monocytes. Here, we focus on how T. gondii impacts host cell signalling that regulates leukocyte motility and systemic migration in tissues. Shortly after active parasite invasion, DCs undergo mesenchymal‐to‐amoeboid transition and adopt a high‐speed amoeboid mode of motility. To trigger migratory activation – termed hypermigratory phenotype – T. gondii induces GABAergic signalling, which results in calcium fluxes mediated by voltage‐gated calcium channels in parasitised DCs and brain microglia. Additionally, a TIMP‐1‐CD63‐ITGB1‐FAK signalling axis and signalling via the receptor tyrosine kinase MET promotes sustained hypermigration of parasitised DCs. Recent reports show that the activated signalling pathways converge on the small GTPase Ras to activate the MAPK Erk signalling cascade, a central regulator of cell motility. To date, three T. gondii‐derived putative effector molecules have been linked to hypermigration: Tg14‐3‐3, TgWIP and ROP17. Here, we discuss their impact on the hypermigratory phenotype of phagocytes. Altogether, the emerging concept suggests that T. gondii induces metastasis‐like migratory properties in parasitised mononuclear phagocytes to promote infection‐related dissemination.

Integrin-dependent migratory switches regulate the translocation of Toxoplasma-infected dendritic cells across brain endothelial monolayers

“…The intracellular parasite achieves migratory activation of DCs by interfering with MAP kinase signalling [ 30 , 31 ] and calcium signalling [ 29 ] via activation of GABAergic signalling in the infected cell [ 23 , 28 ]. Here, we add that the hypermigration of parasitised DCs [ 40 ] is modulated by external cues in the cellular environment. In the blood circulation, it is unlikely that the sequestration of parasitised DCs to endothelium solely depends on the migratory mode per se but rather on the ability to adhere.…”

Integrin-dependent migratory switches regulate the translocation ofToxoplasma-infected dendritic cells across brain endothelial monolayers

“…The intracellular parasite achieves migratory activation of DCs by interfering with MAP kinase signalling [30,31] and calcium signalling [29] via activation of GABAergic signalling in the infected cell [28,23]. Here, we add that the hypermigration of parasitised DCs [40] is modulated by external cues in the cellular environment. In the blood circulation, it is unlikely that the sequestration of parasitised DCs to endothelium solely depends on the migratory mode per se but rather on the ability to adhere.…”

Interaction Between the Complement System and Infectious Agents – A Potential Mechanistic Link to Neurodegeneration and Dementia

“…It is also notable that the virulence can vary depending on Toxoplasma genotype ( Howe and Sibley, 1995 ; Behnke et al, 2011 ; Pomares et al, 2018 ; Taniguchi et al, 2018 ). Once disseminated into the brain, the parasite transforms into bradyzoite form (cyst) and establishes a life-long infection in neurons and glia ( Ólafsson and Barragan, 2020 ). The presence of Toxoplasma cysts in the CNS has been linked to various neuropsychiatric disorders, such as schizophrenia ( Elsheikha et al, 2016 ; Del Grande et al, 2017 ; Fuglewicz et al, 2017 ; Fond et al, 2018 ; Stepanova et al, 2019 ; Tyebji et al, 2019a , b ), possibly via the direct modulation of dopaminergic/serotonergic signaling as well as neuroinflammation ( Henriquez et al, 2009 ; Mahmoud et al, 2017 ).…”