Rapid cytoskeleton remodelling in dendritic cells following invasion byToxoplasma gondiicoincides with the onset of a hypermigratory phenotype

Abstract

SummaryHost cell manipulation is an important feature of the obligate intracellular parasite Toxoplasma gondii. Recent reports have shown that the tachyzoite stages subvert dendritic cells (DC) as a conduit for dissemination (Trojan horse) during acute infection. To examine the cellular basis of these processes, we performed a detailed analysis of the early events following tachyzoite invasion of human monocyte-derived DC. We demonstrate that within minutes after tachyzoite penetration, profound morphological changes take place in DC that coincide with a migratory activation. Active parasite invasion of DC led to cytoskeletal actin redistribution with loss of adhesive podosome structures and redistribution of integrins (CD18 and CD11c), that concurred with the onset of DC hypermotility in vitro. Inhibition of parasite rhoptry secretion and invasion, but not inhibition of parasite or host cell protein synthesis, abrogated the onset of morphological changes and hypermotility in DC dose-dependently. Also, infected DC, but not by-stander DC, exhibited upregulation of C-C chemokine receptor 7 (CCR7). Yet, the onset of parasite-induced DC hypermotility preceded chemotactic migratory responses in vitro. Collectively, present data reveal that invasion of DC by T. gondii initiates a series of regulated events, including rapid cytoskeleton rearrangements, hypermotility and chemotaxis, that promote the migratory activation of DC.

Toxoplasma gondii disrupts β1 integrin signaling and focal adhesion formation during monocyte hypermotility

“…Several studies have demonstrated that immune cells infected with T. gondii become hypermotile (27)(28)(29)(30)(31)(32)(33)(34)41), an effect that has been proposed to facilitate the dissemination of the intracellular parasite in the infected host. In the present study, we have demonstrated that the hypermotility of T. gondii-infected human monocytes is linked to a dysregulation in integrin-dependent cell adhesion through defects in FAK-regulated focal adhesions.…”

Dysregulation of focal adhesion kinase upon Toxoplasma gondii infection facilitates parasite translocation across polarised primary brain endothelial cell monolayers

“…Despite that the two cell types exhibited dramatically dif- (Varughese, Kasper, Anneken, & Yadav, 2015). Additionally, because redistribution of β1-integrins is observed upon T. gondii infection in DCs (Weidner et al, 2013), it is also possible that FAK dysregulation impacts on β1-integrin signalling and focal adhesion reorganisation in endothelial and epithelial cells and that the resulting increased vascular or epithelial permeability facilitates passage of T. gondii (Izawa et al, 2017). Alternatively, toxoplasma-derived regulatory molecules or phosphatases delivered to the host cell cytosol upon host cell invasion could mediate the observed effects (Daher et al, 2007;Delorme, Garcia, Cayla, & Tardieux, 2002;Gao et al, 2014;Gilbert, Ravindran, Turetzky, Boothroyd, & Bradley, 2007).…”

Brains and Brawn: Toxoplasma Infections of the Central Nervous System and Skeletal Muscle

“…These in turn are infected by Toxoplasma and become hypermigratory, a process that increases their emigration from the intestine to peripheral tissues [11]. Parasite induction of hypermigratory dendritic cells and inflammatory monocytes is a multi-step process that includes alterations of the host cells’ actin cytoskeleton, upregulation of the CCR7 chemokine receptor, and activation of gamma-aminobutyric acid (GABA) receptor signaling [12, 13]. …”