Induction of dendritic cell migration upon Toxoplasma gondii infection potentiates parasite dissemination.
The processes leading to systemic dissemination of the obligate intracellular parasite Toxoplasma gondii remain unelucidated. In vitro studies on human and murine dendritic cells (DC) revealed that active invasion of DC by Toxoplasma induces a state of hypermotility in DC, enabling transmigration of infected DC across endothelial cell monolayers in the absence of chemotactic stimuli. Infected DC exhibited upregulation of maturation markers and co-stimulatory molecules. While modulation of cell adhesion molecules CD11/CD18 was similar for Toxoplasma-infected DC and lipopolysaccharide (LPS)-matured DC, Toxoplasma-infected DC did not exhibit upregulation of CD54/ICAM-1. Induction of host cell migration in vitro required live intracellular parasite(s) and was inhibited by uncoupling the Gi-protein signalling pathway with pertussis toxin, but did not depend on CCR5, CCR7 or Toll/interleukin-1 receptor signalling. When migration of Toxoplasma-infected DC was compared with migration of LPS-stimulated DC in vivo, similar or higher numbers of Toxoplasma-infected DC reached the mesenteric lymph nodes and spleen respectively. Adoptive transfer of Toxoplasma-infected DC resulted in more rapid dissemination of parasites to distant organs and in exacerbation of infection compared with inoculation with free parasites. Altogether, these findings show that Toxoplasma is able to subvert the regulation of host cell motility and likely exploits the host's natural pathways of cellular migration for parasite dissemination.
Lambert
Henrik
H
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, SE-141 86 Stockholm, Sweden.
Hitziger
Niclas
N
Dellacasa
Isabel
I
Svensson
Mattias
M
Barragan
Antonio
A
D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D002465:Cell Movement; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000469:parasitology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D008198:Lymph Nodes / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D019713:Receptors, CCR5 / Q000378:metabolism; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000469:parasitology; D014122:Toxoplasma / Q000276:immunology / Q000469:parasitology* / Q000472:pathogenicity; D014123:Toxoplasmosis / Q000276:immunology / Q000469:parasitology*
C515370:CCR7 protein, human; C515371:Ccr7 protein, mouse; D007375:Interleukin-1; D019713:Receptors, CCR5; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D049452:Green Fluorescent Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go