Induction of dendritic cell migration upon Toxoplasma gondii infection potentiates parasite dissemination

Abstract

SummaryThe 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 G i -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 Toxoplasmainfected 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.

Parasitized Natural Killer cells do not facilitate the spread of Toxoplasma gondii to the brain

“…At 4 and 7 days post‐infection (dpi), we determined the percentage of NK cells in a lymphoid tissue (where NK cells become parasitized) and in the brain (a preferential site for the establishment of chronic T. gondii infection) 2, 21, 22. These time points were selected as they coincide with the earliest infiltration of T. gondii into the brain, when we might expect immune cell‐mediated trafficking to be important 4. The percentage of NK cells in the spleen decreased from 3.75% in noninfected animals to 1.96% in infected animals after 4 dpi and from 3.6% to 1% after 7 dpi (Figure 1A,B), suggesting that NK cells may have migrated away.…”

“…Adoptive transfer of parasitized DCs or CD11b + cells can transport the parasite into the host when they contained the parasite,4, 29 allowing the access of tachyzoites into the brain 5, 30. To determine if NK cells can also play a role in spread of T. gondii to the brain, we compared parasite loads in the brains of mice infected with free tachyzoites or with in vitro parasitized NK cells.…”

“…Splenic NK cells were selected as, upon adoptive transfer, they have been shown to recirculate through all organs ordinarily containing NK cells 31. Previous studies showed that tachyzoites are detected in lymphoid tissues early after infection (between 2 and 6 days),4, 12, 32, 33 while parasites were detected in the brains of infected animals by 7 dpi 4, 8, 30, 34. We therefore decided to evaluate the parasite burden in the spleen and the brain of infected animals by PCR at 4 and 7 dpi.…”

“…Previous studies have demonstrated that the parasite can utilize immune cells as “Trojan Horses” to disseminate throughout the host 3. For example, when parasitized dendritic cells (DCs) were administered intraperitoneally to naïve mice, parasite loads in the brain increased more rapidly than in mice given free tachyzoites, with the greatest differences observed at 4 days post‐inoculation 4. Similarly, tachyzoites were observed within CD11b+ blood cells which, upon adoptive transfer, could establish infection in the brain 5.…”

“…T. gondii may exploit the natural migratory pathways of host cells, or actively manipulate host cell migration to augment spread. In vitro studies have shown that parasitized DC displays rapid cytoskeletal remodelling, induction of a hypermotile phenotype and enhanced transmigration across endothelial monolayers 4, 6, 7. It is therefore reasonable to suggest that T. gondii is transported across the blood‐brain barrier within host immune cells.…”