Toxoplasma gondii‐infected natural killer cells display a hypermotility phenotype in vivo

Abstract

Toxoplasma gondii is a highly prevalent intracellular protozoan parasite that causes severe disease in congenitally infected or immunocompromised hosts. T. gondii is capable of invading immune cells, and it has been suggested that the parasite harnesses the migratory pathways of these cells to spread through the body. While in vitro evidence suggests that the parasite further enhances its spread by inducing a hypermotility phenotype in parasitized immune cells, in vivo evidence for this phenomenon is scarce. Here, we use a physiologically relevant oral model of T. gondii infection, in conjunction with two-photon laser scanning microscopy, to address this issue. We found that a small proportion of natural killer (NK) cells in mesenteric lymph nodes contained parasites. Compared to uninfected “bystander” NK cells, these infected NK cells showed faster, more directed, and more persistent migratory behavior. Consistent with this, infected NK cells showed impaired spreading and clustering of the integrin, LFA-1, when exposed to plated ligands. Our results provide the first evidence for a hypermigratory phenotype in T. gondii-infected NK cells in vivo, providing an anatomical context for understanding how the parasite manipulates immune cell motility to spread through the host.

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

“…A recent study showed that direct invasion with T. gondii could also impaired NK cell effector function 28. Consistent with this, we have previously found impaired clustering of the integrin LFA‐1, involved in NK cell cytotoxicity, in parasitized NK cells 20. We can speculate that invasion of NK cells by the parasite leads to impaired formation of lytic contacts.…”

“…Consistent with this, we observe an increase in cell surface α2 on the total splenic NK cell population following infection. In contrast to the bulk NK cell population, parasitized NK cells become hypermotile, and we might therefore expect a decrease in α2 expression 20. However, our analysis of in vitro parasitized NK cells suggests that this is not the case.…”

“…Therefore, although the changes we observed in integrin expression in the bulk NK cell population were not consistent with migration to the brain (Figure 1B,C), we wanted to determine if integrin expression was differentially regulated on directly parasitized NK cells compared with population as a whole. However , in vivo , only a very small proportion of NK cells are directly invaded by the parasite,20 making this difficult to assess (Figure 1B). To circumvent this, cultured NK cells isolated from the spleen of naïve C57BL6/J mice were infected with the type II Prugniaud strain expressing GFP.…”

“…Despite their protective role during parasitic infections, recent evidence indicates that NK cells can be directly invaded by T. gondii 19, 2019, 20.…”

“…T. gondii ‐invaded NK cell are not efficiently targeted for destruction by other NK cells and are hypermotile 19, 20. This may allow the parasite to use NK cells to protect themselves from immune mediated destruction, while transiting successfully from the site of infection to muscles or brain.…”