Endothelial cells are a replicative niche for entry of Toxoplasma gondii to the central nervous system

Abstract

An important function of the blood–brain barrier is to exclude pathogens from the central nervous system, but some microorganisms benefit from the ability to enter this site. It has been proposed that Toxoplasma gondii can cross biological barriers as a motile extracellular form that uses transcellular or paracellular migration, or by infecting a host cell that then crosses the blood–brain barrier. Unexpectedly, analysis of acutely infected mice revealed significant numbers of free parasites in the blood and the presence of infected endothelial cells in the brain vasculature. The use of diverse transgenic parasites combined with reporter mice and intravital imaging demonstrated that replication in and lysis of endothelial cells precedes invasion of the central nervous system, and highlight a novel mechanism for parasite entry to the central nervous system.

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

“…However, in agreement with our findings, transfer of a mixed lymphocyte population (predominantly B cells) did not augment parasite dissemination relative to free tachyzoite controls 36. Our findings are also in agreement with more recent data demonstrating that free tachyzoites are able to cross the blood‐brain barrier without the assistance of host immune cells 8. While this latter study did not exclude the idea that immune cells may facilitate invasion of endothelial cells by bringing parasites in close contact with endothelial cells, our own analysis showed no increase in the presence of NK cells in either the brain or associated vasculature following infection.…”

“…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.…”

“…It is therefore reasonable to suggest that T. gondii is transported across the blood‐brain barrier within host immune cells. However, more recent studies reveal that free tachyzoites are present in blood, and in the endothelium of brain, suggesting that the motile extracellular form of the parasite may be capable of crossing blood‐brain barrier without assistance of host cells 8. Nevertheless, host immune cells may play an important role in the dissemination from the site of infection to the bloodstream, or in the delivery of parasites to the brain vasculature.…”

Parasite pathogenesis: Breaching the wall for brain access

“…Despite the existence of a powerful immune system and cells specialized in protection against foreign invaders, pathogens have developed clever strategies to cross or circumvent these defences and ultimately access the brain. In this issue of Nature Microbiology, Konradt et al 1 report a new route of entry for the parasite Toxoplasma gondiireplication within and lysis of cerebral endothelial cells. This mechanism of entry into the CNS contrasts with the previously proposed 'Trojan horse' decoy strategy that recruits motile host immune cells 2 and facilitates dissemination.…”

An interesting year

“…In March, we learned how Toxoplasma gondii accesses the central nervous system through the infection and lysis of endothelial cells in the brain vasculature 3 . Perhaps the most visible study published (and certainly the most read) came in the May issue, with an update to the 'tree of life' from Laura Hug and colleagues, revealing the dominance of bacterial diversity and extensive evolution in some branches of the tree 4 .…”