From the blood to the brain: avenues of eukaryotic pathogen dissemination to the central nervous system

Abstract

Infection of the central nervous system (CNS) is a significant cause of morbidity and mortality, and treatments available to combat the highly debilitating symptoms of CNS infection are limited. The mechanisms by which pathogens in the circulation overcome host immunity and breach the blood-brain barrier are active areas of investigation. In this review, we discuss recent work that has significantly advanced our understanding of the avenues of pathogen dissemination to the CNS for four eukaryotic pathogens of global health importance: Toxoplasma gondii, Plasmodium falciparum, Trypanosoma brucei, and Cryptococcus neoformans. These studies highlight the remarkable diversity of pathogen strategies for trafficking to the brain and will ultimately contribute to an improved ability to combat life-threatening CNS disease.

Figure 1

Eukaryotic pathogens utilize a diverse range of strategies to migrate from the blood to the CNS. A schematic shows the cross section of a blood vessel of the BBB and potential pathways of CNS entry for four global pathogens. T. gondii can invade and replicate in brain endothelial cells and may undergo transendothelial migration either as a free tachyzoite or inside an infected leukocyte. Cerebral malaria is associated with sequestration of P. falciparum-infected red blood cells (iRBCs) in the brain microvasculature and binding of iRBCs to uninfected RBCs in a process known as rosetting. This leads to the obstruction of blood flow and may contribute to breakdown of the BBB and vascular leakage. T. brucei likely crosses the BCB via fenestrated vessels inside the choroid plexus, followed by trafficking to the meninges. Some evidence suggests that enhanced vascular permeability induced by host inflammatory responses may allow the parasite to directly cross the BBB. C. neoformans can cytoadhere to endothelium, often at narrow points in the blood vessels and undergo transcytosis. Endothelial cells that internalize yeast lose their structural integrity, resulting in cell stress and injury.