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

•The central nervous system is protected from pathogens by highly restrictive barriers.•Eukaryotic pathogens have evolved diverse strategies to infect the brain.•Intravital imaging systems using rodent models reveal novel mechanisms of CNS entry.

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.