A lmost 15 years have passed since Jitender P. Dubey and colleagues proposed that the agent causing equine protozoal myeloencephalitis (EPM) is the protozoan parasite Sarcocystis neurona. EPM is a progressive and potentially fatal neurodegenerative disease. Although the incidence is relatively low, associated deaths continue to be reported, in large part because of late diagnoses and delayed treatment. Death often is attributable to neurologic dysfunction caused by the spread of the infection to any part of the central nervous system (CNS). Since its discovery, S. neurona has attracted a broad interest because of its unique mechanism of propagation. The infection process in equids by S. neurona differs fundamentally from that normally found in all Sarcocystis spp. or any other non-equid hosts in that no intramuscular cysts (sarcocysts) are formed in horses, but, instead, the schizont stages develop in the CNS and either destroy or functionally impair neural cells, leading to the severe neuropathology or clinical neurological abnormalities associated with EPM. What is unique about S. neurona is its ability to invade and replicate in the equine CNS. S. neurona is the only Sarcocystis spp. that has both neurotropic and neurovirulent species-specific pathogenicity traits. Neuroinvasion—S. neurona infection acquired by and transmitted through oral uptake of the sporocyst stage or peripheral administration such as intramuscular, intravenous, intraperitoneal, or subcutaneous injection of the merozoite stage and, to a lesser extent, sporocyst stage—raises the question of how S. neurona finds its way to the CNS. Neurotropism of S. neurona implies that the protozoan can move from general circulation to neural tissues by crossing the blood-brain barrier (BBB). In fact, our current understanding of EPM suggests a sequential mechanism of molecular pathogenesis in which the organism must cross the BBB of infected horses or mouse models. What are the possible portals of entry for S. neurona into the CNS? Themost widely suspected mechanism by which S. neurona merozoites enter the CNS is with the entry of infected monocytes crossing the brain vascular barrier. Infected leukocytes, especially lymphocytes, are also likely to serve as a possible transport mechanism of the protozoan into the CNS. This pathway has been claimed by Siobhan P. Ellison (Animal model for infection by an apicomplexan parasite; United States Patent 6780415). Once inside the CNS,merozoites can egress and invade additional cells and cause encephalitis. Other pathways can be postulated. S. neurona could cross the BBB by extracellular pathways. Cell-free parasites may be able to cross the BBB. S. neurona also could enter the brain tissue at the circumventricular organs (CVO), small areas of the brain with an absent or diminished BBB. Although these areas are separated from the rest of the brain, they do provide a possible site of CNS infection that does not require penetration of the BBB. However, whether S. neurona can use these pathways remains to be confirmed. How does S. neurona cross the brain endothelial cells? No information is available concerning how S. neurona interacts with the functional site of the BBB (the endothelial lining of the brain capillaries), invades the CNS, and causes encephalitis. One would assume that S. neurona could not cross the brain endothelium. However, infected macrophages can bind to activated brain endothelial cells. This may be the initial stage in a process that eventually leads to the macrophage crossing the BBB and taking up residence in the CNS as an infected microglial cell. The proof that this mechanism occurs during the course of the disease is still missing. Another hypothesis is that S. neurona may disrupt the BBB via infection of the cerebral endothelial cells themselves followed by dissemination of the parasite into the CNS. Experimental infection of horses and mice with S. neurona is always followed by acute and often lethal encephalitis. However, no evidence has been reported for a passage of this parasite through breakdown in the BBB and details of the mechanism(s) of entry of cellassociated and cell-free parasites into the CNS compartments through the BBB still escape our understanding. The availability of experimental mouse and horse models to study the mechanisms responsible for neurotropism of S. neurona and the pathogenesis of CNS disease in horses is therefore of prime interest. One of the crucial questions remaining to be answered is why S. neurona infection leads to CNS damage only in affected horses and not in any other vertebrate hosts. Perhaps, this speciesspecific susceptibility of only horse brain neural and endothelial cells to infection by S. neurona could be attributable to the presence of suitable ligands or receptors expressed on these Division of VeterinaryMedicine, The School of Veterinary Medicine and Science, The University of Nottingham, Sutton Bonington, Leicestershire, LE12 5RD, United Kingdom, elsheik2@gmail.com. 0737-0806/$ see front matter O 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.jevs.2007.01.005