Reconsidering the blood-brain barrier: histopathology and microanatomy of cryptococcal CNS infection

SUMMARY Meningoencephalitis is the most severe form of cryptococcal infection. Pathogenic cryptococcal species enter the body primarily via the respiratory system. The central nervous system (CNS) is by far the most common site of cryptococcal dissemination, despite its reputation as a privileged anatomical space. Results from both in vitro and in vivo experiments have suggested multiple cellular and molecular mechanisms for entering the CNS, but no single one has been proven responsible for this remarkable neurotropism. While experimental approaches to the problem have centered around a uniform conception of the blood-brain barrier, a review of the histopathological forms of CNS disease shows marked variety in the locations and forms of lesions and their relevant anatomical barriers. Based on the microanatomy, it is likely that the pathway from blood into the CNS differs from lesion type to lesion type. In considering the genesis of cryptococcal CNS infection, we will first summarize cryptococcal virulence determinants of relevance to CNS infection and the conceptualization of the blood-brain barrier, its history, and functions. Next, we will summarize modes of cryptococcal entry through the blood-brain barrier and the interplay between fungal virulence determinants and host factors. We will outline the common histological findings of cryptococcal meningoencephalitis and examine the relevant vascular structures, discussing their implications for mechanisms of dissemination in the context of the vasculature, the host cellular and metabolic environment, and cryptococcal virulence factors in different parts of the CNS. Finally, we will discuss the value of different animal and in vitro models of cryptococcal infection and the endothelial glycocalyx, a ubiquitous feature of endothelial surfaces seldom considered in microbial pathogenesis.