Abstract
Fungal infections of the central nervous system are responsible for significant morbidity and mortality. Cryptococcus neoformans (Cn) is the primary cause of fungal meningitis. Infection begins in the lung after inhalation of fungal spores but often spreads to other organs, particularly the brain in immunosuppressed individuals. Cn’s ability to survive phagocytosis and endure the onslaught of oxidative attack imposed by the innate immune response facilitates dissemination to the central nervous system (CNS). Despite the success of Cn at bypassing innate immunity, entry into the heavily protected brain requires that Cn overwhelm the highly restricted blood-brain barrier (BBB). This is a formidable task but mounting evidence suggests that Cn expresses surface-bound and secreted virulence factors including urease, metalloprotease, and hyaluronic acid that can undermine the BBB. In addition, Cn can exploit multiple routes of entry to gain access to the CNS. In this review, we discuss the cellular and molecular interface of Cn and the BBB, and we propose that the virulence factors mediating BBB crossing could be targeted for the development of anti-virulence drugs aimed at preventing fungal colonization of the CNS.
Highlights
The ability to grow at the host temperature separates Cryptococcus neoformans (Cn) from other species of fungi that are unable to infect mammals
For reasons that are still not completely understood, Cn has a predilection for the brain making it the leading cause of fungal meningitis worldwide
We propose that mechanisms of central nervous system (CNS) penetration are a high-value target, and should be considered in the development of anti-virulence therapies
Summary
The ability to grow at the host temperature separates Cn from other species of fungi that are unable to infect mammals. The new way forward in the development of antifungals should encompass new targets that are associated with mechanisms of pathogenesis – i.e., anti-virulence agents (Dickey et al, 2017) These drugs differ from conventional therapeutics in that they do not affect the growth or viability of the organism and their efficacies are often more restricted. Once Cn crosses into the brain parenchyma, the growth and proliferation of Cn continued, resulting in cryptococcomas This entire process can occur without the involvement of macrophages (Kozel and Gotschlich, 1982), suggesting that Cn can associate directly with the surface of brain microvascular endothelial cells (BMECs). By inducing membrane-related changes, Cn facilitates its migration through a more permeable brain endothelium likely via the upregulation of endocytic-vesicles during transcellular migration
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