Molecular mechanisms of cryptococcal meningitis

Abstract

Fungal meningitis is a serious disease caused by a fungal infection of the central nervous system (CNS) mostly in individuals with immune system deficiencies. Fungal meningitis is often fatal without proper treatment, and the mortality rate remains unacceptably high even with antifungal drug interventions. Currently, cryptococcal meningitis is the most common fungal meningitis in HIV-1/AIDS, and its disease mechanism has been extensively studied. The key steps for fungi to infect brain and cause meningitis after establishment of local infection are the dissemination of fungal cells to the bloodstream and invasion through the blood brain barrier to reach the CNS. In this review, we use cryptococcal CNS infection as an example to describe the current molecular understanding of fungal meningitis, including the establishment of the infection, dissemination, and brain invasion. Host and microbial factors that contribute to these infection steps are also discussed.

Figure 1. (A) The illustration of the blood-brain barrier (BBB). The BBB is a multi-cellular structure at the interface of circulation and the central nervous system. It is composed of brain microvascular endothelial cells, astrocytes, pericytes and neurons. The main function of the BBB is to maintain the neural microenvironment by regulating the changes of the levels of molecules in the blood, and protect the brain by blocking the entry of toxins and microorganisms that are circulating in the blood. (B) Pathogens can cross the BBB transcellularly, paracellularly and/or in infected phagocytes (the Trojan horse mechanism). In the transcellular traversal model (a), pathogens across the barrier by direct endocytosis of brain microvascular endothelial cells without disruption of intercellular tight junction. In the Paracellular traversal model (b), pathogens penetrate between barrier cells through loosen tight junction, and may or may not lead to tight-junction disruption. The “Trojan horse” mechanism (c) involves phagocytic microbial penetration of the barrier cells using transmigration within infected phagocytes. Pathogen cells are released from macrophages after penetration.