Cryptococcus neoformans Infection in the Central Nervous System: The Battle between Host and Pathogen

Abstract

Cryptococcus neoformans (C. neoformans) is a pathogenic fungus with a global distribution. Humans become infected by inhaling the fungus from the environment, and the fungus initially colonizes the lungs. If the immune system fails to contain C. neoformans in the lungs, the fungus can disseminate to the blood and invade the central nervous system, resulting in fatal meningoencephalitis particularly in immunocompromised individuals including HIV/AIDS patients. Following brain invasion, C. neoformans will encounter host defenses involving resident as well as recruited immune cells in the brain. To overcome host defenses, C. neoformans possesses multiple virulence factors capable of modulating immune responses. The outcome of the interactions between the host and C. neoformans will determine the disease progression. In this review, we describe the current understanding of how C. neoformans migrates to the brain across the blood-brain barrier, and how the host immune system responds to the invading organism in the brain. We will also discuss the virulence factors that C. neoformans uses to modulate host immune responses.

Keywords: Cryptococcus neoformans; NK cells; T cells; Trojan horse; brain invasion; central nervous system; chitin; cryptococcosis; cytokines; fungal dissemination; fungal pathogenesis; fungus; laccase; macrophages; melanin; meningoencephalitis; microglia; monocytes; paracellular crossing; phospholipase B1; polysaccharide capsule; transcytosis; urease; virulence factors.

Figure 1

C. neoformans’ transmigration to the brain across the BBB. Three pathways have been proposed for the BBB crossing of C. neoformans. (A) Trojan horse. Phagocytes can carry ingested C. neoformans across the BBB through paracellular and transcellular migration. Phagocytes containing C. neoformans can also directly transfer the fungal cell to brain endothelial cells through lateral transfer, leading to BBB crossing of the organism. (B) Transcytosis. Interactions of cryptococcal hyaluronic acid with endothelial CD44 or receptor of hyaluronan-mediated motility (RHAMM) lead to endocytosis of the yeast cell. Following endocytosis, cryptococcal Mpr1 interacts with Annexin A2 (AnxA2) to facilitate exocytosis of the organism from the endothelial cells. In addition, cryptococcal phospholipase B1 (PLB1) promotes transcytosis through activation of host cell Rac1. (C) Paracellular crossing. Host plasminogen (white) binds to C. neoformans and is converted to the serine protease plasmin (red). Plasmin degrades the extracellular matrix (ECM), facilitating fungal crossing of the BBB. The tight junction of the BBB can be damaged by cryptococcal urease (due to the toxic effects of urease-induced ammonia) and other secreted cryptococcal proteases. C. neoformans can invade the brain across the damaged BBB.

Figure 2

Host immune responses to C. neoformans in the brain. (A) Following brain infection of C. neoformans, TNF-α and chemokines are produced, facilitating leukocytes’ migration to the brain parenchyma. IFN-γ produced by CD4⁺/CD8⁺ T cells and NK/NKT cells promotes the activation of microglia and macrophages. Activated microglia and macrophages secrete TNF-α, further driving brain inflammation. Recruited inflammatory monocytes differentiate into inflammatory macrophages and help shape Th1 immune responses, which are required for fungal clearance. (B) As the resident glial cells, microglia and astrocytes are the first cells to respond to invading yeast cells. Later, recruited leukocytes including CD4⁺/CD8⁺ T cells, NK/NKT cells, and inflammatory monocyte/macrophages accumulate in and around the fungal clusters. As effector cells, microglia and macrophages internalize the fungal cells. T cells and NK cells secrete IFN-γ to promote fungicidal activity of these phagocytes. NK cells and T cells are also involved in direct killing of the fungal cells through release of perforin or granulysin (GNLY). (C) Inflammatory responses are required for fungal clearance in the brain but must be tightly controlled. Inflammatory monocytes and IFN-γ-secreting CXCR3⁺ CD4⁺ T cells facilitate neuronal damage and cause immunopathology during cryptococcal meningoencephalitis.

Figure 3

Cryptococcal virulence factors as immune modulators. Fungal virulence factors mediate cryptococcal pathogenesis and function as host immune modulators. Glucuronoxylomannan (GXM) from the polysaccharide capsule inhibits phagocytosis of C. neoformans by macrophages, suppresses antigen presentation, and induces apoptosis of macrophages and T cells. Melanin protects the yeast cells from oxidants and antimicrobial peptides. Melanization suppresses the production of cytokines such as IL-1β, TNF-α, and IL-12. Laccase, an enzyme required for biosynthesis of melanin, is involved in regulation of nonlytic exocytosis of C. neoformans from macrophages and contributes to the skewing of Th1/Th17 to Th2 immune responses. Chitin fragments promote Th2 responses and inhibit neutrophil influx. PLB1 promotes fungal dissemination and inhibits macrophage killing. Urease facilitates fungal brain invasion and induces Th2 responses. Secreted protein CPL1 promotes arginase-1 production and shapes the M2 polarization.