Mechanisms of fungal dissemination

Abstract

Fungal infections are an increasing threat to global public health. There are more than six million fungal species worldwide, but less than 1% are known to infect humans. Most of these fungal infections are superficial, affecting the hair, skin and nails, but some species are capable of causing life-threatening diseases. The most common of these include Cryptococcus neoformans, Aspergillus fumigatus and Candida albicans. These fungi are typically innocuous and even constitute a part of the human microbiome, but if these pathogens disseminate throughout the body, they can cause fatal infections which account for more than one million deaths worldwide each year. Thus, systemic dissemination of fungi is a critical step in the development of these deadly infections. In this review, we discuss our current understanding of how fungi disseminate from the initial infection sites to the bloodstream, how immune cells eliminate fungi from circulation and how fungi leave the blood and enter distant organs, highlighting some recent advances and offering some perspectives on future directions.

Keywords: Aspergillus fumigatus; Candida albicans; Cryptococcus neoformans; Fungal pathogenesis; Fungus; Invasive aspergillosis; Invasive candidiasis; Meningoencephalitis; Paracellular crossing; Transcytosis; Trojan horse.

Fig. 1

Mechanisms mediating extrapulmonary dissemination of C. neoformans a Trojan horse: following phagocytosis, C. neoformans (green) is able to survive within alveolar macrophages (purple) and is transported across the epithelium inside these migrating phagocytes where they can access the interstitium, lymph system and/or bloodstream. C. neoformans can exit macrophages through vomocytosis and disseminate throughout the host as free fungi or be taken up by peripheral monocytes in the bloodstream and transported to the vasculature of various organs including the brain. b Transcytosis: C. neoformans adheres to epithelial cells through interactions between glucuronoxylomannan (GXM) and CD14 as well as palmitic acid (PA) and surfactant protein-D (SP-D) receptors. Following adherence, epithelial cells endocytose yeast, transporting them across the epithelium. c Paracellular crossing and loss of barrier integrity: C. neoformans induces the production of IL-33 (peach), which along with urease (purple) disrupts tight junctions and allows fungal cells to pass between epithelial cells. C. neoformans also secretes Plb1 (green), urease (purple) and proteases (yellow) which damage epithelial barriers, allowing fungi to cross the epithelium and access the bloodstream

Fig. 2

Clearance of intravascaular C. neoformans a Neutrophils (dark purple) are recruited to intravascular C. neoformans (green) in a C5a-dependent manner. Fungal cells are phagocytosed by neutrophils via iC3b–CR3 interactions and are killed through oxidative and nonoxidative mechanisms. b Liver-resident Kupffer cells (light purple) recognize and bind C3b/iC3b on circulating C. neoformans through CRIg receptors. Following phagocytosis, Kupffer cells can inhibit cryptococcal growth and limit fungal dissemination to target organs

Fig. 3

Mechanisms mediating brain invasion by C. neoformans a Trojan horse: peripheral monocytes (dark pink) ingest intravascular C. neoformans (green) and transport them to the brain vasculature. Monocytes can carry yeast across the BBB through transendothelial pores (transcellular transmigration), or can paracellularly transmigrate between endothelial cells. In addition, monocytes can transfer C. neoformans directly to endothelial cells (red) (lateral transfer), facilitating transmigration of cryptococci across the BBB. b Transcytosis: hyaluronic acid (HA)–CD44 interactions along with Mpr1 promote C. neoformans adherence to brain endothelial cells. Engagement of CD44 activates EphA2, while cryptococcal Plb1 activates host cell Rac1 which in turn activates PKCα. Activation of these pathways induces endocytosis of C. neoformans. Following internalization, C. neoformans engages host AnxA2 via Mpr1 which facilitates exit of endothelial cells and successful crossing of the BBB. c Paracellular crossing and loss of barrier integrity: C. neoformans disrupts the BBB through the utilization of host plasmin (pink) and secretion of urease (purple) and other proteases (yellow) and migrates across the endothelium into the brain parenchyma