Redundant Trojan horse and endothelial-circulatory mechanisms for host-mediated spread ofCandida albicansyeast

Abstract

The host innate immune system has developed elegant processes for the detection and clearance of invasive fungal pathogens. These strategies may also aid in the spread of pathogens in vivo, although technical limitations have previously hindered our ability to view the host innate immune and endothelial cells to probe their roles in spreading disease. Here, we have leveraged zebrafish larvae as a model to view the interactions of these host processes with the fungal pathogen Candida albicans in vivo. We examined three potential host-mediated mechanisms of fungal spread: movement inside phagocytes in a “Trojan Horse” mechanism, inflammation-assisted spread, and endothelial barrier passage. Utilizing both chemical and genetic tools, we systematically tested the loss of neutrophils and macrophages and the loss of blood flow on yeast cell spread. Both neutrophils and macrophages respond to yeast-locked and wild type C. albicans in our model and time-lapse imaging revealed that macrophages can support yeast spread in a “Trojan Horse” mechanism. Surprisingly, loss of immune cells or inflammation does not alter dissemination dynamics. On the other hand, when blood flow is blocked, yeast can cross into blood vessels but they are limited in how far they travel. Blockade of both phagocytes and circulation reduces rates of dissemination and significantly limits fungal spread distance from the infection site. Together, this data suggests a redundant two-step process whereby (1) yeast cross the endothelium inside phagocytes or via direct uptake, and then (2) they utilize blood flow or phagocytes to travel to distant sites.Author summaryAlthough Candida albicans is the most common cause of fungal bloodstream infection, we know little about how it spreads from one tissue to another. Host processes often inadvertently assist pathogens that can hijack immune cells or induce endothelial endocytosis. Here we have used transparent zebrafish to visualize how specific host cells and processes contribute to yeast spread in vivo. We find that Candida is a sophisticated pathogen that uses redundant strategies to disseminate in the host: it can either use host immune cells or cross into the circulatory system and use blood flow. These data suggest that both of these mechanisms must be targeted to limit Candida dissemination during infection.

The Trojan Horse Model in Paracoccidioides: A Fantastic Pathway to Survive Infecting Human Cells

“…Candida albicans survive within macrophages and can be released far from the site of infection through non-lytic exocytosis. The intracellular viable yeast is able to get into the bloodstream and use blood flow to transmigrate to other tissues ( Scherer et al., 2020 ).…”

Comparative miRNA Transcriptomics of Mouse and Macaque Reveals MYOC is An Inhibitor for C. neoformans Invasion into Brain

“…To date, massive researches have focused on CNS invasion during fungal meningitis and numerous milestones achieved, including the fact that cryptococcal cells can interact with brain epithelial cells directly and indirectly by microscopy or electron microscope [18][19][20]28]. However, blocking this progression is still on the way.…”

“…Studies have shown the raised body temperature, limited nutrients of glucose and metal ions, phagocytosis by phagocytes and cellular immunities are powerful weapons for fungal elimination in hosts [4][5][6][7][8][9][10], while fungal evolved strategies in return, such as temperature resistance, polysaccharide capsule and melanin production, morphology switching, and virulence gene expressions [11][12][13][14][15][16]. Nonetheless, the mechanisms of fungal central nervous system (CNS) invasion have not been determined, which is also a mystery in cryptococcosis, a life-threatening fungal invasive disease, initialized by human pathogen Cryptococcus neoformans [17][18][19][20]. Cryptococcal diseases are predominant prevalent among immune compromised patients, such as HIV/AIDS, organ transplanted, systemic lupus erythematosus, and other immune associated diseases, and contribute about 15% of deaths in HIV/AIDS patients [21][22][23].…”