Mechanisms of Candida albicans intracellular filamentation in human macrophages leading to peptide toxin secretion and escape

Phagocytes are essential for the initial immune response to infections with the opportunistic fungal pathogen Candida albicans. While the fungus is efficiently phagocytosed by macrophages, it also possesses strategies to survive inside phagosomes and to escape from these phagocytes within hours.

Rapid initiation of filamentation inside the phagosome is a critical step for C. albicans escape since subsequently, filamentation leads to exertion of physical forces and drives damage to the macrophage. Filamentation also occurs in conjunction with the production of the peptide toxin candidalysin. After phagosomal escape, the toxin contributes to host cell damage, activation of caspase-1, and the NLRP3 inflammasome leading to the release of IL-1β. However, candidalysin is mostly dispensable for the induction of caspase-1-dependent pyroptosis. This undermines the importance of understanding how filamentation is initiated in the host phagosome.

This key process is likely triggered by the amino acid arginine. Under phagosome-mimetic conditions such as acidic pH and nutrient deprivation, addition of arginine and the related amino acids ornithine and proline selectively induces filamentation. This is the case in both arginine-prototrophic and -auxotrophic strains. During infection with human primary monocyte-derived macrophages, the same strains exhibit similar filamentation and escape rates and induce comparable levels of damage. These data support the hypothesis that fungal arginine biosynthesis is not required for induction of intraphagosomal filamentation, but rather host-derived arginine. Our initial data suggests that an amino acid transporter expressed by macrophages localizes to the phagosome, yielding a potential source for this signal.

In summary, host-cell escape requires a combination of hyphal extension and candidalysin production. In ongoing work, we are investigating the role of fungal arginine catabolism on the escape of C. albicans, especially with regard to the importance of arginine in macrophage polarization and the function of candidalysin in macrophage cell death.