Identification of host immune mediators promoting Candida albicans adaptation to inflammation

During microbial infections, there is a dynamic interplay between the host and the pathogen. An appropriate adaptation to the inflammatory environment of the host during infection is crucial for pathogen success and persistence within the host. Candida albicans is an opportunistic pathogen that can cause invasive life-threatening infections in immunocompromised individuals. Yet, its existence as a common commensal yeast on human mucosal surfaces fostered the evolution of different adaptation strategies that allow it to evade or escape from the host immune response. In line with this, we have investigated how C. albicans uses soluble signals from activated human macrophages to increase its stress resistance and, consequently, its ability to escape macrophages.

To understand how C. albicans senses and adapts to the inflammatory environment during its pathogenic stage, an inflammation-adaptation model has been established. In this model, monocyte-derived macrophages (MDMs) are stimulated with inactivated C. albicans morphotypes, which elicit inflammatory responses. Macrophage activation results in the release of a complex mixture of immune mediators into the supernatant, which is then used for C. albicans culture in vitro and assessment of fungal adaptations. Supernatant composition was analyzed by fractionation and proteomics to identify potential immune mediators inducing fungal adaptation.

Several immune mediators that could potentially be sensed by the fungus to trigger fungal adaptations were identified. Among the molecules present in the supernatants, the macrophage cytoplasmic enzyme lactate dehydrogenase (LDH) has been identified as a potential promoter of fungal stress resistance. Specific effects on C. albicans virulence, growth, and metabolism are currently being assessed.

Collectively we observe that changes in the host inflammatory environment can induce C. albicans stress resistance. Understanding how specific immune mediators influence this adaptation and the host-pathogen interplay can foster the understanding of the persistence of pathogens like C. albicans and might be relevant to identify new therapeutic avenues.