Abstract
Interspecies interactions greatly influence the virulence, drug tolerance and ultimately the outcome of polymicrobial biofilm infections. A synergistic interaction is observed between the fungus Candida albicans and the bacterium Staphylococcus aureus. These species are both normal commensals of most healthy humans and co-exist in several niches of the host. However, under certain circumstances, they can cause hospital-acquired infections with high morbidity and mortality rates. Using a mouse model of oral co-infection, we previously showed that an oral infection with C. albicans predisposes to a secondary systemic infection with S. aureus. Here, we unraveled this intriguing mechanism of bacterial dissemination. Using static and dynamic adhesion assays in combination with single-cell force spectroscopy, we identified C. albicans Als1 and Als3 adhesins as the molecular players involved in the interaction with S. aureus and in subsequent bacterial dissemination. Remarkably, we identified the host immune response as a key element required for bacterial dissemination. We found that the level of immunosuppression of the host plays a critical yet paradoxical role in this process. In addition, secretion of candidalysin, the C. albicans peptide responsible for immune activation and cell damage, is required for C. albicans colonization and subsequent bacterial dissemination. The physical interaction with C. albicans enhances bacterial uptake by phagocytic immune cells, thereby enabling an opportunity to disseminate.
Highlights
The fungus C. albicans is a commensal organism of the oral cavity, skin, gastro-intestinal and urogenital tracts (Berman, 2012; Mayer et al, 2013)
The als1 als3 mutant strain was impaired in adhesion (Supplementary Figure 2A) and both the C. albicans als3 and als1 als3 strain were strongly impaired in biofilm formation compared to the wild type (Supplementary Figure 2B)
These findings indicate that C. albicans Als1 and Als3 adhesins are crucial for S. aureus to disseminate
Summary
The fungus C. albicans is a commensal organism of the oral cavity, skin, gastro-intestinal and urogenital tracts (Berman, 2012; Mayer et al, 2013). One of the key players in C. albicans biofilm formation is the Als protein (Zhao et al, 2004; Nobile et al, 2006), a member of the agglutinin-like sequence (ALS) family which is only expressed during the hyphal or pseudo-hyphal phase (Hoyer et al, 2008; Hoyer and Cota, 2016). Another ALS family member, ALS1, shows 81% sequence homology to ALS3 and has overlapping functions but different expression patterns (Hoyer et al, 1998; Liu and Filler, 2011; Ho et al, 2019). A C. albicans ALS3 deletion strain is only impaired in biofilm formation in vitro but not in vivo, presumably due to the activation of additional adhesin genes, such as ALS1 (Nobile et al, 2006)
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