High levels of short chain fatty acids secreted by Candida albicans hyphae induce neutrophil chemotaxis via Free Fatty Acid Receptor 2.

Candida albicans belongs to our commensal mucosal flora and in immune-competent individuals in the absence of epithelial damage, this fungus is well tolerated and controlled by our immune defense. However, C. albicans is an opportunistic microorganism that can cause different forms of infections, ranging from superficial to life-threatening systemic infections. C. albicans is polymorphic and switch between different phenotypes, e.g., from yeast form to hyphal form. C. albicans hyphae are invasive and can grow into tissues to eventually reach circulation. During fungal infections, particularly neutrophils play a critical role for the defense, but how neutrophils are directed towards the invasive forms of fungi is less well understood. We set out to investigate possible neutrophil chemoattractants released by C. albicans into culture supernatants. We found that cell free culture supernatants from the hyphal form of C. albicans induced both neutrophil chemotaxis and concomitant intracellular calcium transients. Size separation and hydrophobic sorting of supernatants, indicated small hydrophilic factors as responsible for the activity. Further analysis showed that the culture supernatants contained high levels of short chain fatty acids (SCFAs) with higher levels from hyphae as compared to yeast. SCFAs are known neutrophil chemoattractants acting via the neutrophil free fatty acid receptor 2 (FFAR2). In line with this, the calcium signaling in neutrophils induced by hyphae culture supernatants was blocked by a FFAR2 antagonist and potently increased in the presence of a positive allosteric modulator. Our data imply that SCFA may act as a recruitment signal whereby neutrophils can detect C. albicans hyphae.