D,L-2-hydroxyisocaproic acid (HICA) attenuates inflammatory responses in a murine Candida albicans biofilm model

Chronic biofilm infections are often accompanied by a chronic inflammatory response thus leading to impaired healing and increased, irreversible damage to host tissues. Biofilm formation is a major virulence factor for <i>Candida albicans</i> and a challenge for treatment. Most current antifungals have proven ineffective in eradicating infections attributed to biofilms. The biofilm structure protects <i>Candida</i> against antifungals and provides a way to evade host immune systems. This leads to a very distinct inflammatory response compared to planktonic counterparts. Previously, we have shown the superior efficacy of D,L-2-hydroxyisocaproic acid (HICA) against various bacteria and fungi. However, the immunomodulatory properties of HICA have not been studied. Our aim was to investigate the potential anti-inflammatory response to HICA <i>in vivo</i>. We hypothesized that HICA reduces the levels of immune mediators and attenuates the inflammatory response. In a murine model a robust biofilm was formed for five days in a diffusion chamber implanted underneath the mouse skin. The biofilm was treated for 12h with HICA while caspofungin and PBS were used as controls. The pathophysiology and immunoexpression in the tissues surrounding the chamber was determined by immunohistochemistry. Histopathological examination showed an attenuated inflammatory response together with reduced expression of matrix metalloproteinase 9 (MMP-9) and myeloperoxidase (MPO) compared to chambers containing caspofungin and PBS. Interestingly, the expression of Del-1, an antagonist of neutrophil extravasation, increased after treatment with HICA. Considering its anti-inflammatory and antimicrobial activity, HICA could provide an enormous therapeutic potential in the treatment of chronic biofilm infections and inflammation, such as chronic wounds