Harnessing calcineurin as a novel anti-infective agent against invasive fungal infections

Key Points Invasive fungal infections are one of the most devastating consequence of the rapidly increasing number of immunocompromised patients. Despite the rising incidence and mortality of infections with Cryptococcus neoformans , Candida albicans and Aspergillus fumigatus , the antifungal armamentarium remains limited, and novel targets focused on fundamental molecular pathogenesis are needed. The calcineurin pathway is a conserved stress-response signalling pathway that has revolutionized today's immunosuppression. The calcineurin inhibitors FK506 and cyclosporine A (CsA) bind to human calcineurin and block signal transduction and T-cell activation, leading to efficient immunosuppression that can prevent organ rejection. Additionally, calcineurin inhibitors have been used clinically to treat a myriad of other conditions. In this article, the authors propose that inhibiting fungal calcineurin pathways could be an effective method of halting the growth of invasive fungal pathogens, thereby preventing or treating disease. The two currently available inhibitors FK506 and CsA delivered in their present intravenous formulations will not solve this problem, as they possess inherent and well-utilized cross-reactive human immunosuppressive activity. However, molecular dissection of the fungal calcineurin pathway is yielding promising results and concepts for new drug development. Current calcineurin inhibitors have been shown to possess antifungal activity against the major fungal pathogens, but under different conditions. Several calcineurin pathway genes in each of the major human fungal pathogens have also been disrupted and show effects on fungal growth and virulence. However, the effects are not uniform, highlighting that while the pathway is genetically conserved, the divergent disruption phenotypes require each individual pathogen to be studied in detail. In C. neoformans , calcineurin inhibition leads to temperature-sensitive growth and fungal clearing in animal models and at the relevant temperatures in patients. Additionally, calcineurin inhibition leads to defects in hyphal elongation and therefore the inability to mate. In C. albicans , calcineurin A is required for growth under stress, growth in serum and virulence in systemic animal models. In A. fumigatus calcineurin A is not essential, in contrast to its essential role in the less pathogenic A. nidulans . Disruption of calcineurin A in A. fumigatus yielded extremely blunted hyphae that were una