From phagocytosis to metaforosis: Calcineurin’s deadly role in innate processing of fungi

Opportunistic fungal infections are a major complication of organ transplantation, with a yearly incidence of 3.1% of invasive fungal disease in the first 3 years after transplantation in large prospective studies [1]. Amongst transplant recipients, lung transplantation recipients are at very high risk of pulmonary aspergillosis, a fatal chronic and progressive lung infection due to the mold Aspergillus fumigatus [1]. Additionally, colonization with A. fumigatus is a key risk factor for the development of bronchiolitis obliterans, leading to organ rejection [2]. While the role of steroids in susceptibility to fungal disease in transplant populations is well appreciated, our understanding of how calcineurin inhibitors, now the core backbone of transplant immunosuppression, affect immunity to fungi has not been extensively studied until recently. The two calcineurin inhibitors widely used in clinical practice, cyclosporin and tacrolimus (FK506), are both thought to inhibit organ cellular rejection responses though inhibition of Tcell lymphoproliferative responses to donor antigen presentation. However, emerging data have demonstrated a wider role for calcineurin across a range of cell types and tissues [3]. Calcineurin–nuclear factor of activated T cells (NFAT) signaling plays an important role in cardiac development, neurological syndromes, and osteoclast differentiation [4]. Notably, an important role of calcineurin in innate immunity has emerged, with calcineurin-dependent innate immune responses important for immunity to Candida albicans, A. fumigatus, and Eschereschia coli [5]. Taken together, these observations suggest that a better understanding of the impact of calcineurin inhibitors on innate immune responses to opportunistic pathogens is required.