Regulated Cell Death as a Therapeutic Target for Novel Antifungal Peptides and Biologics

Figure 1

Model of host defense peptide mechanisms versus C. albicans. (1) Host cells activated by C. albicans deploy prestored and upregulate nuclear- (N-) encoded host defense peptides that directly interact with C. albicans to (2) target electronegative cell wall components (e.g., glycosylceramide or all specific cell proteins); (3) permeabilization of the cytoplasmic membrane during or following entry into the cytoplasm; (4) target the electronegative phospholipid composition and transnegative potential (Δψ) of mitochondria (Mito); (5) perturb mitochondrial functions essential to cell cycle and trafficking, as well as de-energization and respiratory decoupling activation of caspase and/or metacaspase pathway responses; (6) combined effects of cell envelope damage and mitochondrial dysfunction invokes the regulated cell death response which corresponds to hallmark features of apoptosis, including phosphatidylserine (PS) expression. This integrated model is supported by recent publications [115, 125, 131]. It should be understood that different antifungal peptides may exert different mechanisms or a different mechanistic sequence. For example, in the case of plant defensins, the sequence of membrane perturbation and ceramide accumulation has not yet been resolved. It could well be that ceramide accumulation is a first consequence of interaction with glucosylceramides (e.g., step 2; as with RsAFP2). Alternatively, membrane perturbation could potentially be a consequence of the induction of RCD and hence, only appears at step 6.