Immunità innata da derivati di proteine sieriche

There is clear evidence that a large group of proteins, including proteins associated with endocrine signalling, the extracellular matrix, the complement cascade and milk, could give rise in vivo, through proteolytic cleavage, to hidden peptides with bioactivities that are often unpredictable from the sequence and activity of the parent protein. The existence of these peptide fragments, designed as cryptides, could reflect an evolutionary mechanism to expand the functionality of proteins, providing additional opportunities for understanding and modulating various biological processes related to a specific protein, and new perspectives for protein-based therapeutic strategies. In this setting, the object of the PhD research project is focused on the study of microbicidal activity of peptide fragments from antibodies and other serum proteins, found in human serum samples. The identified peptide fragments are derived from CH3 constant region of IgM µ chain (K40H), albumin, C4 and C3 complement fragments, and fibrinogen (K13L, G17K, S17K, D15R e D15T). In particular, K40H and K13L peptides showed the most significant fungicidal activity against various yeast isolates in vitro, including strains resistant to common antifungal agents. The research showed different structural properties for these peptides, and the involvement of different mechanisms of fungicidal action was suggested. K40H and K13L were shown to be effective in an ex vivo model of Candida albicans infection using porcine oral mucosa. The in vivo therapeutic activity of K40H and K13L was demonstrated in a model of systemic experimental candidiasis using the larval form of the insect Galleria mellonella. In the same in vivo model, as well as against cultured mammalian cells, human erythrocytes and peripheral blood mononuclear cells, both peptides showed to be devoid of toxicity, haemolytic and genotoxic activity. Overall, the results show that peptide fragments found in the serum, derived from antibodies and other serum proteins, can exert microbicidal activity, similarly to what previously demonstrated for peptides with sequence identical to fragments of the complementarity determining regions and the constant regions of antibodies. Serum proteins, including antibodies, could represent an unlimited source of peptides endowed with anti-infective potential. The demonstration of the presence of fungicidal peptide fragments in vivo include antibodies and albumin in the group of proteins, which already comprised components of the complement cascade and fibrinogen, that could give rise to cryptic fragments and could suggest a new role of these proteins in antifungal homeostasis.