Cesare MONTECUCCO
Main Achievements
He has worked for the past twenty years on the mechanism of action of bacterialvirulence factors (including classical protein toxins) acting as major determinants of human diseases. More recently, he has expanded his research activities to study the inflammatory and immune response. His research activity is not limited to the experimental activity, but is characterized by the development of models and theoretical contributions, which are mentioned below.
1986: Proposed the double "protein-and-lipid" model for the binding of tetanus and botulism neurotoxins to nerve terminals. This model is now fully supported by the 3D structures of the receptor binding domains of tetanus and botulinum neurotoxins.
1986-1988: Identification of active site residues of diphtheria toxin.
1987: Proposed the “cleft model” for the membrane translocation of bacterial protein toxins with intracellular targets. A similar model has been proven in 1995 for the ER translocon.
1991: discovered the zinc-endopeptidase activity of tetanus and botulinum neurotoxins.
1992-1995: identified the intraneuronal targets and peptide bond specifity of all clostridial neurotoxins. This was the first demonstration of the essential role of VAMP/synaptobrevin, SNAP-25 and syntaxin in the release of neurotransmitters, and in exocytosis in general.
1993: Provided evidence that the different sensitivity of animal specifies to tetanus and botulism type B may be due to mutation of VAMP at the site of proteolytic cleavage.
1994: Elaborated the concept that bacterial toxins with intracellular activity enter cells via a four-step mechanism. All the present available experimental evidence fit in this model.
1994: Identified the SNARE motif as a major determinant in the specific recognition of the three SNARE proteins by the eight clostridial neurotoxins.
1993-1998: Discovered the acid activation of the VacA cytotoxin of H. pylori, the late endosomal/prelysosomal nature of the vacuoles induced by the VacA and determined some immunological and pathological consequences of the alterations of membrane trafficking at the level of late endosomes, such as the inhibition of antigen processing and of the invariant chain dependent antigen presentation. Discovered that VacA induces a specific change of the trans-epithelial resistance of epithelial cell monolayers.
1998-1999: his laboratory discovered that VacA toxin forms anion specific channels in planar lipid bilayers and on cells.
1999-2000: Identified the neutrophil activating protein of H. pylori (HP-NAP) as a major antigen in the human response and determined its structural, biochemical and cell activation properties.
The results obtained with VacA and HP-NAP lead to the present formulation of an anti-H. pylori vaccine, containing CagA, VacA and HP-NAP, currently under clinical trial. Preliminary results show thatthis vaccine is non toxic and it is highly immunogenic.
1998: Discovered that the anthrax lethal factor is a zinc-endopeptidase specific for the MAPkinasekinases, which are cleaved within their N-terminus. Identified the cleavage consensus motif.
2000: proposed a novel model for the mechanism of action of snake PLA2 presynaptic neurotoxins.
2002: development of a high throughput assay of the metalloproteolytic activity of the Anthrax Lethal Factor and identified useful inhibitors.
