HOST-PATHOGEN INTERACTION IS A PRIVILEGED POINT OF OBSERVATION OF NATURE because virulence factors and biological toxins are the product of a process of co-evolution of microorganisms with their hosts or prey. During evolution a pathogen “learns” how to subvert host/prey physiology to its own advantage, as to say that toxins and virulence factors are “tailored” around key physiological functions of the host. This starting observation led to the “manifesto” of the laboratory which can be summarized as it follows.
By studying the mechanism of action of virulence factors (toxins) we can: a) understand the pathogenesis of the disease caused by the pathogen; b) learn more about specific physiological functions of the host itself; c) develop novel therapeutics (vaccines, inhibitors etc.); d) even use the virulence factor itself as a therapeutic. At the same time, an analysis of the evolution and life style of the toxigenic pathogen may help us to understand the mechanism of action of the toxin(s) and to put it/them in the context of the disease caused in the host.
We have begun with studies on the mechanism of cell and tissue intoxication by diphtheria toxin, followed by tetanus and botulinum neurotoxins. We have then enlarged our activity to Helicobacter pylori virulence factors such as the vacuolating cytotoxins and the neutrophil activating protein and then we have extended our studies to anthrax and the anthrax toxins. More recently, we have furthered our studies to include snake neurotoxins and myotoxins.
Always we have chosen pathogens that impact strongly on human health.
An analysis of the selected production of the laboratory shows that we have provided, over the years, very relevant contributions to all the points of our manifesto.
At the present time, we are focussing our attention to the mechanism of action of presynaptic neurotoxins of bacterial origin (tetanus and botulinum neurotoxins) and of animal origin (snake presynaptic PLA2 neurotoxins, snake PLA2 myotoxins and spider neurotoxins). We are studying how they bind, how they interact/enter into neurons of different kind, how they display their toxic activity. We are using both neurons in culture and animals (mice, frogs, fish and insects) and a variety of experimental approaches (just see the experimental part of our recent papers).
Some of the neurotoxins we are studying cause a complete degeneration of the motoneuron nerve terminal, followed by a complete, or nearly complete, recovery and we are actively investigating the biochemical and cellular players of the regeneration process by various techniques, including videoimaging and advanced high resolution microscopic techniques coupled to electrophysiology. Once the read out of the regeneration of the neuromuscular junction is achieved we will use it to test different therapeutic protocols in order to improve the recovery of the neuromuscular junction in human patients following trauma that have damaged their motoneurons.
Funded by:
University of Padova, Strategic: “Physiopathology of signalling in neuronal tissues: an in vivo approach.” Period 2009-2011
University of Padova, ex-60% 2009: “Patogenesi dell’antrace.” Period: 2009-2012
University of Padova, ex-60% 2008: “Studio del meccanismo d’azione delle tossine dell’antrace.” Period: 2008-2011
University of Padova, ex-60% 2007: “Meccanismo d’azione delle tossine proteiche.” Period: 2007-2010
Network of Excellence in the FP6, European Community: “European Virtual Institute for Functional Genomics of Bacterial pathogens” Period: 2006-2010
Publications:
5 recent publications:
PAOLI M., RIGONI M., KOSTER G., ROSSETTO O., MONTECUCCO C. and POSTLE A.D. Mass spectrometry analysis of the phospholipase A2 activity of snake presynaptic neurotoxins in cultured neurons. J Neurochem. (2009) 111: 737-744.
CINTRA-FRANCISCHINELLI M., CACCIN P., CHIAVEGATO A., PIZZO P., CARMIGNOTO G., ANGULO Y., LOMONTE B., GUTIERREZ JM., MONTECUCCO C. Botrops snake myotoxins induce a large efflux of ATP and potassium with spreading of cell damage and pain. Proc Natl Acad Sci U S A (2010) 107:14140-14145.
MEGIGHIAN A., SCORZETO M., ZANINI D., PANTANO S., RIGONI M., BENNA C., ROSSETTO O., MONTECUCCO C., ZORDAN M. Arg206 of SNAP-25 is essential for neuroexocytosis at the Drosophila melanogaster neuromuscular junction. J Cell Sci. (2010) 123:3276-83.
RIGONI M., PAOLI M., MILANESI E., CACCIN P., RASOLA A., BERNARDI P. and MONTECUCCO C. Snake phospholipase A2 neurotoxins enter neurons, bind specifically to mitochondria and open their transition pores. J Biol Chem (2008) 283: 34013-20.
ZORNETTA I., BRANDI L., JANOWIAK B., DAL MOLIN F., TONELLO F., COLLIER RJ., MONTECUCCO C. Imaging the cell entry of the anthrax oedema and lethal toxins with fluorescent protein chimeras. Cell Microbiol. (2010) 12:1435-1445.
5 selected publications (all career):
RIGONI M., CACCIN P., GSCHMEISSER S., ROSSETTO O., SCHIAVO G. and MONTECUCCO C. Equivalent effects of snake PLA2 neurotoxins and lysophospholipid-fatty acid mixtures. Science (2005) 310: 1678-1680.
TONELLO F., SEVESO M., MARIN O., MOCK M. and MONTECUCCO C. Pharmacology: Screening inhibitors of anthrax lethal factor. Nature (2002) 418: 386.
MONTECUCCO C. and RAPPUOLI R. Living dangerously: how Helicobacter pylory survives in the human stomach. Nature Rev Cell Biol (2001) 2: 457-466.
SCHIAVO G., ROSSETTO O., CATSICAS S., POLVERINO DE LAURETO P., DASGUPTA B.R., BENFENATI F. and MONTECUCCO C. Identification of the nerve-terminal targets of botulinum neurotoxins serotypes A, D and E. J Biol Chem (1993) 268: 23784-23787.
SCHIAVO G., BENFENATI F., POULAIN B., ROSSETTO O., POLVERINO DE LAURETO P., DASGUPTA B.R. and MONTECUCCO C. Tetanus and botulinum B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature (1992) 359: 832-835.
Recent books:
MOCK M. and MONTECUCCO C. (Editors). Molecular Aspects of Medicine Vol. 30 (2009)
JOHNSON E.A & MONTECUCCO C. Botulism. Handb Clin Neurol. (2008) 91:333-368.
1. RIGONI M., CACCIN P., GSCHMEISSER S., ROSSETTO O., SCHIAVO G. and MONTECUCCO C. Equivalent effects of snake PLA2 neurotoxins and lysophospholipid-fatty acid mixtures. Science (2005) 310: 1678-1680.
3. MONTECUCCO C. and RAPPUOLI R. Living dangerously: how Helicobacter pylory survives in the human stomach. Nature Rev Cell Biol (2001) 2: 457-466.
4. SCHIAVO G., ROSSETTO O., CATSICAS S., POLVERINO DE LAURETO P., DASGUPTA B.R., BENFENATI F. and MONTECUCCO C. Identification of the nerve-terminal targets of botulinum neurotoxins serotypes A, D and E. J Biol Chem (1993) 268: 23784-23787.
5. SCHIAVO G., BENFENATI F., POULAIN B., ROSSETTO O., POLVERINO DE LAURETO P., DASGUPTA B.R. and MONTECUCCO C. Tetanus and botulinum B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature (1992) 359: 832-835.
Ultimo aggiornamento Mercoledì 25 Maggio 2011 13:56
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