Lines of Research
This laboratory is devoted to the study of the mechanism of action of bacterial virulence factors,
most notably protein toxins, at the molecular, cellular and tissue levels.
In general terms, our action is governed by different aims and objectives:
- We aim at a more profound understanding of the pathogenesis of diseases caused by defined virulence factors.
- At the same time, we wish to understand more about the key physiological event(s) which is/are the target(s)of the virulence factors.
In fact, each virulence factor is the product of a long term coevolution of the pathogenic organism with its host/prey and we want to capitalize on this evolutive learning process.
- We would like to use the acquired knowledge to contribute to the generation of novel therapeutical treatments of the diseases under study, novel vacciones based on the studies virulence factors etc.
- We would like to test the possibility that the virulence factors themselves or their products are used as novel therapeutics.
More in particular, we are at the moment following four lines of research:
Study of the mechanism of action and of the therapeutical appilications of tetanus and botulinum neurotoxins
We have begun to study the single toxin (tetanus neurotoxin, TeNT) responsible of tetanus and the seven neurotoxins (botulinum neurotoxins, BoNT/A, /B . . . . . . /G) responsible for botulism in 1984 and we have provided important contributions to the present knowledge of their mode of action. At the present time, we are involved in the study of their enzymatic activity, substrates and inhibition, of their receptors, of their mechanism of internalization and membrane translocation in the cytosol. We are collaborating with several groups of neurophysiologists and clinical neurologists to extend the range of their therapeutical application and use as tools in research (see collaborations and funding links).
Study of the mechanism of action and of the snake presynaptic phospholipase A2 neurotoxins (SPANs)
This lines of research sprouted in 1997 from our studies on TeNT and BoNTs (sec. A) essentially from the fact that SPANs are proteins as the clostridial neurotoxins are and that their biochemical mechanism of action was not known. We have made the general hypothesis that their phospholipase A2 activity causes, after neuropresynaptic binding, a localised change in lipid composition which enhances neuroexocytosis and inhibits, at the same time, the recycling of synaptic vesicles leading to paralysis of peripheral nerve terminals. We are currently testing this hypothesis with different experimental approaches using a variety of techniques and in collaboration with other groups (see collaborations and funding links).
Study of the mechanism of action of anthrax lethal and edema factors and of their role in the pathogenesis of anthrax
We have begun to study these toxins following the initial observation that the enthral lethal factor sequence included the HExxH zinc binding motif present in TeNT and BoNT and we have contributed to the demonstration that the lethal factor is a metalloprotease specific for the MAPK kinases and that both the lethal and edema factors are very potent toxins which synergise in the inhibition of cells of the innate and adaptive immunes responses. We are currently studying the effect in vitro and in vivo of specific inhibitors of these toxins and of their precise role in the pathogenesis of skin and inhalational forms of anthrax using a variety of biochemical, cell biology and imaging techniques. (see collaborations and funding links).
Identification and study of the mechanism of action of virulence factors of Helicobacter pylori
This bacterium is specific human pathogen which chronically infects the majority of the human population. A sizeable proportion of the infected patient develop over the years severe gastroduodenal diseases. We are currently studying the role in pathogenesis and the mode of action of the vacuolating cytotoxin VacA and of the neutrophil activating protein HP-NAP, which are major components of the anti-H. pylori vaccine developed by the Chiron Vaccines Research Laboratories of Siena, whomwith we are collaborating. We are also attempting to identify the structure and activity of the products of genes included in the cagPAI pathogenicity island. We are also investigating the mode and targets of action proteins related to VacA and to HP-NAP produced by other bacteria. . (see collaborations and funding links).
