CPE is the cause of around 20% of all food poisoning; this equates to approximately
1 million cases per year in mainland UK. CPE is produced in large amounts by
sporulating C.perfringens, and can make up over 15% of the total protein
mass of a sporulating cell. Similar to all Enterotoxins, CPE causes diarrhoea
by altering membrane permeability in the small intestines of mammals.
However, its method of action is poorly understood, and currently,
there are 2 school of thought as to how CPE accomplishes this:
1.CPE forms pores in epithelial membrane plasma membranes
2.CPE removes host tight junction proteins (certain Claudins and
Occludin), allowing interstitial fluid to seep into the gut
Pore forming
It is thought that CPE binds certain host membrane protein and uses them as
anchors to raise the local concentration of CPE until it is sufficient to
causes oligomerisation/membrane insertion. It has been shown that small
complexes (CPE containing complexes isolated weighing ~90Kda) can be formed at
4oC but larges complexes (CPE containing complexes weighing 210Kda
) only form at 37oC. It is assumed that these large complexes
require a certain degree of membrane fluidity to form and are post-insertion
complexes – i.e. the active pore form. Upon formation of this pore, ions, amino
acids, nucleotides (anything small than 3Kda) may flow out of the cell, and
water rushes in. This influx of water bursts the cell – i.e CPE has cytolethal activity.
Tight junction degradation
CPE has shown to both bind to tight junctions (via immuno-fluorescence
studies) and degrade the characteristic protein belt observed in
electron microscopy of
these structures.
Progress
Several crystal forms have been obtained and initial diffraction has been
characterised. We are currently screening for heavy atom derivatives.
The Project is in collaboration with Prof
Bruce McClane at the University of Pittsburgh School of Medicine.
