Bacterial metalloprotease as the toxic factor in infection

Metalloproteases, in which zinc metal ion is essential for catalytic activity, are produced by various human pathogenic bacteria. These metalloproteases have the consensus sequence HEXXH, in which two histidine residues function as the first and second zinc ligands. However, on the basis of the location of the third zinc ligand, they are classified into three families: the thermolysin, serralysin and neurotoxin families. Members of the thermolysin family are synthesized as an inactive precursor with a N-terminal propeptide, and maturation of the precursor is achieved by several processing stages. The metalloprotease in the serralysin family is generated without a conventional propeptide, and its transport is supported by additional secreted proteins. A wide variety of pathological actions of bacterial metalloproteases have been documented. In local bacterial infections, such as keratitis, dermatitis and pneumonia, the metalloprotease functions as a decisive virulence determinant. The protease generated at the site of the infection causes necrotic or hemorrhagic tissue damage through digestion of structural components of the ground substance. The protease also enhances vascular permeability and forms edematous lesions through generation of the inflammatory mediators, histamine and bradykinin. Additionally, permeability enhancement and/or tissue damage allows bacterial dissemination into the systemic circulation. In systemic infections such as septicemia, the metalloprotease acts as a synergistic virulence factor. The disordered proteolysis of many plasma proteins by the bacterial protease causes imbalance of endogenous proteinase-proteinase inhibitor systems, disturbs physiological homeostasis, and eventually elicits an immunocompromised state in the host. The disintegration of iron-carrier proteins triggers the uptake of iron, an essential element for the bacterium. The metalloproteases produced by enteropathogens can activate enterotoxins, including cholera toxin, through limited proteolysis. Clostridial neurotoxins were recently demonstrated to be zinc-containing proteins possessing proteolytic activity. These neurotoxins specifically cleave a synaptic vesicle membrane protein or the presynaptic plasma membrane protein. Bacteroides fragilis enterotoxin is also a zinc metalloprotease.