Matrix metalloproteinases as therapeutic targets in protozoan parasitic infections

Abstract

Matrix metalloproteinases (MMPs) are associated with processes of tissue remodeling and are expressed in all infections with protozoan parasites. We here report the status of MMP research in malaria, trypanosomiasis, leishmaniasis and toxoplasmosis. In all these infections, the balances between MMPs and endogenous MMP inhibitors are disturbed, mostly in favor of active proteolysis. When the infection is associated with leukocyte influx into specific organs, immunopathology and collateral tissue damage may occur. These pathologies include cerebral malaria, sleeping sickness (human African trypanosomiasis), Chagas disease (human American trypanosomiasis), leishmaniasis and toxoplasmic encephalitis in immunocompromised hosts. Destruction of the integrity of the blood-brain barrier (BBB) is a common denominator that may be executed by leukocytic MMPs under the control of host cytokines and chemokines as well as influenced by parasite products. Mechanisms by which parasite-derived products alter host expression of MMP and endogenous MMP inhibitors, have only been described for hemozoin (Hz) in malaria. Hence, understanding these interactions in other parasitic infections remains an important challenge. Furthermore, the involved parasites are also known to produce their own metalloproteinases, and this forms an extra stimulus to investigate MMP inhibitory drugs as therapeutics. MMP inhibitors (MMPIs) may dampen collateral tissue damage, as is anecdotically reported for tetracyclines as MMP regulators in parasite infections.