Matrix Metalloproteinase-9 and Haemozoin: Wedding Rings for Human Host andPlasmodium falciparumParasite in Complicated Malaria

Mauro Prato,Giuliana Giribaldi

doi:10.1155/2011/628435

Abstract

It is generally accepted that the combination of both Plasmodium falciparum parasite and human host factors is involved in the pathogenesis of complicated severe malaria, including cerebral malaria (CM). Among parasite products, the malarial pigment haemozoin (HZ) has been shown to impair the functions of mononuclear and endothelial cells. Different CM models were associated with enhanced levels of matrix metalloproteinases (MMPs), a family of proteolytic enzymes able to disrupt subendothelial basement membrane and tight junctions and shed, activate, or inactivate cytokines, chemokines, and other MMPs through cleavage from their precursors. Among MMPs, a good candidate for targeted therapy might be MMP-9, whose mRNA and protein expression enhancement as well as direct proenzyme activation by HZ have been recently investigated in a series of studies by our group and others. In the present paper the role of HZ and MMP-9 in complicated malaria, as well as their interactions, will be discussed.

Highlights

Among protozoan parasites of the genus Plasmodium, P. falciparum is the most deadly agent of human malaria, causing a broad spectrum of clinical manifestations ranging from asymptomatic to severe multiorgan disease
In some cases, including cerebral malaria (CM), renal failure, lung pathology and malaria during pregnancy, it appears associated with cytoadherence and sequestration of P. falciparum-parasitized red blood cells to vascular endothelium, leading to microcirculatory obstruction, tissue hypoxia, and metabolic disturbances [3,4,5]
In the last decade, growing evidence on involvement of matrix metalloproteinases (MMPs) in falciparum malaria became available: human postmortem studies showed enhanced protein levels of MMP-1 in brains of CM patients [15], whereas MMP-8 was found increased in plasma of severe malaria patients [16]; activation of the human MMP-9 gene by P. falciparum has been reported in microarray studies on whole blood from Journal of Tropical Medicine

Summary

Introduction

Among protozoan parasites of the genus Plasmodium, P. falciparum is the most deadly agent of human malaria, causing a broad spectrum of clinical manifestations ranging from asymptomatic to severe multiorgan disease. Despite recent major efforts by the research community, malaria remains one of the major diseases in poor areas, including SubSaharan Africa and South-East Asia. It is associated with several million clinical cases per year and leads annually to over one million deaths [1, 2]. In the last decade, growing evidence on involvement of MMPs in falciparum malaria became available: human postmortem studies showed enhanced protein levels of MMP-1 in brains of CM patients [15], whereas MMP-8 was found increased in plasma of severe malaria patients [16]; activation of the human MMP-9 gene by P. falciparum has been reported in microarray studies on whole blood from. The present paper will explore the effects of HZ on functions of mononuclear and endothelial cells, focusing on regulation of human MMP-9, which at present among the malaria-related MMPs is the most studied and could be a potential target for adjunctive therapy of complicated severe malaria

Effects of HZ on Human Mononuclear and Endothelial Cells

Involvement of MMP-9 in Complicated Severe Malaria

Interactions between HZ and MMP-9

Conclusions