The paradox of matrix metalloproteinases in infectious disease

Abstract

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that perform multiple roles in the normal immune response to infection. MMPs facilitate leucocyte recruitment, cytokine and chemokine processing, defensin activation and matrix remodelling. However, excess MMP activity following infection may lead to immunopathology that causes host morbidity or mortality and favours pathogen dissemination or persistence. Here, we review the normal functions of MMPs in immunity and then discuss viral and bacterial infections where excess MMP activity has been implicated in pathology, specifically examining HIV, HTLV-1, hepatitis B, endotoxin shock, Helicobacter pylori and Mycobacterium tuberculosis. Tissue destruction may be exacerbated further by bacterial-derived enzymes which activate the host pro-MMPs. Finally, the potential for therapeutic targeting of excess MMP activity in infection is considered.

Fig. 1

The paradox of matrix metalloproteinases (MMPs) in infectious disease. MMPs are responsible for numerous functions in the normal immune response, but in infection excess MMP activity results in immunopathology by multiple mechanisms.

Fig. 2

Schematic representation of Mycobacterium tuberculosis (MTb)-driven tissue destruction. MTb infection of monocytes increases matrix metalloproteinase (MMP)-1 and MMP-9 gene expression and secretion. However, no compensatory increase in secretion of the tissue inhibitor of metalloproteinase (TIMP)-1, occurs. After activation, MMP-1 cleaves type I collagen fibrils to gelatin, which is in turn degraded by MMP-9.