Matrix Metalloproteinase 9 Activity Enhances Host Susceptibility to Pulmonary Infection with Type A and B Strains of Francisella tularensis

Abstract

A striking feature of pulmonary infection with the Gram-negative intracellular bacterium Francisella tularensis, a category A biological threat agent, is an intense accumulation of inflammatory cells, particularly neutrophils and macrophages, at sites of bacterial replication. Given the essential role played by host matrix metalloproteinases (MMPs) in modulating leukocyte recruitment and the potentially indiscriminate destructive capacity of these cells, we investigated whether MMP-9, an important member of this protease family released by neutrophils and activated macrophages, plays a role in the pathogenesis of respiratory tularemia. We found that F. tularensis induced expression of MMP-9 in FVB/NJ mice and that the action of this protease is associated with higher bacterial burdens in pulmonary and extrapulmonary tissues, development of more extensive histopathology predominated by neutrophils, and increased morbidity and mortality compared with mice lacking MMP-9 (MMP-9−/−). Moreover, MMP-9−/− mice were able to resolve infection with either the virulence-attenuated type B (live vaccine strain) or the highly virulent type A (SchuS4) strain of F. tularensis. Disease resolution was accompanied by diminished leukocyte recruitment and reductions in both bacterial burden and proinflammatory cytokine production. Notably, neutrophilic infiltrates were significantly reduced in MMP-9−/− mice, owing perhaps to limited release of Pro-Gly-Pro, a potent neutrophil chemotactic tripeptide released from extracellular matrix through the action of MMP-9. Collectively, these results suggest that MMP-9 activity plays a central role in modulating the clinical course and severity of respiratory tularemia and identifies MMPs as novel targets for therapeutic intervention as a means of modulating neutrophil recruitment.

Helicobacter pylori-Induced Th17 Responses Modulate Th1 Cell Responses, Benefit Bacterial Growth, and Contribute to Pathology in Mice

“…MMP expression is likely to contribute to tissue damage during H. pylori-associated gastritis and may accelerate an oncogenic progression by disrupting epithelial organization and increasing invasion (37). It has also been reported that MMP-9 enhances the host susceptibility to pulmonary infection with Francisella tularensis (38). We therefore deduce that the Th17/IL-17 pathway may lead to gastritis by triggering the recruitment of inflammatory cells including Th1 cells into the gastric mucosa by inducing chemokines and may destroy the tissue by inducing MMP production, favoring subsequent pathogen dissemination and persistent infection.…”

Role of the pulmonary epithelium and inflammatory signals in acute lung injury

“…Mmp9 −/− mice are also protected from lung injury and lethality of pulmonary infection with Francisella tularensis via modification of neutrophil chemokine gradients [77]. These mice have diminished neutrophil accumulation in the lung and reduced lung injury due to a significant decrease in Pro-Gly-Pro (PGP), a chemotactic fragment generated from MMP9-mediated hydrolysis of collagen that has homology to KC and binds and activates the KC receptor CXCR2 [78].…”

CD14 Signaling Reciprocally Controls Collagen Deposition and Turnover to Regulate the Development of Lyme Arthritis

“…However, at the other extreme, complete antibody-mediated depletion of neutrophils increases mortality after challenge of mice with a sublethal dose of Francisella. 14,39 In a sepsis model, where MMP-9 Ϫ/Ϫ mice were challenged with Escherichia coli, animals showed severe impairment of neutrophil recruitment in late-phase disease and higher bacterial burden. 40 Staphylococcus aureus-triggered septic arthritis also is exacerbated by MMP-9 deficiency wherein mice display a higher frequency and severity of arthritis and harbor increased numbers of bacteria in their joints.…”

“…In fact, we recently reported a positive correlation between MMP-9 activity and susceptibility to infection with the gram-negative bacterium Francisella tularensis. 14 Regardless of whether its role is protective or destructive, the ability of MMP-9 to orchestrate the continuous recruitment of neutrophils has been demonstrated using several infectious and noninfectious disease models. 14 -17 MMPs belong to a multigenic family of proteinases that perform diverse functions, such as tissue remodeling during development, wound healing, establishment and maintenance of chemokine gradients, and cell migration.…”