Inhalation of the Gram-negative intracellular bacterium Francisella tularensis, a Category A biothreat agent, results in respiratory tularemia. A striking feature of pulmonary infection is the accumulation of neutrophils and macrophages at sites of bacterial replication. Given the role played by host matrix metalloproteinase 9 (MMP-9) in modulating leukocyte recruitment and the somewhat indiscriminate destructive capacity of these cells, this proposal seeks to define the role of MMP-9 in tularemia pathogenesis and validate its potential as a target for therapeutic intervention. MMP-9, a type B gelatinase capable of degrading extracellular matrix (ECM) fibrillar collagens (types I, II, and III) and basement membrane components, including type IV collagen, is released by neutrophils and activated macrophages. As described in Preliminary Studies, mice deficient for this molecule exhibit a lower bacterial burden in pulmonary and extrapulmonary tissues, less severe and focal histopathology, and significantly decreased morbidity and mortality. These findings led us to hypothesize that the extent of MMP-9- mediated recruitment of neutrophils in response to infection with F. tularensis influences the clinical outcome of respiratory tularemia. Using highly virulent F. tularensis SchuS4, the following Specific Aims will test this hypothesis: 1) Elucidate the role played by Pro-Gly-Pro, an MMP-9-generated ECM degradative product, in orchestrating neutrophil recruitment into the pulmonary and extrapulmonary tissues of infected mice and 2) Evaluate the therapeutic efficacy of modulating neutrophil recruitment to diminish the severity of respiratory tularemia. Therapeutic strategies that seek to minimize recruitment of neutrophils may lessen the severity of disease and thus represent an important adjunct to the use of antibiotics. The overall objective of this proposal is to define the pathophysiological consequences of leukocyte recruitment and to validate MMP-9-facilitated neutrophil migration as a broad-spectrum (innate) immune-based pre/post-exposure therapeutic target in respiratory tularemia.
The proposed studies will validate whether small molecule antagonists are an effective means of reducing or eliminating the acute and severe inflammation triggered by infection with respiratory bacterial pathogens. Therapeutic strategies which minimize recruitment of inflammatory cells will lessen the severity of infectious respiratory diseases and will provide an important adjunct to the use of antibiotics.
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