Identifier

etd-04182012-091506

Degree

Doctor of Philosophy (PhD)

Department

Veterinary Medical Sciences - Pathobiological Sciences

Document Type

Dissertation

Abstract

Acute gram-negative bacterial infections are a leading cause of mortality among the nosocomial infections. Increasing numbers of immunosuppressed individuals and growing numbers of antibiotic resistant strains make antibiotic treatment difficult. Neutrophils are the first cells recruited to the site of infection and are critical players in the host defense against gram-negative bacterial pneumonia. Therefore, identification of targets that boost neutrophil-associated host defense in the lung is essential in designing better therapies to control pulmonary infections. Production of chemokines is an important step for neutrophil recruitment. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that is important for monocyte and T-lymphocyte influx. It is important for the host defense during Listeria monocytogenes and Streptococcus pneumoniae infection. However, the role of MCP-1 during pulmonary gram-negative infections is not known. We hypothesized that MCP-1 is essential for the host defense during a gram-negative infection. To test the hypothesis, we infected MCP-1 gene-deficient (MCP-1-/-) mice and controls intratracheally (i.t.) with E. coli (106 CFUs/mouse) and Klebsiella pneumoniae (103 CFUs/mouse). We found that MCP-1 is critical for host defense against gram-negative infections, mainly by recruiting neutrophils to the site of infection. MCP-1 utilizes it’s receptor, CCR2, to recruit neutrophils directly and indirectly by regulating the expression of cytokines (IL-6, TNF-a) and chemokines (KC, MIP-2) through activation of NF-kB and MAPKs. We also observed that MCP-1 can regulate expression of G-CSF and thereby neutrophil numbers in circulation during Kp infection. In addition, exogenous administration of rG-CSF can restore the defects in host defense in MCP-1-/- mice following gram-negative Kp infection. This study demonstrates an unrecognized role of MCP-1 in host defense during gram negative bacterial pneumonia. These findings bolster pleiotropic effects of MCP-1 in the host defense and demonstrate a potential role as a therapeutic agent to augment host defense during acute bacterial pneumonia.

Date

2012

Document Availability at the Time of Submission

Release the entire work immediately for access worldwide.

Committee Chair

Jeyaseelan, Samithamby

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