Title page for ETD etd-04182012-091506


Type of Document Dissertation
Author Balamayooran, Gayathriy
Author's Email Address gmahad1@tigers.lsu.edu
URN etd-04182012-091506
Title Essential Role of Monocyte Chemoattractant Protein-1 in Gram-negative Bacterial Pneumonia
Degree Doctor of Philosophy (Ph.D.)
Department Pathobiological Sciences (Veterinary Medical Sciences)
Advisory Committee
Advisor Name Title
Jeyaseelan, Samithamby Committee Chair
Chowdury, Shafiqul Committee Member
Guerrero-Plata, Antonieta Committee Member
Penn, Arthur Committee Member
Wang, Guoshun Committee Member
Carstens, Bryan Dean's Representative
Keywords
  • Pneumonia
  • Bacteria
  • chemokine
Date of Defense 2012-03-27
Availability unrestricted
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 itís 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.
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