Monday, April 29, 2024
4/29/2024
Abstract Klebsiella pneumoniae is a leading cause of nosocomial and community-acquired pneumonia. Infections from this pathogen have become more common and severe due to the emergence of antimicrobial resistant strains. Neutrophils play a critical role in pulmonary bacterial clearance but an excessive pulmonary recruitment of these cells leads to collateral lung damage, acute lung injury, and worse patient outcomes. The mechanisms underlying an excessive neutrophil recruitment in bacterial pneumonia patients are poorly understood. We have previously reported a critical role for leptin and its receptor (LepR) in neutrophil recruitment, phagocytosis, bacterial killing and eicosanoids synthesis during bacterial pneumonia. A common LepR polymorphism, (Q223R LepR) has been found in approximately 50% of the general population with no effects on BMI. Homozygous expression of Arginine (R) at the 223 position (RR LepR) as compared with the ancestral allele A, encoding for Glutamine Q, QQ or the heterozygous QR, of the extracellular domain of the LepR is associated with worse outcomes in intra-abdominal E.histolytica, Clostridium difficile infections (CDI) in humans and mice and in patients with non-appendicular secondary peritonitis. Poor outcomes in CDIs were associated with tissue and blood neutrophilia in humans and mice and enhanced leukocyte CXCR2 and Cd11b expression, and elevated cytokines (IL-1¿, IL-6, IFN-¿, MIF and TNF-a) in RR LepR mice. Excessive neutrophil recruitment in RR LepR mice in CDI could be ameliorated by pretreating mice with a neutralizing antibody against IL-1ß, MIF or by blocking CXCR2.The impact of Q223R LepR mutation in host defense against bacterial pneumonia is unknown. It is critically important to determine the impact of host genetic factors that regulate neutrophil recruitment during bacterial infections since they might provide novel insights into mechanisms of disease. The long-term goal is to determine the consequences of common leptin mutations in host defense against pulmonary infections. The overall objective of this proposal is to determine the impact of the Q223R LepR polymorphism on the host response against Klebsiella pneumoniae in mice and in bacterial pneumonia patients with the RR LepR mutation. Achieving these objectives will determine if the RR LepR mutation has a negative impact on mechanisms of pulmonary host defense in mice, if this mutation is a risk factor for more severe illness from bacterial pneumonia patients, and provide preliminary data for a subsequent grant proposal. The central hypothesis is that the RR LepR mutation impairs host defense against Klebsiella pneumonia by inducing an excessive pulmonary inflammatory response characterized by elevated blood and lung neutrophils, higher lung injury, and greater mortality compared with QQ LepR mice. In patients with the RR LepR mutation will have a more severe presentation of bacterial pneumonia and worse outcomes compared with patients with the QQ or QR LepR genotype. The results of these experiments lend themselves to translational medicine with the LepR signaling pathways as targets for therapy.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
