Degree

Doctor of Biomedical and Veterinary Medical Sciences-Pathobiological Sciences (PVMPB)

Department

PBS

Document Type

Dissertation

Abstract

Severe bacterial pneumonia and septicemia are pressing health problems. A better understanding of cellular and molecular players of neutrophil immunity and homeostasis in bacterial pneumonia and sepsis is critical for inspiring novel therapeutics. Chemokine CXCL1 is a widely secreted neutrophil attractant and Nod-like receptor (NLRC4) is commonly expressed cytoplasmic pathogen sensor in hematopoietic compartments. How these innate mediators convert pathogen signals into molecular cues of immune response in context of Gram-positive bacterial pneumonia and septicemia largely remain unknown. Utilizing Cxcl1 gene deficient mice, we demonstrate CXCL1 regulates neutrophil influx, bacterial clearance, and host survival in pneumococcal pneumonia-derived sepsis. Furthermore, Cxcl1-/- mice displayed a defect in neutrophil generation in bone marrow and subsequent CD62L and CD49d-dependent release into bloodstream following pneumococcal infections. In stark contrast to CXCL1, NLRC4 exhibits a detrimental role in Methicillin-resistant Staphylococcus aureus (MRSA)-induced pneumonia and polymicrobial sepsis. Nlrc4-/- mice had improved neutrophil recruitment, bacterial clearance, and survival advantage over wild-type mice following MRSA-pneumonia. Mechanistically, the activation of NLRC4 contributes to dampening of IL-17A/neutrophil axis through necroptosis and IL-18 signaling. In polymicrobial sepsis, NLRC4 contributes to sepsis-induced mortality through mediating hyper inflammation, cytokine storm, and cellular dysfunction. Nlrc4-/- mice were protected from sepsis-induced loss and dysfunction of macrophage and lymphocytes. Our results show that CXCL1 and NLRC4 have divergent roles during infections and the modulation of their activity may represent attractive therapeutic targets in treating bacterial pneumonia and sepsis.

Committee Chair

Jeyaseelan, Samithamby

DOI

10.31390/gradschool_dissertations.5064

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