Date on Master's Thesis/Doctoral Dissertation
12-2024
Document Type
Doctoral Dissertation
Degree Name
Ph. D.
Department
Microbiology and Immunology
Degree Program
Microbiology and Immunology, PhD
Committee Chair
Bagaitkar, Juhi
Committee Co-Chair (if applicable)
Lawrenz, Matthew
Committee Member
Potempa, Jan
Committee Member
Mitchell, Thomas
Committee Member
Bodduluri, Haribabu
Author's Keywords
neutrophil; macrophage; efferocytosis; host pathogen interaction
Abstract
Porphyromonas gingivalis (Pg) is etiologically associated with chronic periodontitis, a highly prevalent chronic inflammatory disease characterized by the destruction of hard and soft tissues of the periodontium. Pg is adapted to live in the human oral subgingival niche, a hostile environment dominated by excessive numbers of activated neutrophils and antimicrobial mediators. Its survival is contingent upon prompt and effective inactivation of neutrophil effector functions. In this dissertation, I uncover a novel pathogenic mechanism employed by Pg that disarms the antimicrobial capacity of live neutrophils and simultaneously sequesters them within macrophages. Mechanistically, RgpB, a cysteine protease produced by Pg proteolytically, modifies the intracellular and extracellular proteins of neutrophils, thus dysregulating neutrophil function. RgpB-exposed neutrophils support intracellular bacterial survival because of compromised antimicrobial capacity due to RgpB-mediated degradation of intracellular microbicidal compounds and depleted phagosomal oxidative burst. Interestingly, RgpB-mediated remodeling of the neutrophil proteome does not induce apoptosis but causes significant remodeling of the neutrophil proteome, resulting in alterations to a repertoire of proteins on the neutrophil surface. The neutrophil surface becomes decorated with degraded neutrophil granule proteins that engage macrophage integrin receptors, resulting in the atypical efferocytosis of live neutrophils. Macrophages that sequester these live RgpB imprinted neutrophils in their efferosomes become transcriptionally and phenotypically dysregulated and produce inflammatory cytokines that prevent the resolution of inflammation in vivo. My work uncovers a vicious inflammatory cycle perpetuated by a previously undescribed mechanism employed by Pg and underscores the potential for developing novel therapeutic strategies that target this unique virulence mechanism.
Recommended Citation
Cooper, Kelley N., "Proteolytic manipulation of neutrophil responses and the efferocytic synapse by porphyromonas gingivalis." (2024). Electronic Theses and Dissertations. Paper 4465.
Retrieved from https://ir.library.louisville.edu/etd/4465
