Date of Award
Doctor of Philosophy (PhD)
Cell & Molecular Biology
Jeffrey N. Weiser
Phagocytic cells comprise a central component of the inflammatory response to pathogens, particularly against extracellular bacteria that proliferate on mucosal surfaces. Mounting evidence suggests that microbes can manipulate phagocyte function dynamically to shape the persistence and efficacy of antibacterial defenses. Successful pathogens often restrain inflammatory responses to evade clearance and promote dissemination within the host. In contrast, commensal bacterial communities have been shown to bolster the functional capacity of phagocytes throughout the body. Despite the critical role of microbe-phagocyte interactions in maintaining health and dictating infection outcome, the mechanisms underlying this influence remain incompletely understood. Here, we examined the impact of pathogenic and commensal microbes on the functions of neutrophils, monocytes, and macrophages, three phagocyte subsets indispensable for antibacterial host defense. Using a mouse model of upper airway infection, we found that the bacterial pathogen Streptococcus pneumoniae (the pneumococcus) exploits molecular mimicry to disarm responding neutrophils. Phosphorylcholine (ChoP) moieties displayed on the exterior of the pneumococcus and within the inflammatory phospholipid platelet-activating factor (PAF) allow the microbe to leverage its ChoP-remodeling enzyme, Pce, to remove PAF from the airway. Neutrophils deprived of PAF signaling fail to eliminate bacteria effectively, allowing the pneumococcus to persist, disseminate systemically, and transmit efficiently between hosts. We found that the pneumococcus also manipulates mononuclear phagocyte responses by stimulating the liberation of macrophage migration inhibitory factor (MIF), a cytokine responsible for retaining macrophages at sites of inflammation. MIF-driven macrophage responses accelerate pneumococcal clearance from the upper airway. However, MIF signaling provokes damaging inflammation and impairs bacterial control during pneumococcal pneumonia, underscoring the tight regulation of phagocyte responses required for effective host defense. Finally, we studied the impact of signals from the intestinal microbiota on systemic phagocyte lifespan, a key component of cellular fitness at homeostasis. We found that a neomycin-sensitive cohort of commensal bacteria augments the survival and circulating lifespan of neutrophils and inflammatory monocytes. This stimulation required signaling through the intracellular peptidoglycan sensor Nod1 and liberation of the pro-inflammatory cytokine IL-17A. Together, these data demonstrate that bacteria modulate phagocyte physiology during infection and health, influencing host readiness and response to pathogenic threats.
Hergott, Christopher Bruce, "Microbial Manipulation of Phagocyte Function During Infection and Health" (2015). Publicly Accessible Penn Dissertations. 1760.
Available for download on Sunday, November 18, 2018