Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Jeffrey N. Weiser


Cytosolic detection of pathogen associated molecular patterns is a key event in host discrimination between commensal and pathogenic microbes. While cytosolic access is critical for the pathogenesis of intracellular bacteria, access to the cytosolic compartment by extracellular bacteria is less well understood. The leading extracellular pathogen Streptococcus pneumoniae (the pneumococcus) activates intracellular innate immune responses, but unlike intracellular bacterial pathogens, S. pneumoniae is killed and degraded upon uptake by phagocytic cells. The pneumococcus serially colonizes the human upper respiratory tract and is eventually cleared over a period of weeks by the host immune response. Previous studies have defined a critical role for the cytosolic pattern recognition receptor Nod2 in driving the macrophage recruitment that leads to clearance of pneumococci, although the mechanism by which pneumococcal cell wall components access the cytosol to activate Nod2 signaling remains unclear.

In these studies, we demonstrate that cytosolic access of pneumococcal components is dependent on bacterial degradation by the host muramidase lysozyme and on the activity of the bacterial pore-forming toxin pneumolysin. We propose a model in which S. pneumoniae is phagocytosed by macrophages whereupon it is killed and degraded by lysozyme, allowing bacterial cell wall components to escape into the host cell cytosol via the action of pneumolysin on the phagosome membrane. We further define a host mechanism that limits the amount of pneumococcal products that transit to the cytosol, although this defense is insufficient and the macrophage undergoes pro-inflammatory cell death.

This cell death is triggered by the formation of inflammasomes, multi-protein cytosolic complexes, that activate caspase-1 to drive secretion of the pro-inflammatory cytokine interleukin-1 beta (IL-1β). We show that sensing by the type 1 IL-1 receptor (Il1r1-/-) is required for the host to effectively recruit macrophages to the nasopharynx and that Il1r1-/- mice have delayed bacterial clearance. Furthermore, sensing of IL-1 cytokines contributes to inflammation in the nasopharynx, which may promote S. pneumoniae growth or transmission, but does not impact the adaptive immune response of the host. This suggests that a bacterial toxin and the subsequent intracellular innate immune sensing it causes may help the pneumococcus promote its extracellular lifestyle.

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