Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Jeffrey N. Weiser

Abstract

Inflammation is a critical host response to a range of potentially harmful stimuli, but it must be tightly controlled in the respiratory tract to maintain the gas-exchange function of the lungs. Mucosal inflammation in the upper respiratory tract, however, is a common response to multiple types of microbial exposures. Some pathogenic bacteria, such as Streptococcus pneumoniae (the pneumococcus), can colonize and persist in the face of these host responses, and can even promote inflammation, raising the question of whether pneumococci evolved to take advantage of inflammation. Here, we examined the hypothesis that airway inflammation promotes pneumococcal colonization, specifically by accelerating bacterial growth, delaying pneumococcal clearance and enhancing bacterial transmission. To study how inflammation promotes bacterial growth, we developed a novel flow cytometric assay using fluorescence dilution to measure the replication of individual bacteria in vivo. Using a mouse model of influenza-pneumococcal coinfection, we found that the host response to influenza infection includes secretion of mucins, which are heavily decorated with sialic acid, onto the mucosal surface. Pneumococci that could catabolize sialic acid were able to exploit this inflammatory response, as seen by increased bacterial density in the airway and accelerated bacterial replication. Next, we examined whether overly exuberant inflammation altered pneumococcal colonization. We found that infant mice tonically expressed high levels of monocyte chemoattractants in the upper respiratory tract, and could not appropriately upregulate these chemokines during colonization. Infants were unable to recruit monocytes, which differentiate into macrophages, the effector cells of clearance, into the nasopharynx, and therefore could not clear carriage as quickly as adult mice. Ectopic overexpression of one such chemokine, CCL2, rescued the infant defects in macrophage trafficking and pneumococcal clearance. Finally, we studied bacterial transmission in the presence of influenza-mediated inflammation in infant mice. Transmission required influenza infection, and was increased in the absence of certain host signals that redirected the inflammatory response. Together, these data demonstrated that inflammation alters three key aspects of pneumococcal biology: early growth to establish colonization, immune evasion to avoid clearance and transmission.

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