Date of Award

Spring 5-15-2016

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type



Uropathogenic E. coli (UPEC) are the principal cause of urinary tract infections (UTIs), one of the most common infections globally. Given the rising incidence of antibiotic resistance among UPEC strains, there is an increasing need to better understand the host response to UPEC and to develop ways to harness the bladder innate immune response that clears infection. In response to infection, the host attempts to limit the ability of UPEC to access iron, a metal critical to UPEC survival. Innate immune cells known as macrophages are known to regulate iron homeostasis through the production of pro-inflammatory cytokines, though it remains unclear what role macrophage iron regulation plays during a UTI. Bladder macrophages are also known to phagocytose UPEC via pathogen-recognition receptors. Innate immune cells such as macrophages and dendritic cells may also use these receptors to clear host apoptotic cells and debris, promoting tissue repair following UPEC infection. Macrophage scavenger receptor expression is known to be negatively regulated by genes involved in autophagy, a pathway for the degradation of intracellular components. This may implicate autophagy genes in the host response to UPEC. Furthermore, the autophagy protein ATG16L1 is also known to limit production of the pro-inflammatory cytokines that promote UPEC clearance. It remains unclear, however, whether ATG16L1 mediates this effect primarily through inhibition of the macrophage inflammatory response to UPEC. In this thesis, I investigated the role of inflammatory cytokines, ATG16L1, iron regulation, and scavenger receptors in the innate immune response to UPEC.

I found that ATG16L1 suppressed the host response to UPEC by suppressing macrophage IL-1 production. Furthermore, macrophages, in response to UPEC infection, retained free iron and took up iron bound to UPEC siderophores, thereby limiting UPEC survival by preventing UPEC from accessing iron. The pro-inflammatory cytokine IL-6 was required for macrophages to limit UPEC access to iron. I also found that both uninfected and UPEC-infected bladders contained dendritic cells that could phagocytose UPEC, particles/debris, and apoptotic cells via scavenger receptors. Moreover, bladder macrophages expressed scavenger receptors for the uptake of extracellular bacteria during the early innate immune cell response to UPEC infection, while expressing receptors for the clearance of bacteria, apoptotic cells, and particles during the tissue repair response that follows a UTI. Taken together, my work suggests that innate immune cell scavenger receptors may play a crucial role in maintaining bladder health in the absence of infection, clearing UPEC during a UTI, and promoting the tissue repair response that follows a UTI. Furthermore, modulating the host iron regulation response, and promoting macrophage inflammatory signaling, may provide an effective treatment for UTIs.


English (en)

Chair and Committee

Indira U. Mysorekar

Committee Members

Mary Dinauer, Abhinav Diwan, Jeff Miner, Gwendalyn Randolph,


Permanent URL: https://doi.org/10.7936/K7PG1Q1S