In this application, I am requesting career development award support to investigate """"""""Mucosal Immune Checkpoints in Chronic Bacterial Cystitis."""""""" I will be undertaking this work in collaboration with my co-mentors, Marco Colonna and Scott Hultgren, both here at Washington University. This marriage of these experts in the fields of Immunology and Microbiology will serve as a great mentoring team as I embark on this joint post- doctoral fellowship. This collaboration arose out of my interest in a murine model of chronic bacterial cystitis. Urinary tract infections (UTI) are common, costly, and very often recurrent. Uropathogenic E. coli (UPEC) are the most common cause of UTI. UPEC elicit host defenses in response to colonization. Understanding the role of the host response in this disease is critical for our ability to develop effective vaccines and therapeutics. We have found that juvenile C3H/HeN mice have two distinct responses to UPEC infection: either they resolve infection within 2 weeks or they develop chronic cystitis that lasts for at least 7 months. Furthermore, development of chronic cystitis strongly correlates with a significantly more severe acute host response. This allergic-like response, which is not seen in other mouse strains studied, forms the basis for the hypothesis of this study, which is that there is a host checkpoint that is being triggered prior to the development of chronic cystitis. This study will test this hypothesis by investigate the cellular and molecular mechanism of this checkpoint and testing for causality. Dr. Colonna will be providing mentorship, knowledge and technical expertise during this project as I address these difficult questions. Dr. Hultgren will be providing mentorship and expertise in the field of infectious disease research and the murine model of UTI. Washington University is a wonderful place to pursue scientific research, with numerous support and core facilities. Upon leaving clinical veterinary practice in 2003, I began my doctoral training with Dr. Hultgren and graduated with a Ph.D. in Microbiology in August, 2008. I became interested in host responses to infection towards the end of my graduate work and decided to pursue a post-doctoral fellowship in Immunology to broaden my expertise in mechanisms of infectious disease. I hope to work at an academic research institution as an independent investigator studying the host-pathogen interaction.

Public Health Relevance

Urinary tract infections (UTI) are a major problem: they are common, costly, and often recurrent or chronic. We have developed a mouse model of chronic urinary tract infection with the bacterium uropathogenic E. coli, and found that development of chronic infection is associated with an allergic-like bladder response early in infection. After having this reaction, these mice are prone to recurrent UTI, providing a possible explanation for recurrent UTI in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI083746-03
Application #
8115921
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Korpela, Jukka K
Project Start
2009-09-15
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
3
Fiscal Year
2011
Total Cost
$121,369
Indirect Cost
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Schreiber 4th, Henry L; Conover, Matt S; Chou, Wen-Chi et al. (2017) Bacterial virulence phenotypes of Escherichia coli and host susceptibility determine risk for urinary tract infections. Sci Transl Med 9:
O'Brien, Valerie P; Hannan, Thomas J; Nielsen, Hailyn V et al. (2016) Drug and Vaccine Development for the Treatment and Prevention of Urinary Tract Infections. Microbiol Spectr 4:
O'Brien, Valerie P; Hannan, Thomas J; Yu, Lu et al. (2016) A mucosal imprint left by prior Escherichia coli bladder infection sensitizes to recurrent disease. Nat Microbiol 2:16196
O'Brien, Valerie P; Hannan, Thomas J; Schaeffer, Anthony J et al. (2015) Are you experienced? Understanding bladder innate immunity in the context of recurrent urinary tract infection. Curr Opin Infect Dis 28:97-105
Schwartz, Drew J; Conover, Matt S; Hannan, Thomas J et al. (2015) Uropathogenic Escherichia coli superinfection enhances the severity of mouse bladder infection. PLoS Pathog 11:e1004599
Nagamatsu, Kanna; Hannan, Thomas J; Guest, Randi L et al. (2015) Dysregulation of Escherichia coli ?-hemolysin expression alters the course of acute and persistent urinary tract infection. Proc Natl Acad Sci U S A 112:E871-80
Hannan, Thomas J; Roberts, Pacita L; Riehl, Terrence E et al. (2014) Inhibition of Cyclooxygenase-2 Prevents Chronic and Recurrent Cystitis. EBioMedicine 1:46-57
Totsika, Makrina; Kostakioti, Maria; Hannan, Thomas J et al. (2013) A FimH inhibitor prevents acute bladder infection and treats chronic cystitis caused by multidrug-resistant uropathogenic Escherichia coli ST131. J Infect Dis 208:921-8
Guiton, Pascale S; Hannan, Thomas J; Ford, Bradley et al. (2013) Enterococcus faecalis overcomes foreign body-mediated inflammation to establish urinary tract infections. Infect Immun 81:329-39
Hannan, Thomas J; Totsika, Makrina; Mansfield, Kylie J et al. (2012) Host-pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection. FEMS Microbiol Rev 36:616-48

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