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Principal Investigator: Jacob Jeffrey Zulk
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $48,974
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Urinary tract infections (UTIs) are responsible for a large public health burden with over half of women
experiencing a UTI during their lifetime. These infections, primarily in women, older adults, and those with
underlying conditions such as diabetes, are responsible for over $3.5 billion in health care costs annually in the
USA alone. The majority of UTIs are caused by uropathogenic E. coli (UPEC) and are readily treated with
antibiotics. However, global rise of antibiotic resistance amongst bacterial pathogens threatens the utility of the
current standard of care. Furthermore, up to 30% of UPEC UTIs will have recurrence within 6 months of treatment
due to intracellular UPEC reservoirs that are hidden from antibiotic therapy. Because of these reasons,
alternatives to antibiotics are desperately needed. Bacteriophages (phage), viruses that infect bacteria, have
long been hypothesized as a treatment for bacterial infection, predating the use of antibiotics by over a quarter
of a century. Unfortunately, like antibiotics, bacteria can become resistant to phage. Preliminary work has
identified several phage-resistant UPEC harboring mutations in lipopolysaccharide (LPS). These bacteria,
although capable of evading phage, are poorer at growing in urine and at colonizing the bladder than their
parental strains. The exact reason(s) for these fitness defects, however, are unknown. This work also aims to
assess the utility of phage for treating intracellular UPEC reservoirs, which are untouched by antibiotic therapy,
and which lead to UTI recurrence. Published and preliminary data suggests phage can interact and be
internalized by bladder cells, although no group has tested the ability of phage to reduce intracellular UPEC
burdens. Taken together, this preliminary data supports the hypothesis that phage therapy, through driving
phage resistance that leaves bacteria less fit, and through phage interactions with the bladder, will be effective
at treating both intracellular and extracellular UTIs. This hypothesis will be investigated by the following specific
aims: 1) Identify mechanisms underlying decreased growth in urine and poor colonization of the murine bladder
in phage resistant (LPS mutant) UPEC, 2) Characterize phage binding and internalization by the uroepithelium,
reduction of intracellular reservoirs, and stimulation of bladder immune responses. In investigating these aims,
several innovative tools such as primary bladder cell-derived organoids, super-resolution microscopy, and in vivo
mouse models of disease and phage therapy will be used. This proposal will provide the candidate with training
in UTI animal models, advanced microscopy techniques, protein isolation, and bladder organoid models. This
training, along with excellent mentorship and career development goals, will provide the candidate with the
necessary skills for an independent research career studying novel translational treatments for infectious
disease. This training will take place at Baylor College of Medicine under the mentorship of leaders in the fields
of antimicrobial resistance, phage therapy, and host-pathogen interactions. Taken together, this research will
provide the information necessary to translate UTI phage therapy from the bench into the clinic.
Terms: <Affect><Animal Model><Animal Models and Related Studies><Anti-Bacterial Response><Antibacterial Response><Antibiotic Agents><Antibiotic Drugs><Antibiotic Resistance><Antibiotic Therapy><Antibiotic Treatment><Antibiotics><Antimicrobial Resistance><Attenuated><Automobile Driving><Bacteria><Bacterial Antibiotic Resistance><Bacterial Infections><Bacteriology><Bacteriophages><Binding><Bladder><Bladder Urinary System><Cell Body><Cells><Clinic><Clinical><Collection><Communities><Data><Defect><Development><Diabetes Mellitus><Diagnosis><E coli><E. coli><ELISA><Environment><Enzyme-Linked Immunosorbent Assay><Epithelium><Escherichia coli><Fellowship><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Generalized Growth><Genetic Alteration><Genetic Change><Genetic defect><Goals><Growth><Health Care Costs><Health Costs><Healthcare Costs><Human><Immune><Immune response><Immunes><Immunoblotting><Immunological response><Impairment><In Vitro><Infection><Intracellular Space><Investigators><Knowledge><Label><Lipopolysaccharides><Mammalian Cell><Medical><Medicine><Membrane><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Mentorship><Methods><Mice><Mice Mammals><Microscopy><Miscellaneous Antibiotic><Modeling><Modern Man><Molecular Interaction><Murine><Mus><Mutation><Nutrient><Nutrient availability><Organoids><Pathogenesis><Patients><Phage Receptors><Phages><Predisposition><Proteins><Public Health><Publishing><Receptor Protein><Recurrence><Recurrent><Research><Research Personnel><Researchers><Resistance><Resistance to antibiotics><Resistant to antibiotics><Route><Safety><Surface Proteins><Susceptibility><Techniques><Testing><Therapeutic><Tissue Growth><Training><Translating><UPEC><United States><Urinary tract><Urinary tract infection><Urinary tract infectious disease><Urine><Uropathogenic E coli><Uropathogenic E. coli><Uropathogenic Escherichia coli><Virus><Western Blotting><Western Immunoblotting><Woman><Work><anti-microbial><anti-microbial peptide><anti-microbial resistant><antibiotic drug resistance><antibiotic resistant><antibiotic resistant bacteria><antimicrobial><attenuate><attenuates><bacteria infection><bacteria pathogen><bacterial antibiotic resistant><bacterial disease><bacterial disease treatment><bacterial fitness><bacterial infectious disease treatment><bacterial pathogen><bacterial resistance to antibiotic><bacterial virus><career><career development><college><collegiate><cost><cytokine><developmental><diabetes><disease model><disorder model><driving><driving force><environmental stresses><environmental stressor><enzyme linked immunoassay><experience><extracellular><fitness><flow cytophotometry><genome mutation><host microbiome><host response><human imaging><immune system response><immunoresponse><in vivo><in vivo Model><infection recurrence><infectious disease treatment><innovate><innovation><innovative><live cell image><live cell imaging><live cellular image><live cellular imaging><membrane structure><model of animal><mouse model><murine model><mutant><novel><older adult><older adulthood><ontogeny><pathogen><pathogenic bacteria><protein blotting><receptor><recurrent infection><recurring infection><resistance to anti-microbial><resistant><resistant to antimicrobial><skills><standard of care><superresolution microscopy><tool><uptake><urinary><urinary bladder><urinary infection>