This document summarizes a review article on urinary tract infections (UTIs). It begins by noting that UTIs affect millions worldwide and often recur despite antibiotic treatment. The review then discusses the molecular pathogenesis of UTI, focusing on how uropathogenic E. coli (UPEC) cause infection by binding bladder cells, forming intracellular bacterial communities (IBCs), and evading immune responses. It highlights gaps in understanding how UPEC escape vacuoles to form IBCs and notes host and bacterial factors that influence infection outcomes. The review concludes by discussing the immune response to UTI and how UPEC subvert defenses to establish infection.
The Human Microbiome Project (HMP) was a United States National Institutes of Health (NIH) research initiative to improve understanding of the microbial flora involved in human health and disease.
Chronic Salmonella typhi carrier state: a precursor to gall bladder cancer KETAN VAGHOLKAR
Typhoid fever is one of the commonest infections of the gastrointestinal tract seen in the Indian subcontinent. Association with gall stones can lead to a chronic carrier state. This is a dangerous situation as it can strongly predispose to the development of carcinoma of the gall bladder which is known to have a very poor prognosis. The pathophysiology of this carcinogenic change and its clinical implications are discussed in this paper.
The Human Microbiome Project (HMP) was a United States National Institutes of Health (NIH) research initiative to improve understanding of the microbial flora involved in human health and disease.
Chronic Salmonella typhi carrier state: a precursor to gall bladder cancer KETAN VAGHOLKAR
Typhoid fever is one of the commonest infections of the gastrointestinal tract seen in the Indian subcontinent. Association with gall stones can lead to a chronic carrier state. This is a dangerous situation as it can strongly predispose to the development of carcinoma of the gall bladder which is known to have a very poor prognosis. The pathophysiology of this carcinogenic change and its clinical implications are discussed in this paper.
Background: The widespread use of antibiotics has resulted in emergence of community-acquired antibiotic resistance among uropathogens in outpatient’s population. This constitutes an impediment in the management of urinary tract infection (UTI) in both community and hospital settings. Objective: The aim of this study was to determine the current antibiotic resistance trends, extended spectrum beta-lactamase (ESBL) production and plasmid profile of uropathogens from outpatients. Methods: A total of 370 mid-stream urine samples were collected and cultured by standard methods. Isolated uropathogens were identified using appropriate biochemical methods. The modified Kirby Bauer disk method was used for antibiotic susceptibility test. The ESBL-producing uropathogens were identified and their plasmid DNA extraction and curing were carried out by standard methods. Results: About 35.7% and 32.7% of uropathogens were multi-drug resistant and ESBL-producing respectively. There was higher prevalence of ESBL-production among isolates from female patients (62.5%) when compared to that from male patients (37.5%). The isolated uropathogens were most resistant to Cefotaxime, and most sensitive to Imipenem. Resistance to antibiotics by ESBL-producing uropathogens was found to be plasmid-mediated. Conclusion: Community acquired Uropathogens from outpatients were multidrug resistant due to ESBL production localized on plasmids, a probable cause of treatment failures experienced in Uyo.
Safety and toxicity evaluation of probiotics foodsSukhveerSingh31
Probiotics can also be defined as “Live microorganisms that when administered in adequate amounts confer a health benefit on the host” (Council for Agricultural Science and Technology).
Microbiota, leaky gut syndrome and gut-related diseasesMaurizio Salamone
Lecture on "Microbiota, Leaky gut Syndrome and gut-related disease" at the 7° International workshop on Immunonutrition "Eating for preventing" Carovigno (BA) May 1st-3th 2014
Microbes are our Friends.. The effective way of microbes treating our diseases and fighting with the pathogens is very effective. The human microbiome project is a current topic the researchers are focusing now. We think we are humans but the research of Human Microbiome Project states that we are 1% Humans 99% microbes. The highlights of this project is fecal transplantation and effective way of killing pathogens with the positive microbes.
The way we treat our body will treat you back and the antigens which are entered in to our body will greatly fight with microbes to survive and make the human body safe and healthy.
Finally Microbes are us and we are them
Evolution in the news (BIOL415) Spring 2014Kevin B Hugins
Mini presentation on current news stories for BIOL 415
This news article was about a journal article published in Nature Communications on April 15, 2014. The article is the result of research that was led by scientists from the Max Planck Institute for Evolutionary Anthropology. The purpose of the research was to study the co-evolution of humans and gut microbiota and examine adaptation that resulted in groups that had different diets. The primary group of interest was a hunter-gatherer group located in Tanzania known as Hadza. This is one of the few remaining true foraging populations in the world. The Hadza diet consists of baobab, game meat, honey, berries and tubers. Hadza do not consume any agricultural crops or livestock.
The prevalence of Escherichia coli Causing Urinary Tract Infections in Aminu ...Premier Publishers
Urinary Tract infections (UTIs) are one of the most common causes of hospital visit worldwide. The study intends to find the prevalence of Escherichia coli in Urinary tract infection cases in Aminu Kano Teaching Hospital (AKTH), Kano. A comprehensive study was conducted on E coli for its prevalence in urine samples, of queried cases of urinary tract infection in patients attending Aminu Kano Teaching Hospital (AKTH), Kano. Two hundred and fourteen urine specimens comprising of 123(57.5%) females and 91(42.5%) males of all age group were screened for bacteria. Of the 214 samples, 68 representing (31.80%) were culture positive with E. coli having 32(47.06%), Klebsiella spp 18(26.47%), Staphylococcus spp 10(14.70%), Proteus spp 6(8.82%) and Pseudomonas spp 2(2.94%). Out of the 32(47.6%) of E. coli isolated, 22 were from female and 10 were from males, the highest prevalence occurred within the age range of 21-30 with females taking the lead. Antibiogram of the isolated E. coli showed a markedly good sensitivity of ofloxacin (96.87%), nitrofurantoin and nalidixic acid (93.70%), colistin phosphate (90.62%) and gentamicin (68.75%). E. coli showed the least sensitivity to ampicillin (18.75%). The frequency of E. coli obtained suggests its high prevalence. And this can be reduced using Flouroquinolones as exhibited by the susceptibility profile in this study.
Food allergy has been long recognized and well documented. Other adverse reactions to foods first referred to as “toxic idiopathies” by John Freeman, co inventor of immunotherapy, at the early part of the 1900s can be mediated by and have their impact on the nervous and endocrine systems. It can also be mediated by pharmacologic mechanisms and can also affect any part of the body. There’s a great clinical need to accurately identify triggers of adverse reactivity as they have now been linked with even the most serious of modern maladies and diseases. In fact, inflammation is the hallmark of metabolic syndrome. Given the multitude of pathogenic mechanisms underlying adverse reactions to foods and other environmental exposures it is necessary that a utilizable and cost effective technology be understood so that its application be utilized under the appropriate circumstances.
KEY LEARNING POINTS
• The natural ability of certain foods to initiate an inflammatory response and induce metabolic disruptions and counterbalancing mechanisms to prevent that
• How foods can trigger “danger signals” for the immune system
Pharmacologic vs. immunologic reactions to foods
• Is there a common final pathway of all these mechanisms that can reliably indicate triggers of clinical pathology?
• Cellular testing vs. serologic testing: The advantages of cellular testing
Your body is home to three pounds of germs, a rich microbiome that weighs as much as your brain! Thanks to the recent plummeting cost of gene sequencing, scientists are just now discovering how important these microbes are to health and wellness, with surprising links to conditions ranging from obesity, autism, allergies, depression, and much more. We’ll discuss the latest developments, and show how new, low-cost testing kits can help you learn more about — and reshape — your own unique microbiome.
ABSTRACT- Urinary Tract Infections (UTI) is a major threat to human health. It is caused due to various physiological changes of the urinary tract by the activity of microorganisms. Urinary Tract infections has also been a major type of hospital acquired infection. Hospital acquired infections (HAI) are of various types: Respiratory Tract Infection (RTI), Urinary Tract Infection (UTI), Blood Stream Infection (BSI), and Surgical Site Infection (SSI) and the most common are Urinary Tract (39%) and Respiratory Tract (20-22%) infection. The main aim of this study was to assess various urine samples collected from patients of the ICU of a tertiary care hospital for microbial growth and create a statistical picture on the contribution of UTI to nosocomial infections. Certain governing factors for UTI like presence of pus cells, epithelial cells, and diabetes mellitus were also kept under consideration along with various patient details like age, sex, primary illness and prior antibiotic treatment. The key findings of the study were: the
mean age of patients with symptomatic and asymptomatic UTI was 51 years and people from both genders within the age group of 41-60 were equally susceptible. E. coli was the most common causative organism (35.7%) followed by Citrobacter (21.42%) and Klebsiella (14.28%). Other organisms included Pseudomonas, Enterococcus and Candida. The rate of UTI was 56.22/1000 days of catheterization. Most of the organisms isolated were found to be multi drug resistant. UTI has been hence concluded to play a major contribution in nosocomial infections which needs to be controlled by integrating proper monitoring of hospital data and surveillance of hospital acquired urinary tract infection.
Key-words- ICU, Urinary Tract Infection, Center for Disease Control, Multi drug resistant, antibiotics, Microorganism
Catheter –Associated Urinary Tract Infection, Management, And Preventionsiosrphr_editor
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
Background: The widespread use of antibiotics has resulted in emergence of community-acquired antibiotic resistance among uropathogens in outpatient’s population. This constitutes an impediment in the management of urinary tract infection (UTI) in both community and hospital settings. Objective: The aim of this study was to determine the current antibiotic resistance trends, extended spectrum beta-lactamase (ESBL) production and plasmid profile of uropathogens from outpatients. Methods: A total of 370 mid-stream urine samples were collected and cultured by standard methods. Isolated uropathogens were identified using appropriate biochemical methods. The modified Kirby Bauer disk method was used for antibiotic susceptibility test. The ESBL-producing uropathogens were identified and their plasmid DNA extraction and curing were carried out by standard methods. Results: About 35.7% and 32.7% of uropathogens were multi-drug resistant and ESBL-producing respectively. There was higher prevalence of ESBL-production among isolates from female patients (62.5%) when compared to that from male patients (37.5%). The isolated uropathogens were most resistant to Cefotaxime, and most sensitive to Imipenem. Resistance to antibiotics by ESBL-producing uropathogens was found to be plasmid-mediated. Conclusion: Community acquired Uropathogens from outpatients were multidrug resistant due to ESBL production localized on plasmids, a probable cause of treatment failures experienced in Uyo.
Safety and toxicity evaluation of probiotics foodsSukhveerSingh31
Probiotics can also be defined as “Live microorganisms that when administered in adequate amounts confer a health benefit on the host” (Council for Agricultural Science and Technology).
Microbiota, leaky gut syndrome and gut-related diseasesMaurizio Salamone
Lecture on "Microbiota, Leaky gut Syndrome and gut-related disease" at the 7° International workshop on Immunonutrition "Eating for preventing" Carovigno (BA) May 1st-3th 2014
Microbes are our Friends.. The effective way of microbes treating our diseases and fighting with the pathogens is very effective. The human microbiome project is a current topic the researchers are focusing now. We think we are humans but the research of Human Microbiome Project states that we are 1% Humans 99% microbes. The highlights of this project is fecal transplantation and effective way of killing pathogens with the positive microbes.
The way we treat our body will treat you back and the antigens which are entered in to our body will greatly fight with microbes to survive and make the human body safe and healthy.
Finally Microbes are us and we are them
Evolution in the news (BIOL415) Spring 2014Kevin B Hugins
Mini presentation on current news stories for BIOL 415
This news article was about a journal article published in Nature Communications on April 15, 2014. The article is the result of research that was led by scientists from the Max Planck Institute for Evolutionary Anthropology. The purpose of the research was to study the co-evolution of humans and gut microbiota and examine adaptation that resulted in groups that had different diets. The primary group of interest was a hunter-gatherer group located in Tanzania known as Hadza. This is one of the few remaining true foraging populations in the world. The Hadza diet consists of baobab, game meat, honey, berries and tubers. Hadza do not consume any agricultural crops or livestock.
The prevalence of Escherichia coli Causing Urinary Tract Infections in Aminu ...Premier Publishers
Urinary Tract infections (UTIs) are one of the most common causes of hospital visit worldwide. The study intends to find the prevalence of Escherichia coli in Urinary tract infection cases in Aminu Kano Teaching Hospital (AKTH), Kano. A comprehensive study was conducted on E coli for its prevalence in urine samples, of queried cases of urinary tract infection in patients attending Aminu Kano Teaching Hospital (AKTH), Kano. Two hundred and fourteen urine specimens comprising of 123(57.5%) females and 91(42.5%) males of all age group were screened for bacteria. Of the 214 samples, 68 representing (31.80%) were culture positive with E. coli having 32(47.06%), Klebsiella spp 18(26.47%), Staphylococcus spp 10(14.70%), Proteus spp 6(8.82%) and Pseudomonas spp 2(2.94%). Out of the 32(47.6%) of E. coli isolated, 22 were from female and 10 were from males, the highest prevalence occurred within the age range of 21-30 with females taking the lead. Antibiogram of the isolated E. coli showed a markedly good sensitivity of ofloxacin (96.87%), nitrofurantoin and nalidixic acid (93.70%), colistin phosphate (90.62%) and gentamicin (68.75%). E. coli showed the least sensitivity to ampicillin (18.75%). The frequency of E. coli obtained suggests its high prevalence. And this can be reduced using Flouroquinolones as exhibited by the susceptibility profile in this study.
Food allergy has been long recognized and well documented. Other adverse reactions to foods first referred to as “toxic idiopathies” by John Freeman, co inventor of immunotherapy, at the early part of the 1900s can be mediated by and have their impact on the nervous and endocrine systems. It can also be mediated by pharmacologic mechanisms and can also affect any part of the body. There’s a great clinical need to accurately identify triggers of adverse reactivity as they have now been linked with even the most serious of modern maladies and diseases. In fact, inflammation is the hallmark of metabolic syndrome. Given the multitude of pathogenic mechanisms underlying adverse reactions to foods and other environmental exposures it is necessary that a utilizable and cost effective technology be understood so that its application be utilized under the appropriate circumstances.
KEY LEARNING POINTS
• The natural ability of certain foods to initiate an inflammatory response and induce metabolic disruptions and counterbalancing mechanisms to prevent that
• How foods can trigger “danger signals” for the immune system
Pharmacologic vs. immunologic reactions to foods
• Is there a common final pathway of all these mechanisms that can reliably indicate triggers of clinical pathology?
• Cellular testing vs. serologic testing: The advantages of cellular testing
Your body is home to three pounds of germs, a rich microbiome that weighs as much as your brain! Thanks to the recent plummeting cost of gene sequencing, scientists are just now discovering how important these microbes are to health and wellness, with surprising links to conditions ranging from obesity, autism, allergies, depression, and much more. We’ll discuss the latest developments, and show how new, low-cost testing kits can help you learn more about — and reshape — your own unique microbiome.
ABSTRACT- Urinary Tract Infections (UTI) is a major threat to human health. It is caused due to various physiological changes of the urinary tract by the activity of microorganisms. Urinary Tract infections has also been a major type of hospital acquired infection. Hospital acquired infections (HAI) are of various types: Respiratory Tract Infection (RTI), Urinary Tract Infection (UTI), Blood Stream Infection (BSI), and Surgical Site Infection (SSI) and the most common are Urinary Tract (39%) and Respiratory Tract (20-22%) infection. The main aim of this study was to assess various urine samples collected from patients of the ICU of a tertiary care hospital for microbial growth and create a statistical picture on the contribution of UTI to nosocomial infections. Certain governing factors for UTI like presence of pus cells, epithelial cells, and diabetes mellitus were also kept under consideration along with various patient details like age, sex, primary illness and prior antibiotic treatment. The key findings of the study were: the
mean age of patients with symptomatic and asymptomatic UTI was 51 years and people from both genders within the age group of 41-60 were equally susceptible. E. coli was the most common causative organism (35.7%) followed by Citrobacter (21.42%) and Klebsiella (14.28%). Other organisms included Pseudomonas, Enterococcus and Candida. The rate of UTI was 56.22/1000 days of catheterization. Most of the organisms isolated were found to be multi drug resistant. UTI has been hence concluded to play a major contribution in nosocomial infections which needs to be controlled by integrating proper monitoring of hospital data and surveillance of hospital acquired urinary tract infection.
Key-words- ICU, Urinary Tract Infection, Center for Disease Control, Multi drug resistant, antibiotics, Microorganism
Catheter –Associated Urinary Tract Infection, Management, And Preventionsiosrphr_editor
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
Biofilm is a community of microorganisms of same or different species encased in a self -produced extracellular polymeric substance on both living and non-living surfaces. Catheters are generally critical indwelling medical devices commonly used in clinical applications to enhanced flow of flu ids out of the patient’s body as well as influx of medications into human biological systems. Like many other indwelling medical devices, catheters are prone to enhanced risk of nosocomial infections which becomes a critical challenge as a result of microbial attachment to the surfaces of the catheters.
Attachment and subsequent biofilm development on catheter surfaces cause a number of persistent infections. The biofilm development increases resistance to antibiotics. However, this sometimes led to high pathogenesis, patient morbidity and mortality. This condition usually calls for a premature catheter removal which will increase the cost of treatment and improvidence of resources. This review focuses on how catheters get infected, microbial diversity among catheter biofilms, factors mediating biofilm formation on catheters and current strategies us ed in controlling biofilm formation on indwelling catheters.
Fitness of Escherichia coli during Urinary Tract InfectionRe.docxlmelaine
Fitness of Escherichia coli during Urinary Tract Infection
Requires Gluconeogenesis and the TCA Cycle
Christopher J. Alteri, Sara N. Smith, Harry L. T. Mobley*
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
Abstract
Microbial pathogenesis studies traditionally encompass dissection of virulence properties such as the bacterium’s ability to
elaborate toxins, adhere to and invade host cells, cause tissue damage, or otherwise disrupt normal host immune and
cellular functions. In contrast, bacterial metabolism during infection has only been recently appreciated to contribute to
persistence as much as their virulence properties. In this study, we used comparative proteomics to investigate the
expression of uropathogenic Escherichia coli (UPEC) cytoplasmic proteins during growth in the urinary tract environment
and systematic disruption of central metabolic pathways to better understand bacterial metabolism during infection. Using
two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) and tandem mass spectrometry, it was found that
UPEC differentially expresses 84 cytoplasmic proteins between growth in LB medium and growth in human urine (P,0.005).
Proteins induced during growth in urine included those involved in the import of short peptides and enzymes required for
the transport and catabolism of sialic acid, gluconate, and the pentose sugars xylose and arabinose. Proteins required for
the biosynthesis of arginine and serine along with the enzyme agmatinase that is used to produce the polyamine putrescine
were also up-regulated in urine. To complement these data, we constructed mutants in these genes and created mutants
defective in each central metabolic pathway and tested the relative fitness of these UPEC mutants in vivo in an infection
model. Import of peptides, gluconeogenesis, and the tricarboxylic acid cycle are required for E. coli fitness during urinary
tract infection while glycolysis, both the non-oxidative and oxidative branches of the pentose phosphate pathway, and the
Entner-Doudoroff pathway were dispensable in vivo. These findings suggest that peptides and amino acids are the primary
carbon source for E. coli during infection of the urinary tract. Because anaplerosis, or using central pathways to replenish
metabolic intermediates, is required for UPEC fitness in vivo, we propose that central metabolic pathways of bacteria could
be considered critical components of virulence for pathogenic microbes.
Citation: Alteri CJ, Smith SN, Mobley HLT (2009) Fitness of Escherichia coli during Urinary Tract Infection Requires Gluconeogenesis and the TCA Cycle. PLoS
Pathog 5(5): e1000448. doi:10.1371/journal.ppat.1000448
Editor: Jorge E. Galán, Yale University School of Medicine, United States of America
Received October 6, 2008; Accepted April 27, 2009; Published May 29, 2009
Copyright: � 2009 Alteri et al. This is an open-access article d ...
Combating Drug Resistance in The Intensive Care Unit (ICU)Apollo Hospitals
Drug resistance of microbes has become a major stumbling block to treating patients successfully in the ICU. There is no doubt that microbes have the capacity to mutate or acquire drug destroying enzymes, but a multitude of errors by health care providers plays a major role in facilitating the development of resistance. The maintenance of drug use discipline in closed ICUs and having a responsive microbiology department are the first steps towards prevention of microbe resistance. Having an infection control committee that is able to collect and disseminate data is the next essential step. Education of health care providers to provide uniformity of health care according to set guidelines is the culmination of this towards the goal of minimizing the development of anti microbial resistance.
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6th International Conference on Machine Learning & Applications (CMLA 2024)ClaraZara1
6th International Conference on Machine Learning & Applications (CMLA 2024) will provide an excellent international forum for sharing knowledge and results in theory, methodology and applications of on Machine Learning & Applications.
Literature Review Basics and Understanding Reference Management.pptxDr Ramhari Poudyal
Three-day training on academic research focuses on analytical tools at United Technical College, supported by the University Grant Commission, Nepal. 24-26 May 2024
ACEP Magazine edition 4th launched on 05.06.2024Rahul
This document provides information about the third edition of the magazine "Sthapatya" published by the Association of Civil Engineers (Practicing) Aurangabad. It includes messages from current and past presidents of ACEP, memories and photos from past ACEP events, information on life time achievement awards given by ACEP, and a technical article on concrete maintenance, repairs and strengthening. The document highlights activities of ACEP and provides a technical educational article for members.
KuberTENes Birthday Bash Guadalajara - K8sGPT first impressionsVictor Morales
K8sGPT is a tool that analyzes and diagnoses Kubernetes clusters. This presentation was used to share the requirements and dependencies to deploy K8sGPT in a local environment.
Hierarchical Digital Twin of a Naval Power SystemKerry Sado
A hierarchical digital twin of a Naval DC power system has been developed and experimentally verified. Similar to other state-of-the-art digital twins, this technology creates a digital replica of the physical system executed in real-time or faster, which can modify hardware controls. However, its advantage stems from distributing computational efforts by utilizing a hierarchical structure composed of lower-level digital twin blocks and a higher-level system digital twin. Each digital twin block is associated with a physical subsystem of the hardware and communicates with a singular system digital twin, which creates a system-level response. By extracting information from each level of the hierarchy, power system controls of the hardware were reconfigured autonomously. This hierarchical digital twin development offers several advantages over other digital twins, particularly in the field of naval power systems. The hierarchical structure allows for greater computational efficiency and scalability while the ability to autonomously reconfigure hardware controls offers increased flexibility and responsiveness. The hierarchical decomposition and models utilized were well aligned with the physical twin, as indicated by the maximum deviations between the developed digital twin hierarchy and the hardware.
Fundamentals of Electric Drives and its applications.pptx
Urinary
1. Urinary Tract Infection: Pathogenesis and Outlook
Lisa K. McLellan1,3 and David A. Hunstad1,2
1Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA
2Department of Molecular Microbiology, Washington University School of Medicine, St. Louis,
Missouri, USA
3Division of Biology and Biomedical Sciences, Washington University School of Medicine, St.
Louis, Missouri, USA
Abstract
The clinical syndromes comprising urinary tract infection (UTI) continue to exert significant
impact on millions of patients worldwide, most of whom are otherwise healthy women. Antibiotic
therapy for acute cystitis does not prevent recurrences, which plague up to one fourth of women
after an initial UTI. Rising antimicrobial resistance among uropathogenic bacteria further
complicates therapeutic decisions, necessitating new approaches based on fundamental biological
investigation. In this review, we highlight contemporary advances in the field of UTI pathogenesis
and how these might inform both our clinical perspective and future scientific priorities.
Keywords
urinary tract infection; Escherichia coli; cystitis; pyelonephritis
A Pervasive and Persistent Problem
Urinary tract infections (UTIs) are among the most common bacterial infections, affecting
150 million people worldwide each year [1–3]. Although both men and women may become
infected, UTIs are traditionally thought of as a disease of women, among whom 50% will be
affected across their lifespan [2]. Approximately 25% of women presenting with a first
episode of bacterial cystitis (see Glossary) go on to suffer recurrent UTI within 6 months,
some having 6 or more infections in the year following the initial episode [2, 4]. Current
therapeutics are suboptimal, as the prevalence of multidrug-resistant uropathogens is
increasing and antibiotic treatment for acute infection does not preclude recurrences [2, 5,
6]. These recalcitrant infections can become a significant health problem and diminish
quality of life for affected men and women (Box 1).
*
Correspondence: dhunstad@wustl.edu (D. A. Hunstad).
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of
the resulting proof before it is published in its final citable form. Please note that during the production process errors may be
discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
CONFLICT OF INTEREST
D.A.H. serves on the Board of Directors of BioVersys AG, Basel, Switzerland.
HHS Public Access
Author manuscript
Trends Mol Med. Author manuscript; available in PMC 2017 November 01.
Published in final edited form as:
Trends Mol Med. 2016 November ; 22(11): 946–957. doi:10.1016/j.molmed.2016.09.003.
AuthorManuscriptAuthorManuscriptAuthorManuscriptAuthorManuscript
2. Bacterial infections of the urinary tract (UT) present clinically with a variety of signs and
symptoms and may be caused by an array of organisms (see Figure 1, Key Figure). In this
review, we focus primarily on uropathogenic Escherichia coli (UPEC) as the etiologic agent
of UTI, as UPEC is responsible for >80% of all community-acquired infections [2]. Other
etiologies include infections from Staphylococcus, Klebsiella, Enterobacter, Proteus, and
Enterococcus; these organisms become particularly relevant during catheter-associated and
hospital-acquired infections [7]. The pathogenic cascade of UPEC cystitis has been
extensively studied in recent years, largely in cell-culture and mouse models, as mice
recapitulate many facets of the bladder epithelial environment (reviewed in [8]). Through
these studies, unprecedented light has been shed on the molecular and cellular basis of
infection. Further, recent years have seen the advent of several new mouse models, enabling
the study of complicated UTIs (pyelonephritis, renal abscess, catheter-associated UTI) and
recurrent cystitis. In addition, recent data suggest that the normal, healthy bladder is not
always sterile, and a picture of the urinary microbiome is emerging. Such advances promise
to further illuminate molecular mechanisms of virulence in UPEC (reviewed recently in [9])
and other uropathogens, as well as the intricacies of the host immune response. With these
tools, we are poised to address heretofore unanswered questions with clinical relevance to
treatment and prevention.
Molecular Pathogenesis of UTI
Infection of the urinary tract begins when UPEC, likely introduced after colonization of the
periurethral area by gastrointestinal tract flora [10–12], accesses and ascends the urethra by
an undetermined mechanism. Upon reaching the urinary bladder, UPEC bind to superficial
epithelial (facet) cells in a type 1 pili-dependent manner [13]. A subset of adherent bacteria
are then internalized into facet cells [14, 15], a dynamic process that likely relies on the
normal cycling of apical membrane segments in these cells [16]. Countering this key
pathogenic activity, bladder epithelial cells undertake active expulsion of internalized UPEC.
Recent data show that UPEC are capable of neutralizing the lysosome, and that this
neutralization is sensed by a lysosomal membrane protein termed mucolipin TRP channel 3
(TRPML3), activating pathways that direct exocytosis of UPEC-containing lysosomes [17].
Through a distinct mechanism, activation of Toll-like receptor 4 (TLR4) by internalized
UPEC leads to specific ubiquitination of TNF Receptor Associated Factor 3 (TRAF3),
enabling its interaction with a guanine-nucleotide exchange factor that directs assembly of
the exocyst complex, thereby accomplishing expulsion of intracellular bacteria [18].
Using incompletely defined strategies, UPEC may gain access to the bladder epithelial cell
cytoplasm, thereafter developing clonal, biofilm-like masses termed intracellular bacterial
communities (IBCs) [14, 19]. As part of the host response, the superficial facet cells are
largely exfoliated [20], liberating IBCs into the urine and ridding the body of thousands of
bacteria. Shed IBC-containing cells are observed in the urine of infected women and
children, supporting their clinical relevance [21, 22]. After 16–24 h in murine UTI models, a
subset of UPEC in remaining IBCs adopt a neutrophil-resistant, filamentous morphology
and escape the IBCs, subsequently re-invading naïve bladder epithelial cells [23]. Some of
these bacteria will go on to infect immature bladder epithelium which is exposed after
exfoliation, later forming quiescent intracellular reservoirs, which avoid immune
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3. clearance and resist systemic antibiotic treatment [24–26]. These persistent UPEC may re-
emerge, in response to currently undefined signals, to cause the recurrent cystitis that is so
clinically common.
A significant gap in our understanding is the mechanism by which UPEC escape the initial
vacuole (after internalization) to reach the cytoplasm, where the IBC is formed. Unlike other
Gram-negative pathogens that escape an endosome, UPEC do not encode a type III
secretion system to deliver virulence factors [27]. Further, the bottleneck imposed by IBC
formation precludes classical in vivo screens, and no in vitro model for IBC formation has
been wholly accepted by the field [13, 14]. As a result, surrogate methods have been used to
illuminate requirements for IBC formation. For example, since IBCs exhibit many
characteristics of biofilms, one group performed a transposon screen for genes necessary for
in vitro biofilm formation, using polyvinyl chloride as a substrate, as well as sampling the
pellicle of standing broth cultures. This screen yielded genes with functions in attachment,
motility, LPS synthesis and modification, metabolism, as well as bacterial cell maintenance
[28]. In other studies, murine UTI models have shown that single-gene mutants of UPEC
exhibit defects in specific steps of the IBC pathogenic cascade, as in the case of OmpA, a
major outer membrane porin. OmpA deletion does not inhibit UPEC binding to superficial
epithelial cells or internalization; however, once within the cytoplasm of these cells, mutant
ΔompA cannot complete the intracellular pathway and, as assessed by dwindling organ
bacterial loads and confocal microscopy, these UPEC fail to progress past very early stages
of IBC formation in mice [29]. Similarly, UPEC harboring a deletion of the small non-
coding RNA Hfq cannot replicate within cultured human bladder epithelial cells, despite
exhibiting normal levels of binding and invasion [30]. Defining the roles of relevant host
factors (exemplified by the exocytosis studies mentioned above) will also help to elucidate
the mechanism by which UPEC gains the critical cytoplasmic niche. Answering questions
such as these will require collaborative and broad-based efforts involving cell biology,
bacteriology, biochemistry, and optimized in vitro or ex vivo models.
Following escape into the cytoplasm, the bacteria find themselves occupying an environment
very different from the nutrient-poor bladder lumen. Transcriptomic analyses of UPEC in
different models (such as during murine UTI or bacterial growth in urine) have suggested
that various metabolic pathways are essential for pathogenesis; these include sialic acid
transport/metabolism, gluconeogenesis, the tricarboxylic acid (TCA) cycle, iron uptake,
ethanolamine and phosphate metabolism, as well as amino acid metabolism [31–34]
(reviewed in [35]). Although this work has provided broad insight into the metabolic
activities required to cause UTI, we are on the verge of being able to specifically interrogate
UPEC populations in defined niches and times during infection. UPEC survival and growth
at distinct spatiotemporal points during infection could rely on very different metabolic
sources. Intracellular survival presumably requires a unique set of metabolic capabilities, but
the precise needs are incompletely defined. Metabolism of a chromogenic substrate during
cystitis provides circumstantial evidence that UPEC can utilize β-galactosidase, perhaps
reflecting a glucoselimited milieu during this intracellular step [36]. Transcriptional profiling
from whole mouse bladders 6 h post infection with UPEC strain UTI89 was posited to
reflect mostly bacteria that are internalized and actively forming IBCs [37]. This analysis
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4. found that 2.3% of the UPEC genome was differentially regulated within the bladder at this
time point (6 h), when compared to the statically grown UPEC broth culture that was used as
inoculum. Genes associated with alternative carbon source utilization pathways, such as lacZ
and srlA for galactose and sorbitol utilization, respectively, were upregulated; deletion of
lacZ was subsequently found to impair virulence [37]. Genes associated with iron
acquisition were also highly expressed, including siderophores (secreted bacterial proteins
that chelate extracellular iron and return it to the bacterial cell). In contrast, tryptophan and
cysteine synthetic genes were downregulated, reflecting an abundance of these amino acids
within the IBC niche [37]. A more specific understanding of bacterial metabolism within
pathogenic niches could reveal points of potential intervention, halt infection, and/or
eliminate reservoirs that seed recurrent UTIs. Of note, the central metabolic pathways in E.
coli do not necessarily represent all uropathogenic species; other pathogens with distinct
metabolism may respond to different nutritional cues during infection [31].
Comparatively less is known about the molecular pathogenesis of infection in the kidney. In
traditional mouse models, severe kidney infection (including renal abscess formation) is
uncommon, hampering the study of this entity. Attenuation in mouse kidney infections has
been observed with UPEC mutants lacking specific virulence factors, such as type 1 pili, P
pili, flagella, α-hemolysin, and cytotoxic necrotizing factor 1 (CNF1) [3, 9]. Further,
genetics appear to play a role in host susceptibility to acute pyelonephritis. For example,
increased risk of acute pyelonephritis and renal scarring have been linked to polymorphisms
that reduce Interferon Regulatory Factor 3 (IRF3) or CXCR1 (encoding the IL-8 receptor)
gene expression in certain UTI-prone patient populations [38]. Compared to bacterial
cystitis, the understanding of pyelonephritis remains limited and, consequently, represents a
fertile area of study.
Immune Control and Pathogen Evasion
After ascending the urethra, bacterial pathogens are challenged by innate defenses within the
bladder. Arrival in the bladder triggers a TLR4-dependent, lipopolysaccharide (LPS)-
stimulated inflammatory response from bladder epithelial cells and resident leukocytes,
culminating in the activation of the NF-κB pathway, which in turn promotes the expression
of inflammatory cytokines and neutrophil chemoattractants [39]. This inflammatory milieu
engenders massive neutrophil influx into the bladder tissue and lumen, correlating with a
diagnostic hallmark of UTI. The importance of this neutrophil influx in controlling UPEC
infection has been well established (e.g., [40–43]). Production of polysaccharide capsule
antigens by UPEC, particularly of the K2 or K1 serotype, may provide some protection
against UPEC eradication by the host [44]. Further, many other soluble factors (e.g.,
antimicrobial peptides, complement, lipocalin 2, lysozyme, lactoferrin) are also released by
host cells into the bladder lumen, potentially creating a less hospitable environment for
arriving bacteria [45, 46]. Antimicrobial peptides likely protecting the urinary tract include
defensins, the human cathelicidin LL-37, and ribonuclease 7 [47–50]. These molecules
may exert direct antimicrobial activity, augment innate cellular recruitment, or function to
alter the environmental niche to make it less favorable for uropathogens (e.g., by
sequestering siderophores and critical nutrients such as iron, from the bacteria) [51]. Other
host transcriptional regulators such as hypoxiainducible factor 1α (HIF-1α) are also
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5. expressed in response to bacteria, potentially boosting innate defense components such as
nitric oxide, cathelicidin, and β-defensin 2 [51, 52]. Recently, the humoral pattern
recognition molecule pentraxin 3 (PTX3) was shown to help control UTI by serving as an
opsonin and promoting bacterial uptake by neutrophils; UTI-prone children and adult
cystitis patients who had suffered recurrent UTI as children exhibited polymorphisms in
PTX3 [53], suggesting that the cellular and soluble components of innate immunity can
influence disease outcomes.
The formation of IBCs is a key means by which bacteria subvert neutrophil activity, as
arriving neutrophils accurately locate IBC-bearing facet cells but cannot access the bacteria
within [39, 54]. UPEC can subvert and delay the innate immune response in multiple ways
(reviewed in [39]). For example, secretion of proteins such as UPEC YbcL can lead to a
measurable dampening of neutrophil infiltration into the bladder [55–57]. Further, UPEC
induces host expression of genes such as IDO, which, via generation of kynurenine
metabolites, can cause decreased neutrophil migration across infected bladder epithelia, as
evidenced from in vitro Transwell systems, as well as in mice [58, 59]. Some UPEC strains,
such as CFT073, can also disrupt host signaling by producing TIR domain-containing
proteins such as TcpC; this virulence factor interacts with the host adaptor MyD88 to disrupt
TLR4 signaling, while also reducing urinary IL-1β in mice and inhibiting the NLRP3
inflammasome in macrophages [60, 61]. While robust innate defenses are able to repel most
bacterial challenges, this inflammatory response may represent a double-edged sword. In
murine cystitis, excessive inflammation and resulting bladder tissue damage predisposes the
host to worse infection outcomes, including chronic cystitis [62, 63].
As mucosal barriers such as the bladder epithelium are repeatedly assaulted with bacteria,
they are generally tolerant to a transient microbial presence, and innate defenses are key to
preventing infection. However, clinical syndromes such as recurrent UTI raise questions
about the importance of adaptive immunity in bladder protection. Pro-inflammatory
cytokines that also elicit adaptive immune effects, such as IL-17, are prominently secreted
during the acute phase of murine experimental UTI [64, 65]. CD8+ T cells are recruited to
the bladder as early as 24 h post infection, but the precise roles of these and other adaptive
immune cell populations are unknown [66]. Regarding humoral immunity, the prevalence of
recurrent UTI in the female population suggests that a lasting protective immune response is
not established following cystitis, at least in this subpopulation of women [67]. Upper-tract
UTI (pyelonephritis) may generate a more robust serological response, although it is not
clear if elicited antibodies would subsequently reach the bladder to provide protection
against future cystitis. In total, the importance of adaptive immunity in controlling UPEC
infection is substantially understudied in comparison with the innate immune system.
Understanding the basis of functional adaptive immunity against UTI could have major
implications for recurrent UTIs and vaccine development, as further discussed below.
Next-generation Therapeutics
Put simply, UTI therapies are in need of innovation. For decades, finite courses of antibiotics
have been prescribed for women with UTIs, often in the absence of bacterial culture data;
such empiric treatment is effective at resolving acute symptoms, but clearly fails to eliminate
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6. a recurrence risk [2]. In addition, the rise of multidrug-resistant uropathogens (e.g., [68])
mandates therapeutic selection based on actual patient bacterial cultures, susceptibility
results and/or local as well as institutional antibiograms. As the pace of resistance
development (especially among Gram-negative uropathogens) has overtaken the pace of new
antibiotic development, fundamentally new approaches are needed [69]. Further,
prophylactic antibiotics are incompletely effective in preventing infection [70], and in one
mouse study, subtherapeutic levels of ciprofloxacin were shown to augment murine UTI
[71]. To move forward in the therapeutic realm, we must extend our molecular
understanding of both the pathogen and the host. Contemporary development of novel UTI
therapeutics has focused on interfering with pathogen binding to bladder epithelium or other
key pathogen processes, the development of vaccines based on bacterial components, as well
as the modulation of host responses -- specifically those promoting exfoliation to eradicate
chronically resident bacteria from the bladder.
An emerging example in which basic biology of the host-pathogen interaction has informed
therapeutics development is that of mannosides and pilicides, compound families which
target the crucial step of bacterial adherence to host cells in distinct ways. Pilicides interfere
with the chaperone-usher pathway for assembly of adhesive type 1 pili, preventing their
presentation on the bacterial surface and thereby abolishing epithelial binding [72, 73]. In
contrast, mannosides serve as competitive inhibitors, occupying the binding pocket of the
type 1 pilus adhesin FimH, with affinities that are orders of magnitude higher than those of
the mannosylated uroplakins decorating the bladder epithelial surface [74]. The oral
bioavailability and efficacy of mannosides in preventing UTI in mice portend substantial
potential utility in the clinic [75, 76]. Beyond uncomplicated cystitis, mannosides have also
shown efficacy in mouse models for prevention of catheter-associated UTI (as reflected by
diminished bladder and catheter colonization) [77]. Mannosides are being rationally
optimized to exhibit more drug-like pharmacokinetic properties, such as improved metabolic
stability and bioavailability [74, 78]. Agents such as the so-called “anti-virulence”
compounds that block specific molecular steps in pathogenesis, apply much less selective
pressure on pathogenic bacteria, thereby reducing the rapidity of resistance development
[79]. Further, due to their known mechanism of action, such agents can be used as tools to
further probe the biology of host-pathogen interactions [80]. Recent structural “snapshots”
of bacterial pilus assembly via the chaperone-usher pathway (see Figure 2) may illuminate
additional routes to inhibition [81–84], with potentially much broader impact, as this
bacterial secretion pathway also underlies virulence factor production by diverse bacterial
pathogens (e.g., Yersinia pestis). Direct application to the bladder luminal surface of
nanoparticles, perhaps coated with the FimH adhesin [85], has also been explored in mice as
a means to accomplish targeted delivery of novel therapeutics to the host [86].
Successful vaccination against UPEC and other uropathogens could have monumental
impact on the lives of those at risk for complicated UTIs or who suffer from recurring
episodes. Multiple groups have worked to identify specific UPEC factors for potential use as
vaccine antigens. Candidate antigens include the FimH adhesin, siderophores such as
yersiniabactin [87], and other immunodominant proteins identified in mouse models [88, 89]
(reviewed in [3, 90]). Two important considerations may hinder the effectiveness of vaccine
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7. candidates against UTI. First, as strains of E. coli (expressing type 1 pili, iron acquisition
systems, and other factors) are present in the normal gut microbiota, vaccination could
potentially alter the populations of proteobacteria in the gut. Second, as noted above, it is not
clear how much antibody (IgG) in the healthy urinary tract should reach the bladder lumen.
Therefore, elicitation of serum antibodies against UPEC antigens may be more effective in
preventing pyelonephritis, where antibodies are more readily delivered. Further studies into
the correlates of adaptive immunity in both the upper and lower urinary tract are thus needed
to advance these efforts.
Another strategy for the management of acute or recurrent UTI may be to modulate or
enhance host responses to UTI. As noted earlier, an exuberant inflammatory response
predisposes women to chronic cystitis [62]. In fact, in a mouse UTI model, inhibiting this
response using an oral anti-inflammatory COX-2 inhibitor yielded better outcomes without
actually targeting the bacteria (and thereby applying no selective pressure). These findings
corroborated small clinical trials in women receiving ibuprofen, in which symptomatic
improvement at 4 and 7 days with ibuprofen treatment alone was equivalent to using oral
antibiotics [91, 92]. Further, as the bladder exfoliation accompanying acute UPEC cystitis is
not complete, bacteria within quiescent reservoirs may re-emerge to seed recurrent infection.
Advanced, more efficacious exfoliants are being designed to unearth these quiescent
reservoirs [93, 94]. Once these bacteria are forced to emerge, they may be more susceptible
to the actions of standard antibiotics. Therefore, combined exfoliant-antimicrobial strategies
might rid the host of the UPEC reservoirs that underlie some recurrent UTIs [94].
Finally, with regard to updated UTI therapeutics, one must consider an impending paradigm
shift regarding the “normal” state of the bladder – which has long been assumed to be sterile
[95]. Enhanced culture techniques, as well as metagenomics on catheter-collected samples,
have detected urinary bacteria in healthy and asymptomatic women [96]. Interactions
between these apparent commensals and soluble mediators such as antimicrobial peptides
might alter susceptibility to UTI [97]. Moreover, specific microbiome structures might also
be related to conditions traditionally thought to be non-infectious, such as stress or urgency
incontinence [98, 99] and interstitial cystitis/chronic bladder pain. As the urinary
microbiome is more extensively defined, we will have to account for it when considering the
pathogenesis of UTI, as well as when choosing therapies for symptomatic patients.
Emerging, Clinically Relevant Models for UTI
Although many uncomplicated UTIs can resolve spontaneously or with antibiotic treatment,
more complicated forms of UTI have not, until recently, been reflected in animal models.
The majority of preclinical work in the last two decades on cystitis and pyelonephritis has
relied on transurethral inoculation of UPEC into the bladder of female mice [100, 101].
Emerging mouse models may enable additional clinically relevant questions to be addressed.
Catheter-associated UTI (CAUTI)
Prolonged urinary catheter usage is a risk factor for UTI, due largely to the ability of
bacteria to establish a biofilm on the catheter that resists clearance by host defense and
antibiotics. CAUTIs represent the most common nosocomial infections and are associated
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8. with increased hospital length of stay, morbidity, and mortality [102, 103]. As UPEC are less
prominent in the epidemiology of CAUTI, other organisms such as Enterococcus faecalis
have emerged as model organisms for study [7]. Insertion of a urinary catheter elicits an
inflammatory environment in the bladder, which is manifested histologically as exfoliation,
edema of the lamina propria and submucosa, urothelial thinning, and mucosal lesions [7].
Damaged mucosa and the catheter itself offer surfaces for bacterial adhesion [104]. Recent
data indicate that enterococcal adherence to urinary catheter material is mediated by
fibrinogen, a host protein that is released into the bladder lumen and deposited on the
catheter following insertion. E. faecalis then binds fibrinogen via the pilus tip adhesin EbpA,
subsequently forming a biofilm on the catheter [105, 106]. These pathogenic events can be
modeled in C57BL/6 mice in which a short length of silicone catheter material is
transurethrally deposited in the bladder, followed by introduction of E. faecalis [104, 107]. A
structural understanding of bacterial pilus association with catheter material and
proteinaceous deposits may enable the design of new strategies to counteract catheter-
associated UTI.
Recurrent UTI
Approximately 20–30% of women with acute cystitis go on to develop recurrent UTI
(rUTI), and those who do suffer on average 2–3 additional UTIs in the year following an
initial episode [2]. The subsequent UTI might arise from reinoculation of the urethra with
flora from the gastrointestinal tract, or from re-emergence of a bladder epithelial reservoir. In
a recent study, isolates from four patients with rUTI were analyzed by whole-genome
sequencing [10]. In two patients, the same UPEC clone dominated both gut and urinary tract
habitats at the initial and subsequent infection; in the other two, a new clone had established
dominance in both habitats at the time of recurrent UTI. Further, isolates causing subsequent
UTI in these patients, when introduced into mice and compared with their initial infecting
strain, exhibited increased fitness in both the gut and the urinary tract, demonstrating that
fitness in these two important niches is not mutually exclusive [10].
In a newly developed mouse model of rUTI, the C3H mouse strain – known to have
increased vesicoureteral reflux compared to C57BL/6 mice [108] – can be sensitized to
later infection. Following an initial infection (experimentally resolved by treatment with
antibiotics) and upon subsequent re-challenge with a later infection, these “sensitized” mice
were more likely than naïve mice to suffer persistent bacteriuria and chronic cystitis [62]. A
leading hypothesis for recurrent UTIs is that an exuberant inflammatory response to initial
infection causes bladder remodeling that somehow predisposes the host to recurrent
infection or more inflammatory outcomes [4, 62, 103]. This model may enable a
mechanistic understanding of apparent predisposition to recurrent infection, in turn
informing therapies that could interfere with or dampen this process.
Male and Complicated UTI
The higher prevalence of UTI in females is chiefly attributed to anatomic factors in women,
such as shorter urethral length, shorter distance from the anus to urethral meatus, and
permissiveness of the vaginal and perineal environments to microbial colonization [12, 103].
However, males at both ends of the age spectrum (mainly infants <1 year of age and elderly
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9. men with prostatic hypertrophy) exhibit a higher incidence of UTI, and other conditions in
males (diabetes, spinal cord injury, catheter use) also promote UTI [109]. Among
individuals with upper-tract UTI (pyelonephritis), males exhibit greater morbidity and
mortality than females [110], suggesting that non-anatomical differences may be at work in
these more severe infections.
Until recently, essentially all cystitis and pyelonephritis studies have been performed in
female mice, as the male mouse bladder is not reliably accessible by catheter. Of note,
instillation of uropathogens into the urethra of male mice elicits prostatic infection [111,
112]. In a recently developed, new model of UTI, a small abdominal incision is made and
bacteria are inoculated via needle into the bladders of male and female mice, permitting
direct sex comparisons [113]. This inoculation method recapitulates the IBC cascade of
acute cystitis established in studies with catheter-infected females. Interestingly, once
anatomic barriers are bypassed in this way, male mice experience more severe infection than
females, mirroring epidemiologic data observed clinically in men; indeed, male C3H mice
uniformly develop severe pyelonephritis and renal abscesses that are seen much less
frequently in female mice [113]. This new model opens doors to study sex differences in
UTI pathogenesis and host response, as well as sequelae of severe pyelonephritis and
abscess formation; these latter phenotypes are relevant to febrile UTI in children, following
which renal scarring is a common complication.
Concluding Remarks
Urinary tract infections continue to be among the most common bacterial infections in
humans, drawing millions of antibiotic prescriptions annually. Available therapies have not
evolved significantly in recent years, do not prevent recurrences, and are challenged by
rising antibiotic resistance. Creative approaches to treatment, including the development of
antivirulence therapeutics, should be prioritized (see Outstanding Questions and Box 2). In
addition, the field lacks a thorough understanding of protective host immunity related to
UTI, if such is generated after natural infection (especially pyelonephritis) or can be elicited
via vaccination. Given the broad range of organisms that can cause UTI and the unavoidable
nature of some risk factors (e.g., urinary catheters), even highly effective novel interventions
will not completely mitigate the impact of these infections on human health. However, the
common pathogenic themes in Gram-negative community-onset UTI make this subset of
infections a particularly important epidemiologic target.
Acknowledgments
This work was supported by the National Institutes of Health (P50-DK064540) and by the Mr. and Mrs. Spencer T.
Olin Fellowship for Women in Graduate Study (to L.K.M.)
GLOSSARY
Cathelicidin
A class of antimicrobial peptide; there is a single cathelicidin encoded in the human and
mouse genomes
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10. Chaperone-usher pathway
A broadly conserved molecular paradigm for Gram-negative bacterial secretion of polymeric
surface structures, including pili
Cyclooxygenase-2 (COX-2)
A mammalian enzyme expressed in many cell types that promotes generation of
immunostimulatory molecules including prostaglandins
Cystitis
Bacterial infection of the urinary bladder
Cytotoxic necrotizing factor 1 (CNF1)
A secreted UPEC toxin that causes cell death to neutrophils and other leukocytes
Defensins
A broad class of antimicrobial peptides, some of which are also secreted in the urinary tract,
especially during infection
Exfoliation
Shedding of the superficial epithelial layer of the bladder
Flagella
Whiplike surface structures, produced by many UPEC, that propel the organism in
swimming motility
Gram-negative
A large subset of bacteria, including pathogenic and nonpathogenic species, possessing an
outer membrane and periplasmic space outside of the cell membrane; so called because they
do not retain the purple crystal violet during the Gram staining procedure
α-Hemolysin
A multifunctional secreted toxin of UPEC and other pathogenic bacteria
Intracellular bacterial communities (IBCs)
Biofilm-like collections of UPEC residing within superficial epithelial cells of the bladder
Mannoside
A small molecule derived from mannose that serves as a high-affinity ligand for FimH, the
adhesive subunit of type 1 pili
Microbiome
An ecological community of commensal, symbiotic, and pathogenic organisms occupying a
body space
NF-κB pathway
A major transcriptional pathway regulating inflammation and apoptosis, stimulated by
activation of Toll-like receptors and other host cell sensors
P pili
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11. Heteropolymeric surface structures expressed by some uropathogenic Escherichia coli
strains and associated with adherence to kidney epithelium in some hosts
Pilicide
A small molecule designed to interrupt the function of the chaperone promoting pilus
assembly
Pyelonephritis
Bacterial infection of the kidney(s)
Quiescent intracellular reservoir
Chronically resident UPEC that persist in bladder tissue following resolution of acute
cystitis, and may represent a seed for recurrent cystitis
Renal abscess
A large collection of neutrophilic pus surrounding a nidus of bacterial infection in the kidney
parenchyma
Siderophore
A bacterial protein with high affinity for iron; secreted from bacteria and re-internalized
once it captures iron from the host
Type 1 pili
Hairlike, adhesive, heteropolymeric surface structures expressed by uropathogenic
Escherichia coli that mediate binding to bladder epithelium
Type III secretion system
A specialized, multi-component protein complex assembled by certain pathogenic Gram-
negative bacteria (e.g., Salmonella) to accomplish delivery of effector proteins directly into
host cells
UPEC
Uropathogenic Escherichia coli, the most common bacterial cause of urinary tract infection
Uroplakins
Mannosylated proteins decorating the apical surfaces of superficial bladder epithelial cells,
providing a permeability barrier but also offering binding sites for UPEC and other
uropathogens
UTI
Urinary tract infections, comprising cystitis, pyelonephritis, renal abscess, urethritis, and
prostatitis
Vesicoureteral reflux
Movement of urine in a retrograde direction from the bladder to the renal pelvis and
collecting system
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18. Box 1
The Clinician’s Corner
• Common uropathogenic bacteria, including Escherichia coli, multiply
within the cytoplasm of bladder epithelial cells during acute cystitis.
• In relevant animal models, oral antibiotic therapy for acute cystitis does
not completely eradicate E. coli from bladder tissue, perhaps enabling
same-strain recurrent cystitis.
• New therapeutics currently in development aim to target adhesive
surface factors of E. coli, such as pili; vaccine targets including pili,
siderophores and toxins are also being studied.
• The bladder, rather than representing a sterile environment, may in fact
host a “urinary microbiome” of commensal organisms that may
influence UTI and other symptomatic urinary tract conditions.
• Recent laboratory advances now permit the modeling of recurrent UTI,
ascending renal abscess formation, and catheter-associated UTI in
mice.
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19. Box 2
The Future of UTI Diagnostics
For decades, the diagnosis of UTI has relied on culturing urine samples and looking
under the microscope for the presence of white blood cells. Providers also utilize point-
of-care dipstick tests to search for the presence of leukocyte esterase, nitrites, and other
compounds. Even in combination with careful symptom history and risk factor
ascertainment, these tests offer only 50–85% sensitivity and 80–90% specificity [114].
Further, community diagnosis of UTI is typically made on clean-catch urine samples,
raising the possibility of contamination and rendering some positive cultures difficult to
interpret (including “false-positives”). In the age of “omics,” widespread mass
spectroscopy, point-of-care molecular detection, bacterial genomic sequencing, and other
tools, the time is right to move towards better UTI diagnostics. These might rely on a
combination of host immune and metabolic markers, as well as on the detection of
uropathogens and their components (DNA, proteins, etc.). For example, if sample
preparation challenges could be circumvented, direct mass spectrometry on infected urine
might be useful, detecting bacteria promptly in urine without the need to wait for growth
on solid media [115]. Alternatively, rapid molecular identification of E. coli at the
substrain level, as well as prediction of antibiotic resistances, might enable more efficient
selection of antibiotics for treatment [116, 117]. Ultimately, improved and accurate
diagnostics for UTI should translate into more satisfying care for patients, less frustration
and speculation on the part of providers, and an overall reduction in antibiotic use.
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20. Outstanding Questions Box
• How does UPEC, upon internalization into the superficial epithelial
cell in the bladder, escape from the endocytic vesicle into the
cytoplasm to form the IBC? A molecular understanding of this
apparently critical step in acute cystitis might illuminate a novel
bacterial strategy for intracellular pathogenesis, as well as informing
new targets for intervention.
• Do antimicrobial peptides provide primarily an antimicrobial or
immunemodulating role during UTI? Many of these peptide species
are secreted into the urinary space, especially upon infection; the
immunostimulatory effects of these peptides may be more important
than their direct antibacterial activity.
• What elicits adaptive immunity to uropathogenic bacteria, and can
such immunity help to protect the bladder? Highly expressed
bacterial targets such as pili and siderophores are enticing vaccine
candidates, but a larger question is whether traditional humoral
immunity has a significant role in protecting the bladder lumen.
• How does biological sex and associated hormonal milieu influence
the outcomes of infection? UTIs are considered a disease of women,
but significant male populations are susceptible and may exhibit higher
morbidity. Male UTI has been largely ignored in preclinical studies but
can now be addressed with updated models.
• How can we better understand the biological basis of susceptibility
to recurrent cystitis? This is perhaps the most frustrating clinical
problem, affecting millions of otherwise healthy women, and remains
unresolved with current treatments and lifestyle changes.
• What can be done therapeutically in the face of emerging
multidrug-resistant UPEC isolates? Advanced diagnostics with
improved performance characteristics, and available at the point of
care, will allow for more accurate selection of empiric therapy (when
indicated). Molecular detection methods may allow earlier
identification of multidrug-resistant isolates that may require parenteral
or inpatient treatment.
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21. Trends Box
• Mouse and human studies have revealed that during acute cystitis,
Escherichia coli and other Gram-negative uropathogens can occupy the
cytoplasm of bladder epithelial cells, using this niche as a haven for
replication while protected from infiltrating neutrophils.
• Novel therapeutics for UTI are being explored, based on detailed
molecular and structural information of bacterial virulence factor
expression, as well as patterns of bacterial binding to urinary
epithelium, iron acquisition, and other pathogenic processes.
• Highly expressed and immunogenic bacterial factors, including
siderophores, have been identified in rodent models, potentially
informing the development of vaccines and immunotherapies for UTI.
However, the putative role of adaptive immunity in control of lower
urinary tract infection remains unclear.
• Though the urinary tract is traditionally considered to be sterile,
advances in metagenomics and other technologies have enabled the
first definitions of a “urinary microbiome,” which may alter the way in
which we think about UTI (e.g., as dysbiosis, rather than simply
introduction of one pathogenic species).
• Technical advances in mouse models now permit detailed modeling of
complicated UTI syndromes common in humans – recurrent UTI,
catheter-associated UTI, UTI in the male host, and ascending renal
abscess formation.
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22. Figure 1. Clinical Features and Virulence Mechanisms in Cystitis and Pyelonephritis
UTIs can present clinically in a variety of ways, most often reflecting cystitis (infection of
the bladder) or pyelonephritis (infection of the kidney). Uropathogenic Escherichia coli
(UPEC) is the most common cause of UTI (especially among community-onset infections),
among other pathogens. Selected virulence factors associated with the pathogenesis of
UPEC cystitis or pyelonephritis are shown and include adhesins, siderophores, toxins,
siderophores, capsule, and other systems (see text for details). UT: urinary tract.
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23. Figure 2. Ribbon Representation of the Chaperone-Adhesin-Usher Complex for Assembly of
Type 1 Pili from Escherichia coli
The periplasmic chaperone FimC (green) delivers structural subunits to the outer membrane
usher (FimD, red) for assembly. Subunits shown represent the pilus tip structure and include
the adhesin FimH (purple) and adapters FimG (yellow, within the barrel of FimD) and FimF
(gray). Each subunit has its immunoglobulin-like fold completed by a strand provided by the
next subunit, in a process called donor-strand complementation (DSC). The energetic
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24. favorability provided by this final structure drives assembly on the periplasmic side of the
usher, as the periplasm is devoid of ATP. Protein Database PDB# 4J3O; adapted from [82].
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