Publications by authors named "Sheryl S Justice"

39 Publications

Acquisition, Divergence, and Personalization of the Female Perineal Microbiomes Are Driven by Developmental Milestones and Disrupted by Urinary Tract Infection: A Pilot Study.

Front Pediatr 2020 8;8:542413. Epub 2020 Dec 8.

Center for Microbial Pathogenesis, Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.

The pediatric perineal microbiomes inhabit a dynamic environment with changes related to diet, toileting habits, and hormonal development. We hypothesized that next-generation sequencing would reveal different perineal bacterial signatures associated with developmental milestones in premenstrual females. Furthermore, we predicted that these microbial changes would be disrupted in premenstrual females with a history of urinary tract infection (UTI). Healthy females were recruited at well-child visits. Subjects were divided into 4 developmental groups: (1) 0-3 month old newborns; (2) 4-10 month old infants transitioning to solid foods; (3) 2-6 year old toddlers peri-toilet training; and (4) 7-12 year old premenstrual girls. A separate group of females with a history of culture proven UTI and off antibiotics >1 month was also recruited. DNA was isolated from swabs of the perineum and subjected to 16S rRNA sequencing. The diversity and species changes between developmental cohorts and age matched children with history of UTI was determined. A total of 75 subjects were recruited: 15 in each group. There was a clear evolution of the perineal microbiomes with development. There was a significant microbial disruption in girls with a history of UTI, irrespective of developmental milestone age group. The periurethral/perivaginal site displayed greater changes in microbiome structure than other sites in girls with a history of UTI. This pilot study evaluates the normal microbiome of the premenstrual girl at specific developmental milestones. Although the number of children per cohort was limited to 15, we observed statistical significance corresponding with developmental milestones. This study provides the first, culture independent delineation of the development of the perineal microbiome in girls. Furthermore, the sites closest to the site of infection appear to be more sensitive to antibiotic remodeling than those more distant. The factors that remodel the perineal microbiomes and predispose females, particularly girls, to UTIs (e.g., increase in uropathogen presence, absence of protective organisms) are unclear. Identification of specific signatures that increase susceptibility to UTI and their sequelae will improve patient care and promote personalized medicine.
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http://dx.doi.org/10.3389/fped.2020.542413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752998PMC
December 2020

Neutrophil-Macrophage Imbalance Drives the Development of Renal Scarring during Experimental Pyelonephritis.

J Am Soc Nephrol 2021 Jan 4;32(1):69-85. Epub 2020 Nov 4.

Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio

Background: In children, the acute pyelonephritis that can result from urinary tract infections (UTIs), which commonly ascend from the bladder to the kidney, is a growing concern because it poses a risk of renal scarring and irreversible loss of kidney function. To date, the cellular mechanisms underlying acute pyelonephritis-driven renal scarring remain unknown.

Methods: We used a preclinical model of uropathogenic -induced acute pyelonephritis to determine the contribution of neutrophils and monocytes to resolution of the condition and the subsequent development of kidney fibrosis. We used cell-specific monoclonal antibodies to eliminate neutrophils, monocytes, or both. Bacterial ascent and the cell dynamics of phagocytic cells were assessed by biophotonic imaging and flow cytometry, respectively. We used quantitative RT-PCR and histopathologic analyses to evaluate inflammation and renal scarring.

Results: We found that neutrophils are critical to control bacterial ascent, which is in line with previous studies suggesting a protective role for neutrophils during a UTI, whereas monocyte-derived macrophages orchestrate a strong, but ineffective, inflammatory response against uropathogenic, -induced, acute pyelonephritis. Experimental neutropenia during acute pyelonephritis resulted in a compensatory increase in the number of monocytes and heightened macrophage-dependent inflammation in the kidney. Exacerbated macrophage-mediated inflammatory responses promoted renal scarring and compromised renal function, as indicated by elevated serum creatinine, BUN, and potassium.

Conclusions: These findings reveal a previously unappreciated outcome for neutrophil-macrophage imbalance in promoting host susceptibility to acute pyelonephritis and the development of permanent renal damage. This suggests targeting dysregulated macrophage responses might be a therapeutic tool to prevent renal scarring during acute pyelonephritis.
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http://dx.doi.org/10.1681/ASN.2020030362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894670PMC
January 2021

UTIGA: a new society for UTI professionals, researchers and patients.

Nat Rev Urol 2020 Jun;17(6):309-310

Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.

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http://dx.doi.org/10.1038/s41585-020-0313-0DOI Listing
June 2020

Continuous Microevolution Accelerates Disease Progression during Sequential Episodes of Infection.

Cell Rep 2020 03;30(9):2978-2988.e3

Center for Microbial Pathogenesis, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA; Infectious Disease Institute, The Ohio State University, Columbus, OH 43205, USA. Electronic address:

Bacteria adapt to dynamic changes in the host during chronic and recurrent infections. Bacterial microevolution is one type of adaptation that imparts a selective advantage. We hypothesize that recurrent episodes of disease promote microevolution through genetic mutations that modulate disease severity. We use a pre-clinical model of otitis media (OM) to determine the potential role for microevolution of nontypeable Haemophilus influenzae (NTHI) during sequential episodes of disease. Whole genome sequencing reveals microevolution of hemoglobin binding and lipooligosaccharide (LOS) biosynthesis genes, suggesting that adaptation of these systems is critical for infection. These OM-adapted strains promote increased biofilm formation, inflammation, stromal fibrosis, and an increased propensity to form intracellular bacterial communities (IBCs). Remarkably, IBCs remain for at least one month following clinical resolution of infection, suggesting an intracellular reservoir as a nidus for recurrent OM. Additional approaches for therapeutic design tailored to combat this burdensome disease will arise from these studies.
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http://dx.doi.org/10.1016/j.celrep.2020.02.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137071PMC
March 2020

Reprioritization of biofilm metabolism is associated with nutrient adaptation and long-term survival of .

NPJ Biofilms Microbiomes 2019;5(1):33. Epub 2019 Nov 5.

1The Abigail Wexner Research Institute at Nationwide Children's Hospital, Center for Microbial Pathogenesis, 700 Children's Drive, Columbus, OH 43205 USA.

Nontypeable (NTHI) is a human-restricted pathogen with an essential requirement for heme-iron acquisition. We previously demonstrated that microevolution of NTHI promotes stationary phase survival in response to transient heme-iron restriction. In this study, we examine the metabolic contributions to biofilm formation using this evolved NTHI strain, RM33. Quantitative analyses identified 29 proteins, 55 transcripts, and 31 metabolites that significantly changed within in vitro biofilms formed by RM33. The synthesis of all enzymes within the tryptophan and glycogen pathways was significantly increased in biofilms formed by RM33 compared with the parental strain. In addition, increases were observed in metabolite transport, adhesin production, and DNA metabolism. Furthermore, we observed pyruvate as a pivotal point in the metabolic pathways associated with changes in cAMP phosphodiesterase activity during biofilm formation. Taken together, changes in central metabolism combined with increased stores of nutrients may serve to counterbalance nutrient sequestration.
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http://dx.doi.org/10.1038/s41522-019-0105-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831627PMC
June 2020

Microevolution in response to transient heme-iron restriction enhances intracellular bacterial community development and persistence.

PLoS Pathog 2018 10 17;14(10):e1007355. Epub 2018 Oct 17.

The Research Institute at Nationwide Children's Hospital, Center for Microbial Pathogenesis, Columbus, Ohio, United States of America.

Bacterial pathogens must sense, respond and adapt to a myriad of dynamic microenvironmental stressors to survive. Adaptation is key for colonization and long-term ability to endure fluctuations in nutrient availability and inflammatory processes. We hypothesize that strains adapted to survive nutrient deprivation are more adept for colonization and establishment of chronic infection. In this study, we detected microevolution in response to transient nutrient limitation through mutation of icc. The mutation results in decreased 3',5'-cyclic adenosine monophosphate phosphodiesterase activity in nontypeable Haemophilus influenzae (NTHI). In a preclinical model of NTHI-induced otitis media (OM), we observed a significant decrease in the recovery of effusion from ears infected with the icc mutant strain. Clinically, resolution of OM coincides with the clearance of middle ear fluid. In contrast to this clinical paradigm, we observed that the icc mutant strain formed significantly more intracellular bacterial communities (IBCs) than the parental strain early during experimental OM. Although the number of IBCs formed by the parental strain was low at early stages of OM, we observed a significant increase at later stages that coincided with absence of recoverable effusion, suggesting the presence of a mucosal reservoir following resolution of clinical disease. These data provide the first insight into NTHI microevolution during nutritional limitation and provide the first demonstration of IBCs in a preclinical model of chronic OM.
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http://dx.doi.org/10.1371/journal.ppat.1007355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205647PMC
October 2018

Transient Nutrient Deprivation Promotes Macropinocytosis-Dependent Intracellular Bacterial Community Development.

mSphere 2018 09 12;3(5). Epub 2018 Sep 12.

Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA

Nutrient limitation restricts bacterial growth in privileged sites such as the middle ear. Transient heme-iron restriction of nontypeable (NTHI), the major causative agent of chronic and recurrent otitis media (OM), promotes new and diverse phenotypes that can influence planktonic, biofilm, and intracellular lifestyles of NTHI. However, the bacterial responses to nutrient restriction that impact intracellular fate and survival of NTHI are unknown. In this work, we provide evidence for the role of transient heme-iron restriction in promoting the formation of intracellular bacterial communities (IBCs) of NTHI both and in a preclinical model of OM. We show that transient heme-iron restriction of NTHI results in significantly increased invasion and intracellular populations that escape or evade the endolysosomal pathway for increased intracellular survival. In contrast, NTHI continuously exposed to heme-iron traffics through the endolysosomal pathway for degradation. The use of pharmacological inhibitors revealed that prior heme-iron status does not appear to influence NTHI internalization through endocytic pathways. However, inhibition of macropinocytosis altered the intracellular fate of transiently restricted NTHI for degradation in the endolysosomal pathway. Furthermore, prevention of macropinocytosis significantly reduced the number of IBCs in cultured middle ear epithelial cells, providing evidence for the feasibility of this approach to reduce OM persistence. These results reveal that microenvironmental cues can influence the intracellular fate of NTHI, leading to new mechanisms for survival during disease progression. Otitis media is the most common bacterial infection in childhood. Current therapies are limited in the prevention of chronic or recurrent otitis media which leads to increased antibiotic exposure and represents a significant socioeconomic burden. In this study, we delineate the effect of nutritional limitation on the intracellular trafficking pathways used by nontypeable (NTHI). Moreover, transient limitation of heme-iron led to the development of intracellular bacterial communities that are known to contribute to persistence and recurrence in other diseases. New approaches for therapeutic interventions that reduce the production of intracellular bacterial communities and promote trafficking through the endolysosomal pathway were revealed through the use of pharmacological inhibition of macropinocytosis. This work demonstrates the importance of an intracellular niche for NTHI and provides new approaches for intervention for acute, chronic, and recurring episodes of otitis media.
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http://dx.doi.org/10.1128/mSphere.00286-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135960PMC
September 2018

Inflammation drives renal scarring in experimental pyelonephritis.

Am J Physiol Renal Physiol 2017 01 19;312(1):F43-F53. Epub 2016 Oct 19.

Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio;

Acquired renal scarring occurs in a subset of patients following febrile urinary tract infections and is associated with hypertension, proteinuria, and chronic kidney disease. Limited knowledge of histopathology, immune cell recruitment, and gene expression changes during pyelonephritis restricts the development of therapies to limit renal scarring. Here, we address this knowledge gap using immunocompetent mice with vesicoureteral reflux. Transurethral inoculation of uropathogenic Escherichia coli in C3H/HeOuJ mice leads to renal mucosal injury, tubulointerstitial nephritis, and cortical fibrosis. The extent of fibrosis correlates most significantly with inflammation at 7 and 28 days postinfection. The recruitment of neutrophils and inflammatory macrophages to infected kidneys is proportional to renal bacterial burden. Transcriptome analysis reveals molecular signatures associated with renal ischemia-reperfusion injury, immune cell chemotaxis, and leukocyte activation. This murine model recapitulates the cardinal histopathological features observed in humans with acquired renal scarring following pyelonephritis. The integration of histopathology, quantification of cellular immune influx, and unbiased transcriptional profiling begins to define potential mechanisms of tissue injury during pyelonephritis in the context of an intact immune response. The clear relationship between inflammatory cell recruitment and fibrosis supports the hypothesis that acquired renal scarring arises as a consequence of excessive host inflammation and suggests that immunomodulatory therapies should be investigated to reduce renal scarring in patients with pyelonephritis.
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http://dx.doi.org/10.1152/ajprenal.00471.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5283888PMC
January 2017

Comparison of the microbiological milieu of patients randomized to either hydrophilic or conventional PVC catheters for clean intermittent catheterization.

J Pediatr Urol 2016 Jun 18;12(3):172.e1-8. Epub 2016 Feb 18.

Center for Microbial Pathogenesis at The Research Institute at Nationwide Children's Hospital, Nationwide Children's Hospital, Columbus, OH, USA; Department of Urology, College of Medicine, The Ohio State University, Columbus, OH, USA.

Introduction: Control of bacteriuria is problematic in patients who perform clean intermittent catheterization for management of neurogenic bladder. This population is often burdened with multiple urinary tract infections (UTIs), placing them at increased risk of end-stage renal disease. Hydrophilic catheters are a potential way to improve smooth and clean insertion, reduce disruption of the urothelium, and reduce bacterial colonization.

Objective: The goal of the study was to compare the type and virulence of microorganisms recovered from the urine of patients that use either a hydrophilic or conventional polyvinyl chloride (PVC) catheter.

Methods: Fifty patients with an underlying diagnosis of myelomeningocele were recruited for a 12-month prospective, randomized, investigator-blinded study. Twenty-five patients were allocated to the hydrophilic catheter intervention, and 25 continued use of a PVC catheter. Cultures were performed on urine obtained by catheterization at enrollment, and 3, 6, and 12 months. Bacterial species were assigned a designation as either potentially pathogenic or non-pathogenic. Escherichia coli isolates were the most predominant and were serotyped to further stratify the pathogenicity of the strains. Lastly, patients were surveyed at enrollment, and at the two later time points evaluating their current catheter for satisfaction.

Results: A total of 232 different bacterial isolates were obtained from the 182 collected urine cultures. In addition, seven species were recovered from the two UTI reported during the study period. Bacterial growth was not detected in 29 of the samples (16%). Although not statistically significant, collectively there was a 40% decrease in the average number of potentially pathogenic species recovered from those patients using hydrophilic catheters (0.81 per urine sample) compared with PVC catheter use (1.24 per urine sample). Since E. coli species can be either pathogenic or non-pathogenic, we examined 14 of the most commonly implicated serotypes associated with uropathogenic E. coli (UPEC). We identified the serotype of 57% of E. coli strains recovered. There was a trend for the recovery of fewer UPEC serotypes from the hydrophilic group (54% hydrophilic verses 64% PVC), further suggesting that the catheter type may influence the microbiological milieu. Although no significant differences were reported in patient satisfaction, almost half of the patients from the hydrophilic catheter cohort continue use of this type of catheter.

Conclusions: There was a trend for reduced recovery of potentially pathogenic bacteria with the use of hydrophilic catheters. The reduction in potentially pathogenic species will reduce antibiotic exposures and some patients may prefer the comfort hydrophilic catheters provide.
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http://dx.doi.org/10.1016/j.jpurol.2015.12.012DOI Listing
June 2016

Association of O-Antigen Serotype with the Magnitude of Initial Systemic Cytokine Responses and Persistence in the Urinary Tract.

J Bacteriol 2016 Jan 11;198(6):964-72. Epub 2016 Jan 11.

The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA The Ohio State University School of Medicine, Columbus, Ohio, USA

Unlabelled: Urinary tract infection (UTI) is one of the most common ailments requiring both short-term and prophylactic antibiotic therapies. Progression of infection from the bladder to the kidney is associated with more severe clinical symptoms (e.g., fever and vomiting) as well as with dangerous disease sequelae (e.g., renal scaring and sepsis). Host-pathogen interactions that promote bacterial ascent to the kidney are not completely understood. Prior studies indicate that the magnitude of proinflammatory cytokine elicitation in vitro by clinical isolates of uropathogenic Escherichia coli (UPEC) inversely correlates with the severity of clinical disease. Therefore, we hypothesize that the magnitude of initial proinflammatory responses during infection defines the course and severity of disease. Clinical UPEC isolates obtained from patients with a nonfebrile UTI elicited high systemic proinflammatory responses early during experimental UTI in a murine model and were attenuated in bladder and kidney persistence. Conversely, UPEC isolates obtained from patients with febrile UTI elicited low systemic proinflammatory responses early during experimental UTI and exhibited prolonged persistence in the bladder and kidney. Soluble factors in the supernatant from saturated cultures as well as the lipopolysaccharide (LPS) serotype correlated with the magnitude of proinflammatory responses in vitro. Our data suggest that the structure of the O-antigen sugar moiety of the LPS may determine the strength of cytokine induction by epithelial cells. Moreover, the course and severity of disease appear to be the consequence of the magnitude of initial cytokines produced by the bladder epithelium during infection.

Importance: The specific host-pathogen interactions that determine the extent and course of disease are not completely understood. Our studies demonstrate that modest changes in the magnitude of cytokine production observed using in vitro models of infection translate into significant ramifications for bacterial persistence and disease severity. While many studies have demonstrated that modifications of the LPS lipid A moiety modulate the extent of Toll-like receptor 4 (TLR4) activation, our studies implicate the O-antigen sugar moiety as another potential rheostat for the modulation of proinflammatory cytokine production.
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http://dx.doi.org/10.1128/JB.00664-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772593PMC
January 2016

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment.

Mol Cell Proteomics 2016 Mar 28;15(3):1117-38. Epub 2015 Dec 28.

From the ‡The Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43205; §The Center for Microbial Interface Biology and Department of Pediatrics, The Ohio State University, Columbus, Ohio 43210;

A thorough understanding of the molecular details of the interactions between bacteria and host are critical to ultimately prevent disease. Recent technological advances allow simultaneous analysis of host and bacterial protein and metabolic profiles from a single small tissue sample to provide insight into pathogenesis. We used the chinchilla model of human otitis media to determine, for the first time, the most expansive delineation of global changes in protein and metabolite profiles during an experimentally induced disease. After 48 h of infection with nontypeable Haemophilus influenzae, middle ear tissue lysates were analyzed by high-resolution quantitative two-dimensional liquid chromatography-tandem mass spectrometry. Dynamic changes in 105 chinchilla proteins and 66 metabolites define the early proteomic and metabolomic signature of otitis media. Our studies indicate that establishment of disease coincides with actin morphogenesis, suppression of inflammatory mediators, and bacterial aerobic respiration. We validated the observed increase in the actin-remodeling complex, Arp2/3, and experimentally showed a role for Arp2/3 in nontypeable Haemophilus influenzae invasion. Direct inhibition of actin branch morphology altered bacterial invasion into host epithelial cells, and is supportive of our efforts to use the information gathered to modify outcomes of disease. The twenty-eight nontypeable Haemophilus influenzae proteins identified participate in carbohydrate and amino acid metabolism, redox homeostasis, and include cell wall-associated metabolic proteins. Quantitative characterization of the molecular signatures of infection will redefine our understanding of host response driven developmental changes during pathogenesis. These data represent the first comprehensive study of host protein and metabolite profiles in vivo in response to infection and show the feasibility of extensive characterization of host protein profiles during disease. Identification of novel protein targets and metabolic biomarkers will advance development of therapeutic and diagnostic options for treatment of disease.
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http://dx.doi.org/10.1074/mcp.M115.052498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4813693PMC
March 2016

Intracellular Bacterial Communities: A Potential Etiology for Chronic Lower Urinary Tract Symptoms.

Urology 2015 Sep 15;86(3):425-31. Epub 2015 Jul 15.

Department of Urology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA.

Patients with persistent lower urinary tract symptoms and negative urine cultures are often difficult to treat. Infection may go undetected in these patients because the concentrations of bacteria in their urine are beneath the threshold of standard urine culture techniques. Empiric treatment may result in temporary relief, followed by recurrent symptoms. Occult and recurrent urinary tract infection may be due to both invasion of the bladder wall by uropathogenic Escherichia coli and the formation of biofilm-like intracellular bacterial communities. This review examines emerging evidence for a role of intracellular bacterial communities in human infection.
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http://dx.doi.org/10.1016/j.urology.2015.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617679PMC
September 2015

DNABII proteins play a central role in UPEC biofilm structure.

Mol Microbiol 2015 Jun 16;96(6):1119-35. Epub 2015 Apr 16.

Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, 43205, USA.

Most chronic and recurrent bacterial infections involve a biofilm component, the foundation of which is the extracellular polymeric substance (EPS). Extracellular DNA (eDNA) is a conserved and key component of the EPS of pathogenic biofilms. The DNABII protein family includes integration host factor (IHF) and histone-like protein (HU); both are present in the extracellular milieu. We have shown previously that the DNABII proteins are often found in association with eDNA and are critical for the structural integrity of bacterial communities that utilize eDNA as a matrix component. Here, we demonstrate that uropathogenic Escherichia coli (UPEC) strain UTI89 incorporates eDNA within its biofilm matrix and that the DNABII proteins are not only important for biofilm growth, but are limiting; exogenous addition of these proteins promotes biofilm formation that is dependent on eDNA. In addition, we show that both subunits of IHF, yet only one subunit of HU (HupB), are critical for UPEC biofilm development. We discuss the roles of these proteins in context of the UPEC EPS.
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http://dx.doi.org/10.1111/mmi.12994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464964PMC
June 2015

Bacterial differentiation, development, and disease: mechanisms for survival.

FEMS Microbiol Lett 2014 Nov 1;360(1):1-8. Epub 2014 Oct 1.

Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA; The Ohio State University School of Medicine, Columbus, OH, USA.

Bacteria have the exquisite ability to maintain a precise diameter, cell length, and shape. The dimensions of bacteria size and shape are a classical metric in the distinction of bacterial species. Much of what we know about the particular morphology of any given species is the result of investigations of planktonic cultures. As we explore deeper into the natural habitats of bacteria, it is increasingly clear that bacteria can alter their morphology in response to the environment in which they reside. Specific morphologies are also becoming recognized as advantageous for survival in hostile environments. This is of particular importance in the context of both colonization and infection in the host. There are multiple examples of bacterial pathogens that use morphological changes as a mechanism for evasion of host immune responses and continued persistence. This review will focus on two systems where specific morphological changes are essential for persistence in animal models of human disease. We will also offer insight into the mechanism underlying the morphological changes and how these morphotypes aid in persistence. Additional examples of morphological changes associated with survival will be presented.
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http://dx.doi.org/10.1111/1574-6968.12602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227932PMC
November 2014

Expression and antimicrobial function of beta-defensin 1 in the lower urinary tract.

PLoS One 2013 21;8(10):e77714. Epub 2013 Oct 21.

Section of Nephrology, Nationwide Children's Hospital, Columbus, Ohio, United States of America ; Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.

Beta defensins (BDs) are cationic peptides with antimicrobial activity that defend epithelial surfaces including the skin, gastrointestinal, and respiratory tracts. However, BD expression and function in the urinary tract are incompletely characterized. The purpose of this study was to describe Beta Defensin-1 (BD-1) expression in the lower urinary tract, regulation by cystitis, and antimicrobial activity toward uropathogenic Escherichia coli (UPEC) in vivo. Human DEFB1 and orthologous mouse Defb1 mRNA are detectable in bladder and ureter homogenates, and human BD-1 protein localizes to the urothelium. To determine the relevance of BD-1 to lower urinary tract defense in vivo, we evaluated clearance of UPEC by Defb1 knockout (Defb1(-/-)) mice. At 6, 18, and 48 hours following transurethral UPEC inoculation, no significant differences were observed in bacterial burden in bladders or kidneys of Defb1(-/-) and wild type C57BL/6 mice. In wild type mice, bladder Defb1 mRNA levels decreased as early as two hours post-infection and reached a nadir by six hours. RT-PCR profiling of BDs identified expression of Defb3 and Defb14 mRNA in murine bladder and ureter, which encode for mBD-3 and mBD-14 protein, respectively. MBD-14 protein expression was observed in bladder urothelium following UPEC infection, and both mBD-3 and mBD-14 displayed dose-dependent bactericidal activity toward UPEC in vitro. Thus, whereas mBD-1 deficiency does not alter bladder UPEC burden in vivo, we have identified mBD-3 and mBD-14 as potential mediators of mucosal immunity in the lower urinary tract.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0077714PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804605PMC
August 2014

Haemophilus responses to nutritional immunity: epigenetic and morphological contribution to biofilm architecture, invasion, persistence and disease severity.

PLoS Pathog 2013 10;9(10):e1003709. Epub 2013 Oct 10.

The Research Institute at Nationwide Children's, Center for Microbial Pathogenesis, Columbus, Ohio, United States of America.

In an effort to suppress microbial outgrowth, the host sequesters essential nutrients in a process termed nutritional immunity. However, inflammatory responses to bacterial insult can restore nutritional resources. Given that nutrient availability modulates virulence factor production and biofilm formation by other bacterial species, we hypothesized that fluctuations in heme-iron availability, particularly at privileged sites, would similarly influence Haemophilus biofilm formation and pathogenesis. Thus, we cultured Haemophilus through sequential heme-iron deplete and heme-iron replete media to determine the effect of transient depletion of internal stores of heme-iron on multiple pathogenic phenotypes. We observed that prior heme-iron restriction potentiates biofilm changes for at least 72 hours that include increased peak height and architectural complexity as compared to biofilms initiated from heme-iron replete bacteria, suggesting a mechanism for epigenetic responses that participate in the changes observed. Additionally, in a co-infection model for human otitis media, heme-iron restricted Haemophilus, although accounting for only 10% of the inoculum (90% heme-iron replete), represented up to 99% of the organisms recovered at 4 days. These data indicate that fluctuations in heme-iron availability promote a survival advantage during disease. Filamentation mediated by a SulA-related ortholog was required for optimal biofilm peak height and persistence during experimental otitis media. Moreover, severity of disease in response to heme-iron restricted Haemophilus was reduced as evidenced by lack of mucosal destruction, decreased erythema, hemorrhagic foci and vasodilatation. Transient restriction of heme-iron also promoted productive invasion events leading to the development of intracellular bacterial communities. Taken together, these data suggest that nutritional immunity, may, in fact, foster long-term phenotypic changes that better equip bacteria for survival at infectious sites.
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http://dx.doi.org/10.1371/journal.ppat.1003709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795038PMC
May 2014

An endogenous ribonuclease inhibitor regulates the antimicrobial activity of ribonuclease 7 in the human urinary tract.

Kidney Int 2014 May 9;85(5):1179-91. Epub 2013 Oct 9.

1] Division of Nephrology, Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio, USA [2] Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA [3] Kidney Innate Immunity Research Group, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.

Recent studies stress the importance of antimicrobial peptides in protecting the urinary tract from infection. Previously, we have shown that ribonuclease 7 (RNase 7) is a potent antimicrobial peptide that has a broad-spectrum antimicrobial activity against uropathogenic bacteria. The urothelium of the lower urinary tract and intercalated cells of the kidney produce RNase 7, but regulation of its antimicrobial activity has not been well defined. Here, we characterize the expression of an endogenous inhibitor, ribonuclease inhibitor (RI), in the urinary tract and evaluate its effect on the antimicrobial activity of RNase 7. Using RNA isolated from non-infected human bladder and kidney tissue, quantitative real-time polymerase chain reaction showed that RNH1, the gene encoding RI, is constitutively expressed throughout the urinary tract. With pyelonephritis, RNH1 expression and RI peptide production significantly decrease. Immunostaining localized RI production to the umbrella cells of the bladder and intercalated cells of the renal collecting tubule. In vitro assays showed that RI bound to RNase 7 and suppressed its antimicrobial activity by blocking its ability to bind the cell wall of uropathogenic bacteria. Thus, these results demonstrate a new immunomodulatory role for RI and identified a unique regulatory pathway that may affect how RNase 7 maintains urinary tract sterility.
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http://dx.doi.org/10.1038/ki.2013.395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981961PMC
May 2014

Aberrant community architecture and attenuated persistence of uropathogenic Escherichia coli in the absence of individual IHF subunits.

PLoS One 2012 25;7(10):e48349. Epub 2012 Oct 25.

Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.

Uropathogenic Escherichia coli (UPEC) utilizes a complex community-based developmental pathway for growth within superficial epithelial cells of the bladder during cystitis. Extracellular DNA (eDNA) is a common matrix component of organized bacterial communities. Integration host factor (IHF) is a heterodimeric protein that binds to double-stranded DNA and produces a hairpin bend. IHF-dependent DNA architectural changes act both intrabacterially and extrabacterially to regulate gene expression and community stability, respectively. We demonstrate that both IHF subunits are required for efficient colonization of the bladder, but are dispensable for early colonization of the kidney. The community architecture of the intracellular bacterial communities (IBCs) is quantitatively different in the absence of either IhfA or IhfB in the murine model for human urinary tract infection (UTI). Restoration of Type 1 pili by ectopic production does not restore colonization in the absence of IhfA, but partially compensates in the absence of IhfB. Furthermore, we describe a binding site for IHF that is upstream of the operon that encodes for the P-pilus. Taken together, these data suggest that both IHF and its constituent subunits (independent of the heterodimer), are able to participate in multiple aspects of the UPEC pathogenic lifestyle, and may have utility as a target for treatment of bacterial cystitis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0048349PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3485042PMC
May 2013

SapF-mediated heme-iron utilization enhances persistence and coordinates biofilm architecture of Haemophilus.

Front Cell Infect Microbiol 2012 3;2:42. Epub 2012 Apr 3.

Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, The Ohio State University School of Medicine, Columbus OH, USA.

Non-typeable Haemophilus influenzae (NTHI) is a common commensal bacterium that resides in the human upper respiratory tract of healthy individuals. NTHI is also a known causative agent of multiple diseases including sinusitis, otitis media, as well as exacerbates disease severity of patients with cystic fibrosis and chronic obstructive pulmonary disease. We have previously shown that the Sap transporter mediates resistance to host antimicrobial peptides (AMPs) and import of the iron-containing compound heme. Here, we analyzed the contribution of the Sap structural ATPase protein, SapF, in these essential functions. In contrast to SapD, SapF was dispensable for NTHI survival when exposed to AMPs in vitro. SapF was responsible for heme utilization and recovery of depleted internal heme-iron stores. Further, a loss of SapF resulted in morphological plasticity and enhanced community development and biofilm architecture, suggesting the potential role of heme-iron availability in coordinating the complexity of NTHI biofilm architecture. SapF was required for colonization of the nasopharynx and acute infection of the middle ear, as SapF deficiency correlated with a statistically significant decrease in NTHI persistence in vivo. These data suggest that SapF is required for proper heme utilization which directly impacts NTHI survival. Thus, these studies further support a role for the Sap complex in the transport of multiple substrates and further defines substrate specificity for the two ATPase subunits. Given the multiple essential functions provided by the Sap transporter, this complex could prove to be an effective therapeutic target for the treatment of NTHI diseases.
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http://dx.doi.org/10.3389/fcimb.2012.00042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3417626PMC
December 2013

New paradigms of urinary tract infections: Implications for patient management.

Indian J Urol 2012 Apr;28(2):154-8

Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.

Urinary tract infections (UTIs) represent one of the most commonly acquired diseases among the general population as well as hospital in-patients, yet remain difficult to effectively and consistently treat. High rates of recurrence, anatomic abnormalities, and functional disturbances of the urinary tract all contribute to the difficulty in management of these infections. However, recent advances reveal important molecular and genetic factors that contribute to bacterial invasion and persistence in the urinary tract, particularly for the most common causative agent, uropathogenic Escherichia coli. Recent studies using animal models of experimental UTIs have recently provided mechanistic insight into the clinical observations that question the effectiveness of antibiotic therapy in treatment. Ultimately, continuing research will be necessary to identify the best targets for effective treatment of this costly and widespread infectious disease.
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http://dx.doi.org/10.4103/0970-1591.98455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3424889PMC
April 2012

Relationship among bacterial virulence, bladder dysfunction, vesicoureteral reflux and patterns of urinary tract infection in children.

J Urol 2012 Jul 15;188(1):236-41. Epub 2012 May 15.

Department of Urology, Naval Medical Center, San Diego, California 92134-5000, USA.

Purpose: We hypothesized that virulence levels of Escherichia coli isolates causing pediatric urinary tract infections differ according to severity of infection and also among various uropathies known to contribute to pediatric urinary tract infections. We evaluated these relationships using in vitro cytokine interleukin-6 elicitation.

Materials And Methods: E. coli isolates were cultured from children presenting with urinary tract infections. In vitro cytokine (interleukin-6) elicitation was quantified for each isolate and the bacteria were grouped according to type of infection and underlying uropathy (neurogenic bladder, nonneurogenic bowel and bladder dysfunction, primary vesicoureteral reflux, no underlying etiology).

Results: A total of 40 E. coli isolates were collected from children with a mean age of 61.5 months (range 1 to 204). Mean level of in vitro cytokine elicitation from febrile urinary tract infection producing E. coli was significantly lower than for nonfebrile strains (p = 0.01). The interleukin-6 response to E. coli in the neurogenic bladder group was also significantly higher than in the vesicoureteral reflux (p = 0.01) and no underlying etiology groups (p = 0.02).

Conclusions: In vitro interleukin-6 elicitation, an established marker to determine bacterial virulence, correlates inversely with clinical urinary tract infection severity. Less virulent, high cytokine producing E. coli were more likely to cause cystitis and were more commonly found in patients with neurogenic bladder and nonneurogenic bowel and bladder dysfunction, whereas higher virulence isolates were more likely to produce febrile urinary tract infections and to affect children with primary vesicoureteral reflux and no underlying etiology. These findings suggest that bacteria of different virulence levels may be responsible for differences in severity of pediatric urinary tract infections and may vary among different underlying uropathies.
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http://dx.doi.org/10.1016/j.juro.2012.03.025DOI Listing
July 2012

Intrauterine growth restriction is a direct consequence of localized maternal uropathogenic Escherichia coli cystitis.

PLoS One 2012 21;7(3):e33897. Epub 2012 Mar 21.

Section of Infectious Diseases, Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio, United States of America.

Despite the continually increasing rates of adverse perinatal outcomes across the globe, the molecular mechanisms that underlie adverse perinatal outcomes are not completely understood. Clinical studies report that 10% of pregnant women will experience a urinary tract infection (UTI) and there is an association of UTIs with adverse perinatal outcomes. We introduced bacterial cystitis into successfully outbred female mice at gestational day 14 to follow pregnancy outcomes and immunological responses to determine the mechanisms that underlie UTI-mediated adverse outcomes. Outbred fetuses from mothers experiencing localized cystitis displayed intrauterine growth restriction (20-80%) as early as 48 hours post-infection and throughout the remainder of normal gestation. Robust infiltration of cellular innate immune effectors was observed in the uteroplacental tissue following introduction of UTI despite absence of viable bacteria. The magnitude of serum proinflammatory cytokines is elevated in the maternal serum during UTI. This study demonstrates that a localized infection can dramatically impact the immunological status as well as the function of non-infected distal organs and tissues. This model can be used as a platform to determine the mechanism(s) by which proinflammatory changes occur between non-contiguous genitourinary organs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0033897PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309957PMC
August 2012

UPEC hemolysin: more than just for making holes.

Cell Host Microbe 2012 Jan;11(1):4-5

Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.

During acute cystitis, uropathogenic Escherichia coli (UPEC) induce bladder epithelial cell exfoliation, which eliminates infected cells and promotes UPEC dissemination. Dhakal and Mulvey (2012) uncover the mechanism that induces this exfoliation and reintroduce the pore-forming toxin, hemolysin, as an effector that surprisingly targets multiple host pathways to facilitate infection.
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http://dx.doi.org/10.1016/j.chom.2012.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267088PMC
January 2012

In vitro analysis of the bactericidal activity of Escherichia coli Nissle 1917 against pediatric uropathogens.

J Urol 2011 Oct 19;186(4 Suppl):1678-83. Epub 2011 Aug 19.

Department of Urology, Naval Medical Center, San Diego, California 92134-5000, USA.

Purpose: The usefulness of prophylactic antibiotics to prevent recurrent urinary tract infections in children was recently questioned. Some groups have attempted to use probiotics, most commonly lactobacillus, to prevent recurrent infections by altering the intestinal bacterial reservoir with variable results. Mutaflor® is a possible alternative probiotic in which the active agent is Nissle 1917. Nissle 1917 is a commensal Escherichia coli strain that eradicates pathogenic bacteria from the gastrointestinal tract. Due to its ability to alter the intestinal biome we hypothesized that Mutaflor may have the potential to prevent recurrent urinary tract infections. Thus, we used an in vitro assay to analyze the effectiveness of Nissle 1917 for eradicating pediatric uropathogens.

Materials And Methods: We established a collection of 43 bacterial pediatric uropathogens. With each isolate a microcin-type assay was performed to determine the effectiveness of Nissle 1917 on bacterial growth inhibition and competitive overgrowth.

Results: Nissle 1917 adversely affected the growth of 34 of the 43 isolates (79%) isolates. It inhibited the growth of 21 isolates and overgrew 13. The percent of species adversely affected by Nissle 1917 was 40% for Pseudomonas, 50% for E. coli, Enterococcus and Staphylococcus, 100% for Klebsiella and Enterobacter, and 0% for Citrobacter and Serratia.

Conclusions: Nissle 1917, the active agent in Mutaflor, inhibited or out competed most bacterial isolates. These mechanisms could be used in vivo to eradicate uropathogens from the gastrointestinal tract. Further study is needed to determine whether Mutaflor can prevent recurrent urinary tract infections in children.
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http://dx.doi.org/10.1016/j.juro.2011.04.021DOI Listing
October 2011

FIND: a new software tool and development platform for enhanced multicolor flow analysis.

BMC Bioinformatics 2011 May 10;12:145. Epub 2011 May 10.

Biophysics Program, The Ohio State University, Columbus, Ohio, USA.

Background: Flow Cytometry is a process by which cells, and other microscopic particles, can be identified, counted, and sorted mechanically through the use of hydrodynamic pressure and laser-activated fluorescence labeling. As immunostained cells pass individually through the flow chamber of the instrument, laser pulses cause fluorescence emissions that are recorded digitally for later analysis as multidimensional vectors. Current, widely adopted analysis software limits users to manual separation of events based on viewing two or three simultaneous dimensions. While this may be adequate for experiments using four or fewer colors, advances have lead to laser flow cytometers capable of recording 20 different colors simultaneously. In addition, mass-spectrometry based machines capable of recording at least 100 separate channels are being developed. Analysis of such high-dimensional data by visual exploration alone can be error-prone and susceptible to unnecessary bias. Fortunately, the field of Data Mining provides many tools for automated group classification of multi-dimensional data, and many algorithms have been adapted or created for flow cytometry. However, the majority of this research has not been made available to users through analysis software packages and, as such, are not in wide use.

Results: We have developed a new software application for analysis of multi-color flow cytometry data. The main goals of this effort were to provide a user-friendly tool for automated gating (classification) of multi-color data as well as a platform for development and dissemination of new analysis tools. With this software, users can easily load single or multiple data sets, perform automated event classification, and graphically compare results within and between experiments. We also make available a simple plugin system that enables researchers to implement and share their data analysis and classification/population discovery algorithms.

Conclusions: The FIND (Flow Investigation using N-Dimensions) platform presented here provides a powerful, user-friendly environment for analysis of Flow Cytometry data as well as providing a common platform for implementation and distribution of new automated analysis techniques to users around the world.
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http://dx.doi.org/10.1186/1471-2105-12-145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119067PMC
May 2011

Ribonuclease 7 is a potent antimicrobial peptide within the human urinary tract.

Kidney Int 2011 Jul 27;80(2):174-80. Epub 2011 Apr 27.

Pediatric Nephrology Fellowship Program, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.

Although the urinary tract is constantly challenged by microbial invasion, it remains free from colonization. Although little is known about how the urinary tract maintains sterility, the presence of antimicrobial peptides (AMPs) in the urine suggests that they may play a role in its protection from infection. Ribonuclease 7 (RNase 7) is a potent AMP that was first identified in the skin. Here, we characterize the expression and relevance of RNase 7 in the human kidney and urinary tract. Using RNA isolated from healthy human tissue, we performed quantitative real-time PCR and found basal RNASE7 expression in kidney and bladder tissue. Immunohistochemical and immunofluorescent analysis localized RNase 7 to the urothelium of the bladder, ureter, and the intercalated cells of the collecting tubules. In control urine samples from healthy individuals, the concentration of RNase 7 was found to be in the low micromolar range; very abundant for an AMP. Antibacterial neutralization assays showed that urinary RNase 7 has potent antimicrobial properties against Gram-negative and Gram-positive uropathogenic bacteria. Thus, RNase 7 is expressed in the human kidney and urinary tract and it may have an important antimicrobial role in maintaining tract sterility.
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http://dx.doi.org/10.1038/ki.2011.109DOI Listing
July 2011

Novel management of urinary tract infections.

Curr Opin Urol 2011 Jul;21(4):328-33

Department of Urology, Naval Medical Center, San Diego, California, USA.

Purpose Of Review: To highlight observations that have suggested the need for changing the conventional approach to the evaluation and management of urinary tract infections (UTIs) and vesicoureteral reflux in children and examine new alternative approaches to prevention of UTI and renal scarring based on research into host-pathogen interaction.

Recent Findings: Recent studies have questioned the traditional approach of using prophylactic antibiotics to prevent recurrence of UTI and development of renal scarring in children with vesicoureteral reflux. Ongoing research on host-pathogen interactions reveals a promising capability to analyze virulence factors in bacteria causing UTIs in children, identify highly virulent bacteria capable of causing pyelonephritis and renal injury, and to selectively target the gastrointestinal reservoirs of these bacteria for elimination using probiotics.

Summary: Promising experimental studies correlating bacterial virulence with pattern of UTI and identification and characterization of a newly available probiotic capable of eradicating uropathogenic bacteria make targeted probiotic prevention of renal injury-inducing UTIs a potential therapeutic reality.
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http://dx.doi.org/10.1097/MOU.0b013e328346d4eeDOI Listing
July 2011

A dynamically masked Gaussian can efficiently approximate a distance calculation for image segmentation.

Adv Exp Med Biol 2011 ;696:425-32

The Biophysics Program, The Ohio State University, Columbus, OH 43210, USA.

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http://dx.doi.org/10.1007/978-1-4419-7046-6_42DOI Listing
June 2011

Morphological plasticity promotes resistance to phagocyte killing of uropathogenic Escherichia coli.

Microbes Infect 2011 May 21;13(5):426-37. Epub 2010 Dec 21.

Center for Microbial Pathogenesis, Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA.

Uropathogenic Escherichia coli proceed through a complex intracellular developmental pathway that includes multiple morphological changes. During intracellular growth within Toll-like receptor 4-activated superficial bladder epithelial cells, a subpopulation of uropathogenic E. coli initiates SulA-mediated filamentation. In this study, we directly investigated the role of bacterial morphology in the survival of uropathogenic E. coli from killing by phagocytes. We initially determined that both polymorphonuclear neutrophils and macrophages are recruited to murine bladder epithelium at times coincident with extracellular bacillary and filamentous uropathogenic E. coli. We further determined that bacillary uropathogenic E. coli were preferentially destroyed when mixed uropathogenic E. coli populations were challenged with cultured murine macrophages in vitro. Consistent with studies using elliptical-shaped polymers, the initial point of contact between the phagocyte and filamentous uropathogenic E. coli influenced the efficacy of internalization. These findings demonstrate that filamentous morphology provides a selective advantage for uropathogenic E. coli evasion of killing by phagocytes and defines a mechanism for the essential role for SulA during bacterial cystitis. Thus, morphological plasticity can be viewed as a distinct class of mechanism used by bacterial pathogens to subvert host immunity.
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http://dx.doi.org/10.1016/j.micinf.2010.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071881PMC
May 2011