Dysregulation of<i>Escherichia coli</i>α-hemolysin expression alters the course of acute and persistent urinary tract infection

Nagamatsu, Kanna; Hannan, Thomas J.; Guest, Randi L.; Kostakioti, Maria; Hadjifrangiskou, Maria; Binkley, Jana; Dodson, Karen W.; Raivio, Tracy; Hultgren, Scott J.

doi:10.1073/pnas.1500374112

Cited by 142 publications

(175 citation statements)

References 70 publications

(68 reference statements)

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“…In contrast, most in vivo studies do not examine TCS expression patterns and instead use a genetic approach to identify TCSs that affect virulence. For example, in uropathogenic E. coli the BarA/UvrY, CpxRA, KguSR, and OmpR/EnvZ TCSs affect in vivo virulence, although their in vivo expression patterns remain unknown (23)(24)(25)(26)(27). In EPEC and EHEC, several TCSs, including CpxRA, FusKR, PhoBR, QseBC, and QseFE, have been implicated in the regulation of virulence genes in vitro and, more recently, in vivo for QseBC and QseFE (28)(29)(30)(31)(32)(33).…”

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confidence: 99%

Systematic Analysis of Two-Component Systems in Citrobacter rodentium Reveals Positive and Negative Roles in Virulence

et al. 2017

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Citrobacter rodentium is a murine pathogen used to model intestinal infections caused by the human diarrheal pathogens enterohemorrhagic and enteropathogenic Escherichia coli. During infection, bacteria use two-component systems (TCSs) to detect changing environmental cues within the host, allowing for rapid adaptation by altering the expression of specific genes. In this study, 26 TCSs were identified in C. rodentium, and quantitative PCR (qPCR) analysis showed that they are all expressed during murine infection. These TCSs were individually deleted, and the in vitro and in vivo effects were analyzed to determine the functional consequences. In vitro analyses only revealed minor differences, and surprisingly, type III secretion (T3S) was only affected in the ΔarcA strain. Murine infections identified 7 mutants with either attenuated or increased virulence. In agreement with the in vitro T3S assay, the ΔarcA strain was attenuated and defective in colonization and cell adherence. The ΔrcsB strain was among the most highly attenuated strains. The decrease in virulence of this strain may be associated with changes to the cell surface, as Congo red binding was altered, and qPCR revealed that expression of the wcaA gene, which has been implicated in colanic acid production in other bacteria, was drastically downregulated. The ΔuvrY strain exhibited increased virulence compared to the wild type, which was associated with a significant increase in bacterial burden within the mesenteric lymph nodes. The systematic analysis of virulence-associated TCSs and investigation of their functions during infection may open new avenues for drug development.

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confidence: 99%

Systematic Analysis of Two-Component Systems in Citrobacter rodentium Reveals Positive and Negative Roles in Virulence

et al. 2017

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“…Although there is clear evidence that host immune responses influence disease progression, human genetics is likely not the only factor that directs the disease course, given the statistics that a woman has a 50% chance of having a UTI in her lifetime. A role for bacterial traits in this process is supported by observations that absence of cytotoxic necrotizing factor, ␣-hemolysin, or the outer membrane chaperone SurA changes the magnitude of immune responses induced by isogenic wild-type strains (22)(23)(24)(25). Current evidence supports a model whereby the magnitude of host immune responses, mediated either by host polymorphisms and/or bacterial traits, influences the disease manifestation observed clinically.…”

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confidence: 80%

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

et al. 2016

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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. IMPORTANCEThe 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. The plasticity of the Escherichia coli genome has led to the evolution of strains that can serve as keystone commensal organisms in the microbiota as well as to the development of multiple virulent pathotypes that cause both intestinal and extraintestinal infections. Comparison of the genetic content of over 180 strains has revealed that the core E. coli genome is composed of about 1,700 genes, with an additional pangenome of over 16,000 genes (1). It has become increasingly apparent that the plasticity of the E. coli genome allows acquisition of virulence traits from diverse genetic origins and, as such, the potential to attain the same phenotypic trait using different mechanisms (2). Given this vast variat...

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“…While underlying mechanisms leading to the cell death and subsequent exfoliation remain to be identified, a number of bacterial factors produced by UPEC have been implicated in promoting exfoliation of BECs. One such factor is α-hemolysin, which induces caspase 1/caspase 4 dependent inflammatory signaling pathways resulting in cell death (39). Conceivably, exfoliation of BECs is a double edged sword.…”

Section: The Last Resortmentioning

confidence: 99%

The multiple antibacterial activities of the bladder epithelium

Wu¹,

Miao²,

Abraham³

2017

Ann. Transl. Med.

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Abstract:The urinary tract is subject to frequent challenges from the gut microflora. Indeed, up to 40% of women will experience at least one urinary tract infection (UTI) during their lifetime. Uropathogenic Escherichia coli (UPEC) contribute to an overwhelming majority of these cases and they typically initiate UTIs by invading the superficial epithelium that lines the bladder lumen. In addition to serving as an effective barrier to noxious agents found in urine, bladder epithelial cells (BECs) play a key physiological role in regulating bladder volume to accommodate urine flow. UPEC appear to coopt this latter property to circumvent this normally impregnable epithelial barrier. However, in spite of this shortcoming, recent studies suggest that BECs possess several immune mechanisms to combat bacterial invasion including expulsion of invading bacteria back into the bladder lumen following infection. These antibacterial activities of BECs are triggered and coordinated by sensory molecules located on the epithelial cell membrane and within the cells. Although, they are the primary targets of microbial attack, BECs appear to be equipped with a diverse repertoire of defense schemes to fend off many of these microbial challenges.

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Dysregulation ofEscherichia coliα-hemolysin expression alters the course of acute and persistent urinary tract infection

Cited by 142 publications

References 70 publications

Systematic Analysis of Two-Component Systems in Citrobacter rodentium Reveals Positive and Negative Roles in Virulence

Systematic Analysis of Two-Component Systems in Citrobacter rodentium Reveals Positive and Negative Roles in Virulence

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

The multiple antibacterial activities of the bladder epithelium

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