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Antibiotic-induced filamentation of extended spectrum beta lactamase (ESBL)-producing uropathogenic E. coli alters host cell responses during an in vitro infection
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Inadequate and delayed antibiotic treatment of extended spectrum beta-lactamase (ESBL)- producing isolates have been associated with increased mortality of affected patients. The purpose of this study was to compare the host response of human renal epithelial cells and polymorphonuclear leukocyte (PMN) cells when infected by ESBL-producing uropathogenic E. coli (UPEC) isolates in the presence or absence of ineffective antibiotics.

The renal epithelial cell line A498 and PMN cells were stimulated with ESBLproducing UPEC isolates in the presence or absence of three different antibiotics (trimetoprim, ceftibuten and ciprofloxacin). Host cell responses were evaluated as release of cytokines (IL-6, IL-8), reactive oxygen species (ROS), ATP and endotoxins. Bacterial morphology and PMNphagocytosis were evaluated by microscopy.

In the presence of ceftibuten, 2 out of 3 examined ESBL-isolates changed their morphology into a filamentous form. The presence of ceftibuten enhanced IL-6, IL-8 and ROS-production from host cells, but only from cells stimulated by the filamentous isolates. The bacterial supernatant and not the filamentous bacteria per se was responsible for the increased release of IL-6, IL-8 and ROS. Increased endotoxin and ATP levels were found in the bacterial supernatants from filamentous isolates. Apyrase decreased IL-6 secretion from A498 cells and polymyxin B abolished the increased ROS production from PMN cells. PMN were able to inhibit the bacterial growth of some ESBL-isolates in the presence of ceftibuten. In conclusion, antibiotic-induced filamentation of ESBL-producing UPEC isolates and the associated release of ATP and endotoxins can alter the host cell response in the urinary tract.

Keywords [en]
urinary tract infections, renal epithelial cells, polymorphonucleated leukocytes, uropathogenic E. coli, extended spectrum beta-lactamases, filamentous bacteria
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-34891OAI: oai:DiVA.org:oru-34891DiVA, id: diva2:714510
Available from: 2014-04-28 Created: 2014-04-28 Last updated: 2017-10-17Bibliographically approved
In thesis
1. Uropathogenic Esherichia coli, multidrug-resistance and induction of host defense mechanisms
Open this publication in new window or tab >>Uropathogenic Esherichia coli, multidrug-resistance and induction of host defense mechanisms
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Uropathogenic Escherichia coli (UPEC) is the primary cause of urinary tract infection (UTI), which is one of the most common infections in humans. UPEC strains have acquired successful strategies to subvert the host defense and antibiotics to persist in the urinary tract. The main aim of this thesis was to investigate the host defense mechanisms during a UPEC infection in vitro.

The results showed that SOCS3, a key regulator of the immune system, was increased in bladder epithelial cells in response to a UPEC infection. In addition, UPEC decreased the phosphorylation of the SOCS3 regulated transcription factor STAT3. Nitric oxide (NO), a host-derived antimicrobial factor was shown to increase the release of IL-6 from renal epithelial cells alone or in combination with UPEC. The induction of IL-6 was mediated by ERK1/2 and p38 MAPK signaling and NO was also shown to attenuate UPEC-induced IL-6 mRNA degradation. Furthermore, extended-spectrum beta-lactamase (ESBL)-producing UPEC isolates were shown to induce higher PMN migration and ROS-production, but lower cytokine secretion from renal epithelial cells than susceptible isolates. Ineffective ceftibuten treatment of ESBL isolates induced bacterial filamentation associated with an increased release of ATP and LPS, with a subsequent enhancement of the ESBL evoked host response.

Taken together, the findings show that UPEC can induce SOCS3, a suppressor of host responses and that NO can regulate proinflammatory mediators. In addition, the data suggest that there are differences between ESBL- and non-ESBL-producing isolates ability to evoke a host response. Exposing resistant isolates to ineffective antibiotics was shown to alter the evoked host response.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2014. p. 87
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 105
Keywords
Urinary tract infection, uropathogenic Escherichia coli, suppressor of cytokine signalling 3, nitric oxide, cytokines, extended-spectrum beta-lactamases, filamentation, IL-6
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-33556 (URN)978-91-7529-013-3 (ISBN)
Public defence
2014-05-23, Campus USÖ (Universitetssjukhuset) X-huset, Hörsal C1, Södra Grev Rosengatan, 703 62 Örebro, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2014-02-04 Created: 2014-02-04 Last updated: 2017-10-17Bibliographically approved

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Demirel, IsakKruse, RobertÖnnberg, AnnaPersson, Katarina

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