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image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao University of Southe...arrow_drop_down
image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao
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The pig as translational model of urinary tract infection: recapitulating important aspects of human disease

Authors: Stærk, Kristian;

The pig as translational model of urinary tract infection: recapitulating important aspects of human disease

Abstract

Blærebetændelse er en hyppig infektionssygdom i Danmark og rammer personer i alle aldersgrupper. Selvom blærebetændelse let kan behandles med antibiotika vil sygdommen ofte vende tilbage og vi ved ikke meget om hvorfor nogle personer, som er ellers sunde og raske, bliver ramt og ikke andre. På hospitalerne er blærebetændelse også den hyppigste hospitals-erhvervet infektionssygdom som i høj grad kan tilskrives det store forbrug af urinvejskatetre. Blærebetændelse udgør således et stort problem både i samfundet og på hospitalerne.Målet med dette ph.d.-projekt var at udvikle og optimere en blærebetændelse-model i grise og karakterisere infektionsforløbet og patogenesen i dette dyr mhp. at afdække grisens muligheder som translationel dyremodel inden for denne sygdom.I modellen anvendtes konventionelle hun-grise (Landrace x Yorkshire) på ca. 40 kg. Infektionen blev induceret via transurethral inokulation (via blærekateter) med uropatogene E. coli (UPEC). Grisene blev inokuleret med aftagende mængder bakterier for at identificere det mindste nødvendige inokulum og derved karakterisere grisensfølsom over for blærebetændelse. Ved at bruge en ΔFimH mutant blev betydningen af type-1 fimbriae undersøgt. Tilstedeværelsen af intracellulære bakterier blev undersøgt ved at behandle (med antibiotika) inficerede griseblærer ex vivo eller in vivo og herefter mikroskopere med konfokal laser scanning mikroskopi samt ved udpladning af homogeniseret blærevæv. Grisemodellen blev også tilpasset til at facilitere et studie med et nyt antimikrobielt blærekateter.Resultaterne er sammenskrevet i 5 manuskripter (3 publikationer og 2 manuskripter under fagfællebedømmelse) og viser at grise er meget følsomme for UVI og at kun ganske få bakterier er tilstrækkeligt til at give ophav til blærebetændelse. infektionspotentialet er meget afhængigt at type-1 fimbriae, da ΔFimH mutanten var betydeligt svækket. Intracellulære bakterier kunne ikke påvises I blærevæv. I katetermodellen var det antimikrobielle kateter I stand til at forhindre infektion i alle grise til sammenligning med kontrol grise som alle udviklede blærebetændelse.Konklusionen er, at blærebetændelses-modellen i grise er en pålidelig model som afspejler mange vigtige parametre ved human infektion. Derfor er grisen velegnet til patogenese-studier og som præ-klinisk model til at validerer nye behandlinger mod blærebetændelse. Herudover viser studierne at der er betydeligeforskelle i patogenesen, særligt i forhold til den intracellulære kolonisering, mellem mus og grise og indikerer herved at resultater fra mus ikke altid kan ekstrapoleres direkte til større dyr. Urinary tract infection (UTI), in particular cystitis, is a widespread disease in Denmark and the whole world and occurs in all age groups [1]. UTIs constitutes the most common nosocomial infection, the most common cause of sepsis and accounts for approximately 3000 deaths every year in Denmark alone [3, 133]. Community-acquired UTIs are characterized by a high frequency of recurrence, even in otherwise healthy women with no apparent risk factors [1].A part from epidemiological data, much of what we know about the pathogenesis of UTI comes from experimental studies in cell-culture based assays and murine models of cystitis. In these models, uropathogenic Escherichia coli (UPEC), the most common etiological agent of UTI, has been shown to invade bladder epithelial cells forming intracellular dormant reservoir [134]. In mice, these reservoirs can survive antibiotic treatment and seed re-infections [121]. The intracellular pathogenic cascade has been suggested as a plausible explanation to recurrent UTIs in humans as well. However, despite being extensively demonstrated in mice through the last 20 years, only very few studies has indicated a similar pathogenesis in humans and the hypothesis have struggled to become accepted in clinical societies [134-137]. This may in part be explained by an increasing skepticism towards the translatability of murine models to human disease [4].To bridge the gap between mice and humans, this Ph.D project aimed to investigate UPEC pathogenesis, including the intracellular pathogenic cascade, in a new large animal model of UTI in pigs. Pigs have been highlighted as excellent models of infectious diseases and share more similarities to humans in terms of genetics, immune physiology and urinary tract anatomy compared to their rodent counterpart [7]. Female domestic pigs (Landrace x Yorkshire, mix) of roughly 40 kg were used here. The pigs were inoculated through a urinary catheter with UPEC to induce cystitis. Pigs were inoculated with varying concentrations of bacteria to determine minimal infectious inoculum, i.e. the susceptibility to infection. Furthermore, by using a mutant lacking the T1F, one of the most well-described virulence factors of UPEC, the influence of thisfimbriae on infectious outcome was assessed in the porcine model. To investigate the intracellular pathogenic cascade, whole-bladders from infected pigs were investigated for the presence of intracellular bacteria following ex vivo and in vivo antibiotic treatment by analyzing splayed bladders with confocal laser scanning microscopy and plating homogenized tissue samples. Lastly, the model was adapted to facilitate studies of catheter-associated UTI (CAUTI), and with this, an efficacy study of a novel antimicrobial catheter was performed. The results are consolidated in 5 manuscripts (3 published papers, 2 in peer-review) and show that pigs are highly susceptible to UTI, with only a few single bacteria of UPEC capable of successfully infecting this animal. This infectious potential is largely dependent on T1F, as the T1F-deficient mutant was strongly attenuated. Surprisingly, we found no evidence of intracellular persistence upon antibiotic treatment. In the CAUTImodel, we demonstrate proof-of-concept of an antimicrobial bladder catheter that effectively prevented CAUTI in all pigs.In conclusion, the pig represents a robust model that recapitulates important aspects of human UTI. Thereby, the model is appropriate for studies of UTI pathogenesis as well as pre-clinical efficacy studies of new therapeutic treatments or interventions against UTI. Furthermore, the results of these studies show important differences in UTI pathogenesis between mice and pigs, particular in relation to intracellular persistence and thereby support that results from experiments in mice should be interpreted with caution.

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Denmark
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    This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
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    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
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popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
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