In vitro Recapitulation of the Polymicrobial Communities Associated with Cystic Fibrosis Airway Infections

The airways of persons with cystic fibrosis (CF) are prone to lifelong colonisation with dense microbial ecosystems comprised of a diverse combination of bacteria and fungi. The role of interspecies interactions in modulating changes in gene expression and the metabolism of individual members of a polymicrobial community, compared with growth as an axenic population, is becoming increasingly apparent within the field of medical microbiology. In part, these poorly understood interactions explain why, regardless of intense research efforts, therapeutic treatments designed to clear such chronic airway infections often fail within the clinical setting. The paucity of existing in vitro and in vivo models used to study CF-associated infections greatly hinders research into the behaviours of polymicrobial communities. Species that coexist within the same in situ environment often outcompete one another when grown as a mixed population using traditional culture methods. The work presented in this dissertation redresses these problems. I describe the development and characterisation of a novel in vitro continuous-flow culture model. This experimental system permits the stable co-cultivation of distinctly different microbial species commonly-associated with CF airway infections; species that ordinarily readily outcompete one another in existing models. I demonstrate that the metabolic state and mutation rates of species cultured within the model remain stable for extended periods of time. Furthermore, I show that antimicrobial compounds display decreased efficacy against their target organism when grown as part of a polymicrobial community. I also show that different combinations of microbial species display different biofilm-forming potential. This work provides the basis of future research efforts aimed at the in vitro recapitulation of an entire polymicrobial community directly derived from persons with CF. Ultimately, this will help to bridge the bench-to-bedside gap for the development of more efficacious airway infection management regimens.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2021

Author dc:creator

• O'Brien, Thomas James

Advisor dc:contributor.advisor

• Welch, Martin

• Microbiology
• Polymicrobial
• Cystic Fibrosis
• Continuous-flow
• In vitro

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/4a49f445-993b-4f8c-a755-f946a281d38b/download
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

eng

Author Identifier

0000-0003-3646-1733

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/323425