An ex vivo cystic fibrosis model recapitulates key clinical aspects of chronic Staphylococcus aureus infection

Abstract

Staphylococcus aureus is the most prevalent organism isolated from the airways of people with cystic fibrosis (CF), predominantly early in life. Yet its role in the pathology of lung disease is poorly understood. In mice, and many experiments using cell lines, the bacterium invades cells or interstitium, and forms abscesses. This is at odds with the limited available clinical data: interstitial bacteria are rare in CF biopsies and abscesses are highly unusual. Bacteria instead appear to localize in mucus plugs in the lumens of bronchioles. We show that, in an established ex vivo model of CF infection comprising porcine bronchiolar tissue and synthetic mucus, S. aureus demonstrates clinically significant characteristics including colonization of the airway lumen, with preferential localization as multicellular aggregates in mucus, initiation of a small colony variant phenotype and increased antibiotic tolerance of tissue-associated aggregates. Tissue invasion and abscesses were not observed. Our results may inform ongoing debates relating to clinical responses to S. aureus in people with CF.

Antibiotic Efficacy Testing in an Ex vivo Model of <em>Pseudomonas aeruginosa</em> and <em>Staphylococcus aureus</em> Biofilms in the Cystic Fibrosis Lung

“…B. Results of S. aureus biofilms in the EVPL model treated with 12 µg/mL linezolid (data reproduced from Sweeney et al 23 ). Please click here to view a larger version of this figure.…”

An in vitro model for the cultivation of polymicrobial biofilms under continuous-flow conditions

“…A different channel of the same pump was used to remove waste culture into a discard jar at the same flowrate ( Figure 1 ). Biofilms were allowed to develop in the continuous-flow culture vessel on two types of solid substratum; agar chunks and ex vivo porcine lung tissue (EVPL) sections, which have been previously reported to closely mimic the airway surface environment ( Harrison et al ., 2014 ; Harrison and Diggle, 2016 ; Sweeney et al ., 2021 ; Harrington et al ., 2020 ). These substrata were suspended in bespoke cylindrical biofilm containers (25 mm diameter × 35 mm length) constructed from stainless steel wire gauze (Fisher Scientific) ( Figure 2A,B ).…”

“…Not only are there significant ethical implications associated with these approaches, but the longitudinal/long-term study of microbial populations becomes impractical. More recently, ex vivo models of CF have redressed some of these issues, enabling the study of microbial biofilm lifestyles reminiscent of those observed in situ ( Harrington et al ., 2020 ; Sweeney et al ., 2021 ). However, owing to the intense competition observed among microbial species, existing ex vivo models do not yet permit the study of more than one microbial species at a time.…”

Microbial Musings – January 2021

“…This remarkable achievement follows a previous paper from the same first author Esther Sweeney (@SweeneyEsther) which was published just last month [19]. In her new paper Esther, working with clinicians Matthew Hurley (@MatthewNHurley) and Alan Smyth (@AlanRSmyth) at the University of Nottingham, along with Marwa Hassan (@DrMarwa_Hassan) and Niamh Harrington (@_NiamhEllen) with other colleagues in Nottingham, have made further progress using a porcine lung model they developed previously [20], to now demonstrate that this also functions as a suitable model for studying how Staphylococcus aureus grows during chronic infections of the cystic fibrosis lung [21]. Read about the article in the Microbiology Society Blog, stay safe and see you next month.…”