Modelling staphylococcal pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology

Shambat, Srikanth Mairpady and Chen, Puran and Hoang, Anh Thu Nguyen and Bergsten, Helena and Vandenesch, Francois and Siemens, Nikolai and Lina, Gerard and Monk, Ian R and Foster, Timothy J and Arakere, Gayathri and Svensson, Mattias and Norrby-Teglund, Anna (2015) Modelling staphylococcal pneumonia in a human 3D lung tissue model system delineates toxin-mediated pathology. In: DISEASE MODELS & MECHANISMS, 8 (11). pp. 1413-1425.

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Abstract

Staphylococcus aureus necrotizing pneumonia is recognized as a toxin-mediated disease, yet the tissue-destructive events remain elusive, partly as a result of lack of mechanistic studies in human lung tissue. In this study, a three-dimensional (3D) tissue model composed of human lung epithelial cells and fibroblasts was used to delineate the role of specific staphylococcal exotoxins in tissue pathology associated with severe pneumonia. To this end, the models were exposed to the mixture of exotoxins produced by S. aureus strains isolated from patients with varying severity of lung infection, namely necrotizing pneumonia or lung empyema, or to purified toxins. The necrotizing pneumonia strains secreted high levels of alpha-toxin and Panton-Valentine leukocidin (PVL), and triggered high cytotoxicity, inflammation, necrosis and loss of E-cadherin from the lung epithelium. In contrast, the lung empyema strain produced moderate levels of PVL, but negligible amounts of alpha-toxin, and triggered limited tissue damage. alpha-toxin had a direct damaging effect on the epithelium, as verified using toxin-deficient mutants and pure alpha-toxin. Moreover, PVL contributed to pathology through the lysis of neutrophils. A combination of alpha-toxin and PVL resulted in the most severe epithelial injury. In addition, toxin-induced release of pro-inflammatory mediators from lung tissue models resulted in enhanced neutrophil migration. Using a collection of 31 strains from patients with staphylococcal pneumonia revealed that strains producing high levels of alpha-toxin and PVL were cytotoxic and associated with fatal outcome. Also, the strains that produced the highest toxin levels induced significantly greater epithelial disruption. Of importance, toxin-mediated lung epithelium destruction could be inhibited by polyspecific intravenous immunoglobulin containing antibodies against alpha-toxin and PVL. This study introduces a novel model system for study of staphylococcal pneumonia in a human setting. The results reveal that the combination and levels of alpha-toxin and PVL correlate with tissue pathology and clinical outcome associated with pneumonia.

Item Type:	Journal Article
Publication:	DISEASE MODELS & MECHANISMS
Publisher:	COMPANY OF BIOLOGISTS LTD
Additional Information:	Copyright for this article belongs to the COMPANY OF BIOLOGISTS LTD, BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND
Keywords:	Staphylococcus aureus; Pneumonia; 3D lung tissue model
Department/Centre:	Autonomous Societies / Centres > Society for Innovation and Development
Date Deposited:	10 Dec 2015 05:33
Last Modified:	17 Oct 2018 09:40
URI:	http://eprints.iisc.ac.in/id/eprint/52839

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