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The influenza virus can cause severe epidemics, which results in significant morbidity and mortality. Beyond the virulence of the virus itself, epidemiological data suggest that bacterial co-infections are the major cause of increased mortality. In this context,\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    represents a frequent causative bacterial pathogen. Currently available models have several limitations in the analysis of the pathogenesis of infections, e.g. some bacterial toxins strongly act in a species-specific manner. Human 2D mono-cell culture models often fail to maintain the differentiation of alveolus-specific functions. A detailed investigation of the underlying pathogenesis mechanisms requires a physiological interaction of alveolus-specific cell types. The aim of the present work was to establish a human\n                    <jats:italic>in vitro<\/jats:italic>\n                    alveolus model system composed of vascular and epithelial cell structures with cocultured macrophages resembling the human alveolus architecture and functions. We demonstrate that high barrier integrity maintained for up to 14 d in our model containing functional tissue-resident macrophages. We show that flow conditions and the presence of macrophages increased the barrier function. The infection of epithelial cells induced a high inflammatory response that spread to the endothelium. Although the integrity of the epithelium was not compromised by a single infection or co-infection, we demonstrated significant endothelial cell damage associated with loss of barrier function. We established a novel immune-responsive model that reflects the complex crosstalk between pathogens and host. The\n                    <jats:italic>in vitro<\/jats:italic>\n                    model allows for the monitoring of spatiotemporal spreading of the pathogens and the characterization of morphological and functional alterations attributed to infection. The alveolus-on-a-chip represents a promising platform for mechanistic studies of host-pathogen interactions and the identification of molecular and cellular targets of novel treatment strategies in pneumonia.\n                  <\/jats:p>","DOI":"10.1088\/1758-5090\/ab7073","type":"journal-article","created":{"date-parts":[[2020,1,29]],"date-time":"2020-01-29T06:27:32Z","timestamp":1580279252000},"page":"025012","update-policy":"https:\/\/doi.org\/10.1088\/crossmark-policy","source":"Crossref","is-referenced-by-count":98,"title":["Co-infection with Staphylococcus aureus after primary influenza virus infection leads to damage of the endothelium in a human alveolus-on-a-chip model"],"prefix":"10.1088","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4495-4052","authenticated-orcid":false,"given":"Stefanie","family":"Deinhardt-Emmer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Knut","family":"Rennert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Schicke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zolt\u00e1n","family":"Cseresny\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Windolph","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandor","family":"Nietzsche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regine","family":"Heller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatina","family":"Siwczak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karoline Frieda","family":"Haupt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swen","family":"Carlstedt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Schacke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc Thilo","family":"Figge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Ehrhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina","family":"L\u00f6ffler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5687-2444","authenticated-orcid":false,"given":"Alexander S","family":"Mosig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"266","published-online":{"date-parts":[[2020,2,19]]},"reference":[{"key":"bfab7073bib1","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/S2213-2600(18)30345-X","article-title":"Acute respiratory failure in immunocompromised adults","volume":"7","author":"Azoulay","year":"2019","journal-title":"Lancet Respiratory Med."},{"key":"bfab7073bib2","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.jhin.2017.12.011","article-title":"Virulence patterns of Staphylococcus aureus strains from nasopharyngeal colonization","volume":"100","author":"Deinhardt-Emmer","year":"2018","journal-title":"J. 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