Human lung ex vivo infection models

Abstract

Pneumonia is counted among the leading causes of death worldwide. Viruses, bacteria and pathogen-related molecules interact with cells present in the human alveolus by numerous, yet poorly understood ways. Traditional cell culture models little reflect the cellular composition, matrix complexity and three-dimensional architecture of the human lung. Integrative animal models suffer from species differences, which are of particular importance for the investigation of zoonotic lung diseases. The use of cultured ex vivo infected human lung tissue may overcome some of these limitations and complement traditional models. The present review gives an overview of common bacterial lung infections, such as pneumococcal infection and of widely neglected pathogens modeled in ex vivo infected lung tissue. The role of ex vivo infected lung tissue for the investigation of emerging viral zoonosis including influenza A virus and Middle East respiratory syndrome coronavirus is discussed. Finally, further directions for the elaboration of such models are revealed. Overall, the introduced models represent meaningful and robust methods to investigate principles of pathogen-host interaction in original human lung tissue.

Keywords: Bacteria; Human lung; Immunity; Pneumonia; Virus.

Fig. 1

Influenza A virus (IAV) targets AEC-II in ex vivo infected human lung tissue. Cross-sections from infected lung explants were stained for IAV antigen (green), for prosurfactant protein C (blue) to detect alveolar epithelial cell II (AEC-II, T II; white arrowheads infected cells [cyan], open arrowheads uninfected cells [blue]) and for CD68 (red) to detect alveolar lung macrophages (asterisk infected cell [yellow]). Nuclear staining with 4,6-diamidino-2-phenylindole is shown in dark orange and lung structure is visualized with differential interference contrast. The stains were visualized by confocal microscopy and tissue autofluorescence was separated from specific fluorescence by spectral unmixing. From Weinheimer et al. (2012). Reproduction by permission of Oxford University Press

Fig. 2

MERS coronavirus (MERS-CoV) causes structural damage in ex vivo infected human lungs. Detachment of MERS-CoV-infected cell (green) from the alveolar epithelial layer disrupts epithelial continuity. An annular formation of tight junction protein occludin (red, white arrowheads) still surrounds the detached cell and is dissolved from the alveolar junctional band (white arrow). Stain visualization by confocal microscopy and separation of tissue autofluorescence from specific fluorescence by spectral unmixing. From Hocke et al. (2013a). Reprinted with permission of the American Thoracic Society. Copyright © 2016 American Thoracic Society