Host - pathogen interactions in respiratory epithelium
When a respiratory pathogen crosses the species barrier through inter-species transmission the pathogen can cause severe disease in the new host. This is well established for influenza A virus that is transmitted from its main natural reservoir, aquatic birds, to a wide spectrum of animal species, including poultry, swine, canine, equine and human and can have severe consequences on both animal and human health. The determinants affecting interspecies transmission or pathogenesis of emerging respiratory infections among different host species are only partially understood on the viral side, and there is still a great gap in our knowledge on cellular effectors and their mechanisms in the airway epithelium among the different host species. Thus, for both epizootic and zoonotic risk assessment and the development of effective counter measurements against these diseases it is necessary to define critical determinants of species barriers for emerging respiratory pathogens.
To address these questions, we make use of a pseudo-stratified primary airway epithelial cell culture (AEC) system as main model. The AEC system is based on the isolation of primary lung epithelial cells that are manipulated with well-defined medium to form pseudo-stratified AECs. The pseudo-stratified AEC contains basal, secretory and ciliated cell populations, and generates mucus. Therefore, this in vitro system recapitulates many aspects of the in vivo airway epithelium, namely epithelial cellular differentiation and repair, the presence of well-defined cell types of the airway epithelium, and the physiological mucus barrier. Over the past years, we have established AEC models from a large repertoire of species, including human, porcine and bats, enabling us to characterize virus – host interaction in different host species (Figure 1).
Figure 1. Identification of the MERS-CoV receptor. Expression of dipeptidyl-peptidase 4 (red), the functional MERS-CoV receptor on non-ciliated but not on ciliated cells (yellow) in primary AEC cultures [cover image: Nature, volume 495, number 7440, 2014; (PubMed)]
More recently, we have made the AEC system amenable to genetic manipulation. Allowing us to both modulate the expression of host determinants and to characterize the innate immune response dynamics in the airway epithelium over time. Thereby this system serve as a paradigm to define critical determinants of species barriers in the airway epithelium among different host species.