Cross-species comparative modelling of antimicrobial host responses ex vivo in human and murine precision cut lung slices and in vivo in mice

Abstract

In biomedical infectious disease research new models to bridge preclinical and clinical research are needed. Mouse models are still one of the most-interrogated experimental systems with the caveat of biological differences in pathogen-host-interaction for some human-relevant pathogens and increasing ethical concerns. Arguably one of the most complex cell culture models are precision cut organ slices, volume defined tissue blocks which can be cultured ex vivo and exposed to various stimuli including human pathogens. They could be applied as 3R model system. However, their response to infectious agents in comparison to in vivo models is understudied. To understand species and model specific differences in the host response (here: influenza A virus (IAV) and Streptococcus pneumoniae (Spn)), we interrogate here the transcriptional reaction of human PCLS (hPCLS) compared to that of murine precision cut lung slices (mPCLS) and a murine in vivo infection model. A direct comparison of hPCLS and mPCLS revealed a more complex early innate immune response against viral and bacterial pathogens in the human model, which beyond this informs about secondary cell-to-cell communication in situ and bystander cell responses to proinflammatory and antiviral cytokines secreted by tissue resident immune cells. In contrast, the murine PCLS model revealed substantial deficits in responding to viral challenge, reproducing only a small fraction of the murine in vivo host response. Our study provides the first cross-species comparison of early transcriptomic responses to relevant human pathogens.

Competing Interest Statement

The authors have declared no competing interest.