Advancing infection science with human tissue models

SUMMARY

Tissue resident host responses to microbial infections in the respiratory tract are highly dynamic in space and time and rely on the interaction of a multitude of cell types. To model these multicellular responses reliably in cell culture, the authors compare here the global transcriptional antimicrobial response to infection with influenza A virus (IAV) in precision cut lung slices (PCLS), volume-defined organ discs largely maintaining the cellular composition and 3D architecture of the donor lung. To permit a fair comparison of host responses in an isogenic background, they first challenged mice in vivo and murine PCLS (mPCLS) and assessed host transcriptomic changes by unbiased RNA-sequencing. While core antiviral responses overlapped substantially, mPCLS lacked certain features-such as type II interferon expression-likely due to the absence of infiltrating immune cell responses. Importantly, when expanding their findings to immune-experienced human precision-cut lung slices (hPCLS), they find a much broader antiviral response after IAV challenge, including types I, II, and III interferons, suggesting the presence of responsive tissue resident lymphocytes. To prove the specificity of this response, they infected hPCLS with Streptococcus pneumoniae. Ex vivo tissues responded with a distinct proinflammatory gene profile including IL1A, IL1B, and IL17 expression. Blocking of IL-1β signaling partially inhibited the proinflammatory response, suggesting cellular cross talk and a complex and specific antimicrobial reaction in this ex vivo model. In conclusion, a diversified tissue resident immune cell compartment distinguishes the human ex vivo model, making it an ideal system for microbiological and immunological research.

Full article: https://doi.org/10.1128/mbio.00056-26

WHY IS THIS IMPORTANT?

Understanding how the lungs fight infections is essential, but traditional laboratory models often fail to capture the complexity of real human tissue. This study compared the response of human and mouse lung tissue to the influenza virus and bacteria using ex vivo lung slices. The human lung slices produced a broad immune response, including multiple antiviral and inflammatory signals. This suggests that immune cells that have previously been 'trained' remain active in lung tissue. In contrast, mouse lung slices showed weaker immune responses unless additional immune cells were present or an infection occurred in living animals.

These results emphasise significant differences between species, demonstrating that human lung tissue retains a memory of past infections and behaves very differently from standard animal models. This suggests that it may better reflect real-life infections, strengthening the case for using PCLS as a powerful tool for studying infections and developing new treatments more aligned with human biology.

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