Ex vivo modeling of lung tissue resident antimicrobial responses

Article Article scientifique Article Ex vivo modeling of lung tissue resident antimicrobial responses eng 2026-04-16 author Choltus Helena 0000-0002-7557-7029 Université de Genève 984092 Département de microbiologie et médecine moléculaire (MIMOL) author Bianchi Niccolo Université de Genève 417383 Département de pathologie et immunologie (PATIM) author Prados Julien 0000-0002-8546-241X Université de Genève 561771 Services communs de la faculté de médecine (SCMU) author Heikkila Nelli Hôpitaux universitaires de Genève 974837 author Karenovics Wolfram Hôpitaux universitaires de Genève 501317 author Serre Beinier Véronique 0000-0002-6016-1645 Université de Genève 123229 Département de chirurgie (CHIRU) author Nissille Yannick Christophe Université de Genève 930457 author Leitner Nina Université de Genève 409319 Département de microbiologie et médecine moléculaire (MIMOL) author Bedat Benoît Hôpitaux universitaires de Genève 565412 Département de chirurgie (CHIRU) author Bezrukov Fedor Université de Genève 849834 Département de microbiologie et médecine moléculaire (MIMOL) author Mazel-Sanchez Beryl Hôpitaux universitaires de Genève 827346 author Prendki Virginie 0000-0003-1315-2938 811987 dept de réadaptation et gériatrie (MIGRG) author Lobrinus Johannes Alexander 647649 author Eberhardt Christiane Sigrid Université de Genève 669023 Département de Pédiatrie, Gynécologie et Obstétrique (PETRI) author Becattini Simone 0000-0001-5985-0403 Université de Genève 949421 Département de pathologie et immunologie (PATIM) author Schmolke Mirco 0000-0002-2491-3029 Université de Genève 821513 Département de microbiologie et médecine moléculaire (MIMOL) e00056-26 10.1128/mbio.00056-26 41989160 2150-7511 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, we 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, we first challenged mice <italic toggle="yes">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 our findings to immune-experienced human precision cut lung slices (hPCLS), we 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, we infected hPCLS with <italic toggle="yes">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 <italic toggle="yes">ex vivo model. In conclusion, a diversified tissue resident immune cell compartment distinguishes the human <italic toggle="yes">ex vivo model, making it an ideal system for microbiological and immunological research. IMPORTANCE : Pathogen interactions with the lungs are very dynamic processes. In biomedical research, it is paramount to model these processes in the laboratory as accurately as possible. Influenza A virus has been extensively studied in epithelial cell culture models, including advanced organoids and organ-on-a-chip systems. Here, we use ex vivo cultured precision cut lung slices (PCLS) and generate transcriptomic data to assess the global tissue resident host response to viral and bacterial challenges. Our data show (i) that murine PCLS faithfully reflect core responses to viral infection, while missing proinflammatory responses linked to infiltrating immune cells and (ii) that human PCLS show a highly diversified tissue resident immune response to viral infection due to previous exposures of the host to this pathogen. These responses are clearly distinct from antibacterial gene profiles. Our data advertise PCLS as a complex and realistic model to study tissue resident immune responses to microbes in a human system. 3R PCLS Streptococcus pneumoniae Antimicrobial Ex vivo model Infectious disease Influenza virus Innate immunity Interferon Interleukin Precision cut lung slices Preclinical model Dewey 616 Dewey 616.07 Dewey 617 Dewey 618.97 Dewey 618 Swiss National Science Foundation Identification and characterization of host factors affecting Inter-and intra-species spreading of influenza A viruses 212216 CH 65 Département de réadaptation et gériatrie 22B 54 Département de microbiologie et médecine moléculaire 21B 137 Département de pathologie et immunologie 21F 58 Département de pédiatrie, gynécologie et obstétrique 223 57 Département de chirurgie 222 56 Département de médecine 221 false 1440 Infections de la personne âgée 1062 0a6434c9-7972-44ea-8708-82e501660dc7 Biomedical Data Science Facility 48a82112-9f30-4dde-a32a-47c02fceac29 Bioinformatics Support Platform 902 Cancer du poumon et mésothéliome pleural malin 944 143 Centre de vaccinologie et d'immunologie néonatale 177 912 Modulation de la flore microbienne dans un hôte infecté par un virus 947 1340 Host-Microbe Interactions 1027 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE306406 https://github.com/BioinfoSupport/rnaseq https://github.com/BioinfoSupport/genomes MBio 54b926c3-023f-44ca-8576-ac4cb88831d4 Article (Published version) Public choltus-et-al-2026-ex-vivo-modeling.pdf 5060149 application/pdf CC BY-4.0 da084cc07e259f0440515fbbd1637ae154a15f07e65a32b6ab3dafd2432dd0bf 2a964433-422f-4d81-af98-35c0016a2447 Supplemental data Public mbio.00056-26-s0001.pdf 16150 application/pdf 427c44e2e247af6706c90fe04a5034af5aac870af7c22fda6d1b0f36df565ff5 42ed308b-3587-499e-b99c-adcac991b4d3 Supplemental data Public mbio.00056-26-s0002.pdf 1070014 application/pdf a99c1775a97532e4757005b2f07571ab9590a87862a4e58b7683056ef908f085 01d9c228-b328-4706-9180-ec863d24c9db Supplemental data Public mbio.00056-26-s0003.pdf 679308 application/pdf 942337fa15279de61ca388a34c62d72d6eaf8746e720c70e650a1f3d81d8d5af 10704139-9cfe-4f2f-a045-2f0e748d10a5 Supplemental data Public mbio.00056-26-s0004.pdf 608733 application/pdf 6fa51b9d0071f07e0444cfbee1909710f3e79090ec9d6634f0562856d5fd1fa8 fbf8c52c-ee40-455d-bfb5-03bf42464436 Supplemental data Public mbio.00056-26-s0005.pdf 462557 application/pdf f3828af607950d7efbce6eb1d1750213140aba5944feb081937ab4b61a4d33da 3053b031-5e5a-4e3e-aa15-ec0692a662b5 Supplemental data Public mbio.00056-26-s0006.docx 22521 application/vnd.openxmlformats-officedocument.wordprocessingml.document 100f323a851ee9409ddc3bc8fcee82b6ad5e7e94cc621de50519466426d1c544 9f11aaaa-e8d5-46b9-bb09-be7f5b201408 Supplemental data Public mbio.00056-26-s0007.pdf 446285 application/pdf 36575e6d8e73464a23910490669767d6dfb94ad445f7b8377c2b507508b36c10 2c12f65b-5914-4ce8-a357-8291ffec50c8 Supplemental data Public mbio.00056-26-s0008.pdf 545389 application/pdf ed28c189b2bc34fec8bfc64f35462a025e94dba12c6cf74ca22b94f57e057830 2ee20f9d-327b-438f-8127-4ef1fb5862cf Supplemental data Public mbio.00056-26-s0009.pdf 184776 application/pdf dccc0b270f05f68dd97596ea2e3bbf32e08cef8c1317b789557ea4a5d4223866 1a09b145-40a9-44dc-b600-e5fbcf208387 Supplemental data Public mbio.00056-26-s0010.pdf 626105 application/pdf 1b6a4f0e0a78c220eeb6d86dce6d306bf5b1d59ef82404f1182fb11447a8aa63 openAccess Faculté de médecine / Section de médecine clinique / Département de réadaptation et gériatrie Faculté de médecine / Section de médecine fondamentale / Département de microbiologie et médecine moléculaire Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine clinique / Département de pédiatrie, gynécologie et obstétrique Faculté de médecine / Section de médecine clinique / Département de chirurgie Faculté de médecine / Section de médecine clinique / Département de médecine

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