Abstract
NF-κB driven cellular immunity is essential for both pro- and anti-inflammatory responses to microbes, which makes it one of the most frequently targeted pathways by bacteria during pathogenesis. How NF-κB tunes the epithelial response to Streptococcus pneumoniae across the spectrum of commensal to pathogenic outcomes is not fully understood. In this study, we compare a commensal-like 6B ST90 strain to an invasive TIGR4 strain and demonstrate, through comparative mass spectrometry of the p65 interactome, that TIGR4 challenge triggers interaction of COMMD2 with p65 and p62. Mechanistically, we show this complex mediates export of p65 for degradation and COMMD2 is necessary for altering host cellular immunity. With these results, we reveal a bacterial pathogenesis mechanism to repress host inflammatory response though COMMD2 and p65 degradation while presenting a paradigm for diverging NF-κB responses to pneumococcus.
Acknowledgements
We would like to thank Emmanuelle Varon and Thomas Kohler for their generous gifts of S. pneumonie strains. We are appreciative of Pierre-Henri Commere and the Institut Pasteur, Flow Cytometry Platform (Paris, France) for sorting of the COMMD2 stable cell line. Finally, we would like to thank Daniel Hamaoui for his help in processing blots during COVID-19-related work personnel restrictions. This work was supported by the French Government’s Investissement d’Avenir program, the Laboratoire d’Excellence “Integrative Biology of Emerging Infectious Diseases” Springboard to Independence grant (AirwayStasis; ANR-10-LABX-62-IBEID) and an Agence nationale de la recherche Jeunes Chercheuses et Jeunes Chercheurs (JCJC) “CommensalNose” (ANR 24 CE15 7975 01) for M.G.C., the French government, through the National Research Agency (ANR) as part of the France 2030 program referenced “ANR-23-CHBS-0001” (ChromaBac), the Institut Pasteur, the Fondation pour la Recherche Médicale (FRM-EQU202003010152), the Fondation iXCore-iXLife, and the Pasteur-Weizmann research fund for M.A.H., the Institut Pasteur, and the European Commission (ERC-STG “PlasmoEpiRNA”) for S.B., the European Commission (ERC-CoG-Endosubvert), the ANR-HBPsensing, the IBEID and Milieu Interieur LabExes for J.E., this work was also supported by EPIC-XS, project number 823839, funded by the Horizon 2020 program for M.G.C., M.A.H.
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Connor, M.G., Sanchez, L., Chevalier, C. et al. Pneumococcus uses COMMD2 to alter host cellular immunity. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72852-4
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DOI: https://doi.org/10.1038/s41467-026-72852-4
