@article{f23ffb355c784a2590b20b54283f4899,
title = "Systemic inflammatory response syndrome triggered by blood-borne pathogens induces prolonged dendritic cell paralysis and immunosuppression",
abstract = "Blood-borne pathogens can cause systemic inflammatory response syndrome (SIRS) followed by protracted, potentially lethal immunosuppression. The mechanisms responsible for impaired immunity post-SIRS remain unclear. We show that SIRS triggered by pathogen mimics or malaria infection leads to functional paralysis of conventional dendritic cells (cDCs). Paralysis affects several generations of cDCs and impairs immunity for 3–4 weeks. Paralyzed cDCs display distinct transcriptomic and phenotypic signatures and show impaired capacity to capture and present antigens in vivo. They also display altered cytokine production patterns upon stimulation. The paralysis program is not initiated in the bone marrow but during final cDC differentiation in peripheral tissues under the influence of local secondary signals that persist after resolution of SIRS. Vaccination with monoclonal antibodies that target cDC receptors or blockade of transforming growth factor β partially overcomes paralysis and immunosuppression. This work provides insights into the mechanisms of paralysis and describes strategies to restore immunocompetence post-SIRS.",
keywords = "antigen presentation, cell development, CP: Immunology, cross-presentation, immunosuppression, infection, inflammation, malaria, phagocytosis, spatiotemporal adaptations, T cells",
author = "Mitra Ashayeripanah and Javier Vega-Ramos and Daniel Fernandez-Ruiz and Shirin Valikhani and Lun, {Aaron T.L.} and White, {Jason T.} and Young, {Louise J.} and Atefeh Yaftiyan and Yifan Zhan and Linda Wakim and Irina Caminschi and Lahoud, {Mireille H.} and Lew, {Andrew M.} and Ken Shortman and Smyth, {Gordon K.} and Heath, {William R.} and Mintern, {Justine D.} and Antoine Roquilly and Villadangos, {Jose A.}",
note = "Funding Information: This work was supported by the National Health and Medical Research Council of Australia (NHMRC) Fellowships 1154970 (G.K.S.), 1058193 (J.A.V.), and 1154502 (J.A.V.), program grants 1016629 (W.R.H. K.S. and J.A.V.) and 1113293 (W.R.H. and J.A.V.), and project grant 1163090 (A.R. and J.A.V.); the Soci{\'e}t{\'e} Fran{\c c}aise d'Anesth{\'e}sie et de R{\'e}animation (A.R.); the Fondation des Gueules Cass{\'e}es (A.R.); Agence National pour le Recherche (A.R.); and the Fundacion Pedro i Pons (J.V.-R.). We thank Prof Axel Kallies (University of Melbourne) for the TGFβR-IIfl/fl CD11ccre mice. Conceptualization, J.A.V. M.A. J.V.-R. and A.R.; data curation, M.A. J.V.-R. A.R. D.F.-R. S.V. A.T.L.L. J.T.W, L.J.Y. and A.Y.; formal analysis, M.A. J.V.-R. A.R. A.T.L.L. and A.Y.; funding acquisition, J.A.V. A.R. G.K.S. and W.R.H.; investigation, M.A. J.V.-R. and A.R.; methodology, M.A. J.V.-R. and A.R.; resources, J.A.V. Y.Z. L.W. I.C. M.H.L. A.M.L. K.S. W.R.H. and J.D.M.; software, G.K.S. and A.T.L.L.; supervision, J.A.V.; validation, J.A.V.; visualization, M.A.; writing – original draft, M.A. J.V.-R. and J.A.V.; writing – review and editing, M.A. A.R. and J.A.V. M.H.L. I.C. and K.S. are listed as inventors on patents relating to Clec9A antibodies. Funding Information: This work was supported by the National Health and Medical Research Council of Australia (NHMRC) Fellowships 1154970 (G.K.S.), 1058193 (J.A.V.), and 1154502 (J.A.V.), program grants 1016629 (W.R.H., K.S., and J.A.V.) and 1113293 (W.R.H. and J.A.V.), and project grant 1163090 (A.R. and J.A.V.); the Soci{\'e}t{\'e} Fran{\c c}aise d{\textquoteright}Anesth{\'e}sie et de R{\'e}animation (A.R.); the Fondation des Gueules Cass{\'e}es (A.R.); Agence National pour le Recherche (A.R.); and the Fundacion Pedro i Pons (J.V.-R.). We thank Prof Axel Kallies (University of Melbourne) for the TGFβR-II fl/fl CD11c cre mice. Publisher Copyright: {\textcopyright} 2024 The Authors",
year = "2024",
month = feb,
day = "27",
doi = "10.1016/j.celrep.2024.113754",
language = "English",
volume = "43",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Elsevier",
number = "2",
}
