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.

• Authors: Mitra Ashayeripanah, Javier Vega-Ramos, Daniel Fernandez-Ruiz, Shirin Valikhani, Aaron T L Lun, Jason T White, Louise J Young, Atefeh Yaftiyan, Yifan Zhan, Linda Wakim, Irina Caminschi, Mireille H Lahoud, Andrew M Lew, Ken Shortman, Gordon K Smyth, William R Heath, Justine D Mintern, Antoine Roquilly, Jose A Villadangos
• Journal: Cell reports (Cell Rep) Vol. 43 Issue 2 Pg. 113754 (Feb 27 2024) ISSN: 2211-1247 [Electronic] United States
• PMID: 38354086 (Publication Type: Journal Article)
• Copyright: Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Topics

• Humans
• Blood-Borne Pathogens
• Immunosuppression Therapy
• Dendritic Cells
• Paralysis
• Systemic Inflammatory Response Syndrome