Systemic inflammatory response syndrome triggered by blood-borne pathogens induces prolonged dendritic cell paralysis and immunosuppression

Mitra Ashayeripanah (1) , Javier Vega-Ramos (1, 2) , Daniel Fernandez-Ruiz (1, 3) , Shirin Valikhani (1) , Aaron T.L. Lun (2, 1) , Jason White (4, 5, 1) , Louise Young (1, 2) , Atefeh Yaftiyan (1) , Yifan Zhan (1, 2) , Linda Wakim (1) , Irina Caminschi (6, 7) , Mireille Lahoud (6, 7) , Andrew Lew (1, 2) , Ken Shortman (2, 1) , Gordon Smyth (2, 4) , William Heath (1) , Justine Mintern (2, 4) , Antoine Roquilly (8, 9, 10, 4) , Jose Villadangos (4, 1)

1 The Peter Doherty Institute for Infection and Immunity [Melbourne]
2 WEHI - The Walter and Eliza Hall Institute of Medical Research
3 University of New South Wales [Kensington]
4 University of Melbourne
5 Charles Sturt University [Australia]
6 Monash Biomedicine Discovery Institute
7 Monash University [Clayton]
8 U1064 Inserm - CR2TI - Centre de Recherche en Transplantation et Immunologie - Center for Research in Transplantation and Translational Immunology
9 Team 6 - U1064 Inserm - CR2TI - Team 6 : Impact of acute inflammation on host pathogen interactions and lung homeostasis
10 Service d'anesthésie et réanimation chirurgicale [Nantes]

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.

Mots clés: CP: Immunology; T cells; antigen presentation; cell development; cross-presentation; immunosuppression; infection; inflammation; malaria; phagocytosis; spatiotemporal adaptations.

Domaines: Sciences du Vivant [q-bio]

Mitra Ashayeripanah, Javier Vega-Ramos, Daniel Fernandez-Ruiz, Shirin Valikhani, Aaron T.L. Lun, et al.. Systemic inflammatory response syndrome triggered by blood-borne pathogens induces prolonged dendritic cell paralysis and immunosuppression. Cell Reports, 2024, 43 (2), pp.113754. ⟨10.1016/j.celrep.2024.113754⟩. ⟨inserm-04526332⟩