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

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

doi:10.1016/j.celrep.2024.113754

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

Cell Rep. 2024 Feb 27;43(2):113754. doi: 10.1016/j.celrep.2024.113754. Epub 2024 Feb 13.

Authors

Mitra Ashayeripanah¹, Javier Vega-Ramos², Daniel Fernandez-Ruiz³, Shirin Valikhani¹, Aaron T L Lun⁴, Jason T White¹, Louise J Young⁴, Atefeh Yaftiyan¹, Yifan Zhan⁴, Linda Wakim¹, Irina Caminschi⁵, Mireille H Lahoud⁵, Andrew M Lew⁴, Ken Shortman⁴, Gordon K Smyth⁶, William R Heath¹, Justine D Mintern⁷, Antoine Roquilly⁸, Jose A Villadangos⁹

Affiliations

¹ Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC 3000, Australia.
² Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC 3000, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
³ Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC 3000, Australia; School of Biomedical Sciences, Faculty of Medicine & Health and the UNSW RNA Institute, The University of New South Wales, Kensington, NSW 2052, Australia.
⁴ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
⁵ Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
⁶ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Mathematics and Statistics, The University of Melbourne, Parkville, VIC 3010, Australia.
⁷ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia.
⁸ Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC 3000, Australia; Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, 44000 Nantes, France; CHU Nantes, INSERM, Nantes Université, Anesthesie Reanimation, CIC 1413, 44000 Nantes, France. Electronic address: antoine.roquilly@chu-nantes.fr.
⁹ Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC 3000, Australia; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: j.villadangos@unimelb.edu.au.

PMID: 38354086
DOI: 10.1016/j.celrep.2024.113754

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

MeSH terms

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