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

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. [Display omitted] • Blood infections cause severe inflammation followed by protracted immunosuppression • Impaired immunity is due to formation of paralyzed conventional dendritic cells (cDCs) • Local secondary signals that persist after resolution of infection induce paralysis • Therapies that overcome or reduce the duration of cDC paralysis restore immunocompetence Ashayeripanah et al. show that severe inflammation triggered by blood infections such as malaria induces formation of functionally impaired (paralyzed) dendritic cells for weeks after resolution of infection. Paralysis causes immune suppression. Transcriptomic, phenotypic, and functional characterization of paralysis leads to designing treatments that restore dendritic cell function and immunocompetence. [ABSTRACT FROM AUTHOR]