Severe infections or trauma trigger SIRS, which is characterized by the release of immune-activating cytokines but is followed by weeks-long immunosuppression. Opportunistic infections post-SIRS are the major contributor to mortality and/or morbidity in critical care patients. Immunosuppression post-SIRS may also contribute to poor vaccination outcomes in areas with high incidence of infection with malaria or other pathogens.

We are characterizing the contribution of Dendritic Cell (DC) functional impairment (paralysis) to immunosuppression in mice where SIRS is triggered by TLR ligands or by infection with viruses, bacteria or the malaria parasite. We show that SIRS changes the local environment where DC undergo final differentiation, leading to weeks-long formation of paralysed DC with poor antigen-presenting function. We have (i) characterized the mechanisms responsible for this defect; (ii) identified a unique genetic program induced in paralysed DC; (iii) devised strategies to overcome the impaired antigen presenting function of paralysed DC; (iv) discovered cytokines that induce local formation of paralyzed DC; and (v) identified DC markers for paralysed DC which can be used as predictors of severity and outcomes in trauma patients. Some of these results have been recently published (1);  others will be presented at the meeting.

Our studies might lead to new therapies to overcome DC paralysis and restore immunocompetence post-SIRS, preventing secondary infections and death in critically ill patients. They may also lead to improved vaccination outcomes in areas with high incidence of pathogen infection.