Dendritic cells (DC) are the most potent antigen presenting cells which link the adaptive and innate arms of immune response. This normal functioning of DC is severely impaired following recovery from acute inflammation caused by sepsis or severe trauma, leading to protracted immunosuppression. This so-called “DC paralysis” results in greater risk of secondary infections and higher rates of mortality and morbidity in patients. We modelled systemic inflammation, DC paralysis and immunosuppression in mice after injecting Toll-like receptor (TLR) ligands or malaria infection. Functional characterization of paralyzed DC following recovery from systemic inflammation and/or infection showed impairments in uptake of antigen, defects in antigen processing and presentation by MHC molecules, diminished cytokine production, and elevated production of inhibitory molecules, altogether leading to impaired priming of antigen-specific T cells by paralyzed DC. We were able to improve paralyzed DC function by targeting antigen to a surface receptor or by blocking interferon type I signaling. We are currently addressing the role of intrinsic and extrinsic factors that induce DC paralysis in our mouse models. In parallel, we are translating our findings to the clinic, characterizing paralyzed DC in peripheral blood of COVID-19 or trauma patients admitted to Intensive Care Units. We ultimately aim to develop diagnostic tests of DC paralysis to identify patients at-risk of secondary infections, and potential therapies to prevent, ameliorate or shorten DC paralysis in critically-ill patients.