The Calm after the Storm: Implications of Sepsis Immunoparalysis on Host Immunity

Abstract

The immunological hallmarks of sepsis include the inflammation-mediated cytokine storm, apoptosis-driven lymphopenia, and prolonged immunoparalysis. Although early clinical efforts were focused on increasing the survival of patients through the first phase, studies are now shifting attention to the long-term effects of sepsis on immune fitness in survivors. In particular, the most pertinent task is deciphering how the immune system becomes suppressed, leading to increased incidence of secondary infections. In this review, we introduce the contribution of numerical changes and functional reprogramming within innate (NK cells, dendritic cells) and adaptive (T cells, B cells) immune cells on the chronic immune dysregulation in the septic murine and human host. We briefly discuss how prior immunological experience in murine models impacts sepsis severity, immune dysfunction, and clinical relevance. Finally, we dive into how comorbidities, specifically autoimmunity and cancer, can influence host susceptibility to sepsis and the associated immune dysfunction.

Figure 1.

The immunological hallmarks of the septic event. The host immune response against systemic pathogens initiates with excessive inflammation known as the cytokine storm. Concurrent declines in cellularity (lymphopenia) develop. Eventually the cytokine storm subsides, and immune cell numbers recover with subsequent poor responses from remaining cellular pools. Image created with BioRender.com.

Figure 2.

The immune dysfunctions of dendritic cells and lymphocytes during immunoparalysis. This illustrates the current understanding from combined murine and human data on the inhibitory markers, cytokines, and antibodies produced during the chronic immunoparalysis. Downward-facing arrows indicate declines, dotted lines indicate murine based mechanism. Image created with BioRender.com.