Host-directed immune therapies: a second front in the battle against sepsis

Each year, sepsis claims more lives in the United States than many major cancers and HIV/AIDS combined, yet therapeutic progress has been modest. Adding to this crisis is the alarming rise of multidrug-resistant "superbugs," which increasingly render conventional antibiotics ineffective. Pathogen-targeted antibiotics will always remain a cornerstone of sepsis treatment, and research into novel antibiotics must continue unabated. However, the consistent mortality in sepsis tells us this approach is insufficient. Most deaths in sepsis do not occur during the early cytokine storm-driven hyper-inflammatory phase but rather days or weeks after the initial insult, during a protracted phase of immune suppression. Here, we make the case that a crucial way to reduce sepsis mortality lies in restoration of the patient's immune competence, enabling the patient to contain and kill the invading microbes. Adjuvant immune therapies will not only enable killing of the initial, invading pathogens but also prevent secondary, hospital-acquired infections. Immunotherapy revolutionized oncology by challenging the assumption that cancer was best treated through cytotoxic or targeted tumor-directed approaches, and sepsis now stands at a similar inflection point. We argue that embracing immune restoration as a core therapeutic objective offers the most promising means to improve survival in this lethal disorder.