Cathelicidin Host Defense Peptides and Inflammatory Signaling: Striking a Balance

Rheumatoid arthritis (RA) occurs in about 5 per 1000 people and can lead to severe joint damage and disability. Significant progress has been made over the past 2 decades regarding understanding of disease pathophysiology, optimal outcome measures, and effective treatment strategies, including the recognition of the importance of diagnosing and treating RA early.

Sepsis is defined as a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. Sepsis can induce acute kidney injury and multiple organ failures and represents the most common cause of death in the intensive care unit. Sepsis initiates a complex immune response that varies over time, with the concomitant occurrence of both pro-inflammatory and anti-inflammatory mechanisms. As a result, most patients with sepsis rapidly display signs of profound immunosuppression, which is associated with deleterious consequences. Scientific advances have highlighted the role of metabolic failure, epigenetic reprogramming, myeloid-derived suppressor cells, immature suppressive neutrophils and immune alterations in primary lymphoid organs (the thymus and bone marrow) in sepsis. An improved understanding of the mechanisms underlying this immunosuppression as well as of the similarities between sepsis-induced immunosuppression and immune defects in cancer or immunosenescence has led to novel therapeutic strategies aimed at stimulating immune function in patients with sepsis. Trials assessing the therapeutic benefit of IL-7, granulocyte-macrophage colony-stimulating factor (GM-CSF) and antibodies against programmed cell death protein 1 (PD1) and programmed cell death 1 ligand 1 (PDL1) for the treatment of sepsis are in progress. The reappraisal of sepsis pathophysiology has also resulted in a novel approach to the design of clinical trials evaluating sepsis treatments, based on an evaluation of the immune status and biomarker-based stratification of patients.

Antimicrobial peptides (AMPs) are essential components of immune defenses of multicellular organisms and are currently in development as anti-infective drugs. AMPs have been classically assumed to have broad-spectrum activity and simple kinetics, but recent evidence suggests an unexpected degree of specificity and a high capacity for synergies. Deeper evaluation of the molecular evolution and population genetics of AMP genes reveals more evidence for adaptive maintenance of polymorphism in AMP genes than has previously been appreciated, as well as adaptive loss of AMP activity. AMPs exhibit pharmacodynamic properties that reduce the evolution of resistance in target microbes, and AMPs may synergize with one another and with conventional antibiotics. Both of these properties make AMPs attractive for translational applications. However, if AMPs are to be used clinically, it is crucial to understand their natural biology in order to lessen the risk of collateral harm and avoid the crisis of resistance now facing conventional antibiotics.