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Published on: June 15, 2019
Augmented Passive Immunotherapy with P4 Peptide Improves Phagocyte Activity in Severe Sepsis
Ben Morton1, Elena Mitsi, Shaun H Pennington
1*Aintree University Hospital NHS Foundation Trust, Liverpool, UK †Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK ‡Clinical Infection, Microbiology and Immunology, Institute of Infection & Global Health, University of Liverpool, Liverpool, UK §Local Comprehensive Research Network, Northwest Coast, Liverpool, UK ||Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK ¶Division of Bacterial Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia #Clinical Infection, Microbiology and Immunology, Institute of Infection & Global Health, University of Liverpool, Liverpool, UK.
Introduction:
Antimicrobial resistance threatens to undermine treatment of severe infection; new therapeutic strategies are urgently needed. Preclinical work shows that augmented passive immunotherapy with P4 peptide increases phagocytic activity and shows promise as a novel therapeutic strategy. Our aim was to determine ex vivo P4 activity in a target population of patients admitted to critical care with severe infection.
Methods:
We prospectively recruited UK critical care unit patients with severe sepsis and observed clinical course (≥3 months postdischarge). Blood samples were taken in early (≤48 h postdiagnosis, n = 54), latent (7 days postdiagnosis, n = 39), and convalescent (3-6 months postdiagnosis, n = 18) phases of disease. The primary outcome measure was killing of opsonized Streptococcus pneumoniae by neutrophils with and without P4 peptide stimulation. We also used a flow cytometric whole blood phagocytosis assay to determine phagocyte association and oxidation of intraphagosomal reporter beads.
Results:
P4 peptide increased neutrophil killing of opsonized pneumococci by 8.6% (confidence interval 6.35-10.76, P < 0.001) in all phases of sepsis, independent of infection source and microbiological status. This represented a 54.9% increase in bacterial killing compared with unstimulated neutrophils (15.6%) in early phase samples. Similarly, P4 peptide treatment significantly increased neutrophil and monocyte intraphagosomal reporter bead association and oxidation, independent of infection source.
Conclusions:
We have extended preclinical work to demonstrate that P4 peptide significantly increases phagocytosis and bacterial killing in samples from a target patient population with severe sepsis. This study supports the rationale for augmented passive immunotherapy as a therapeutic strategy in severe sepsis.
