Ben Morton1, Elena Mitsi, Shaun H Pennington, Jesús Reiné, Angela D Wright, Robert Parker, Ingeborg D Welters, John D Blakey, Gowrisankar Rajam, Edwin W Ades, Daniela M Ferreira, Duolao Wang, Aras Kadioglu, Stephen B Gordon. 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.
Abstract
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.
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.
Authors: Ankur Gupta-Wright; Dumizulu Tembo; Kondwani C Jambo; Elizabeth Chimbayo; Leonard Mvaya; Shannon Caldwell; David G Russell; Henry C Mwandumba Journal: Front Immunol Date: 2017-09-28 Impact factor: 7.561
Authors: Katie Watson; Clark D Russell; J Kenneth Baillie; Kev Dhaliwal; J Ross Fitzgerald; Timothy J Mitchell; A John Simpson; Stephen A Renshaw; David H Dockrell Journal: Front Immunol Date: 2020-06-05 Impact factor: 7.561
Authors: Chloé Albert-Vega; Dina M Tawfik; Sophie Trouillet-Assant; Laurence Vachot; François Mallet; Julien Textoris Journal: Front Immunol Date: 2018-10-16 Impact factor: 7.561
Authors: Simon P Jochems; Fernando Marcon; Beatriz F Carniel; Mark Holloway; Elena Mitsi; Emma Smith; Jenna F Gritzfeld; Carla Solórzano; Jesús Reiné; Sherin Pojar; Elissavet Nikolaou; Esther L German; Angie Hyder-Wright; Helen Hill; Caz Hales; Wouter A A de Steenhuijsen Piters; Debby Bogaert; Hugh Adler; Seher Zaidi; Victoria Connor; Stephen B Gordon; Jamie Rylance; Helder I Nakaya; Daniela M Ferreira Journal: Nat Immunol Date: 2018-10-29 Impact factor: 25.606