Innate immune induction and influenza protection elicited by a response-selective agonist of human C5a.

Ana Fernandez-Sesma,Sam D Sanderson,Marilyn L Thoman,Stephanie Widmann,Homero Sepulveda,Joy A Phillips,Edgar B Herrera,Kornelia Kis,Elizabeth L Virts

doi:10.1371/journal.pone.0040303

Abstract

The anaphylatoxin C5a is an especially potent mediator of both local and systemic inflammation. However, C5a also plays an essential role in mucosal host defense against bacterial, viral, and fungal infection. We have developed a response-selective agonist of human C5a, termed EP67, which retains the immunoenhancing activity of C5a at the expense of its inflammatory, anaphylagenic properties. EP67 insufflation results in the rapid induction of pulmonary cytokines and chemokines. This is followed by an influx of innate immune effector cells, including neutrophils, NK cells, and dendritic cells. EP67 exhibits both prophylactic and therapeutic protection when tested in a murine model of influenza A infection. Mice treated with EP67 within a twenty-four hour window of non-lethal infection were significantly protected from influenza-induced weight loss. Furthermore, EP67 delivered twenty-four hours after lethal infection completely blocked influenza-induced mortality (0% vs. 100% survival). Since protection based on innate immune induction is not restricted to any specific pathogen, EP67 may well prove equally efficacious against a wide variety of possible viral, bacterial, and fungal pathogens. Such a strategy could be used to stop the worldwide spread of emergent respiratory diseases, including but not limited to novel strains of influenza.

Highlights

The primary role of the innate immune system is to provide an immediate line of defense against foreign pathogens [1,2,3]
Activation of innate immunity to pathogens typically involves release of acute-phase proteins including IL-6, IL-8 and TNF. This results in a rapid influx of PMNs, natural killer (NK) cells, and macrophages to the site of infection
Two hours after EP67 insufflation, IL-6, TNF, GM-CSF, and KC/CXCL1 were all detected at increased concentrations in the BAL fluid

Summary

Introduction

The primary role of the innate immune system is to provide an immediate line of defense against foreign pathogens [1,2,3]. Activation of innate immunity to pathogens typically involves release of acute-phase proteins including IL-6, IL-8 and TNF. This results in a rapid influx of PMNs (polymorphonuclear leukocytes, primarily neutrophils), natural killer (NK) cells, and macrophages to the site of infection. This innate response acts to contain the pathogen during development of the acquired immune response. Due to its rapid onset and non-specific nature, there is a great deal of interest in developing therapeutic agents that combat infection via innate immune induction This could result in therapeutics able to protect against multiple, diverse pathogens, moving away from the current ‘‘one bug, one drug’’ system

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