A Protective Role for Complement C3 Protein during Pandemic 2009 H1N1 and H5N1 Influenza A Virus Infection

Kevin B O'Brien,David Y Dundore,Stacey Schultz-Cherry,Mark T Heise,Thomas E Morrison,Jean-Pierre Vartanian

doi:10.1371/journal.pone.0017377

Abstract

Highly pathogenic H5N1 influenza infections are associated with enhanced inflammatory and cytokine responses, severe lung damage, and an overall dysregulation of innate immunity. C3, a member of the complement system of serum proteins, is a major component of the innate immune and inflammatory responses. However, the role of this protein in the pathogenesis of H5N1 infection is unknown. Here we demonstrate that H5N1 influenza virus infected mice had increased levels of C5a and C3 activation byproducts as compared to mice infected with either seasonal or pandemic 2009 H1N1 influenza viruses. We hypothesized that the increased complement was associated with the enhanced disease associated with the H5N1 infection. However, studies in knockout mice demonstrated that C3 was required for protection from influenza infection, proper viral clearance, and associated with changes in cellular infiltration. These studies suggest that although the levels of complement activation may differ depending on the influenza virus subtype, complement is an important host defense mechanism.

Highlights

Since emerging in 1997, highly pathogenic avian influenza (HPAI) H5N1 viruses have been associated with over 500 human infections with an unprecedented fatality rate exceeding 60%
The severe disease associated with HPAI H5N1 infections in humans and animals could result from several factors including dissemination of the virus beyond the respiratory tract, higher and prolonged viral replication leading to increased viral cytolytic damage, differences in the host response induced by the H5N1 viruses, or a combination of all these factors
Similar results were observed in animal models where H5N1 infection is associated with elevated cytokine and chemokine levels [2,6,7,8,9], enhanced recruitment of macrophages and neutrophils into the lungs leading to acute lung inflammation [10], and premature apoptosis of dendritic cells [11]

Summary

Introduction

Since emerging in 1997, highly pathogenic avian influenza (HPAI) H5N1 viruses have been associated with over 500 human infections with an unprecedented fatality rate exceeding 60%. Similar results were observed in animal models where H5N1 infection is associated with elevated cytokine and chemokine levels [2,6,7,8,9], enhanced recruitment of macrophages and neutrophils into the lungs leading to acute lung inflammation [10], and premature apoptosis of dendritic cells [11]. This aberrant host response is reminiscent of 1918 influenza virus infected animals [10,12]

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Conclusion