Differential Host Response, Rather Than Early Viral Replication Efficiency, Correlates with Pathogenicity Caused by Influenza Viruses

Peter S Askovich,Peter Vogel,Pradyot Dash,Catherine J Sanders,Paul G Thomas,Garnet Navarro,Alan Aderem,Carrie M Rosenberger,Peter C Doherty,Alan H Diercks

doi:10.1371/journal.pone.0074863

Peter S Askovich, Peter Vogel + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0074863

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Abstract

Influenza viruses exhibit large, strain-dependent differences in pathogenicity in mammalian hosts. Although the characteristics of severe disease, including uncontrolled viral replication, infection of the lower airway, and highly inflammatory cytokine responses have been extensively documented, the specific virulence mechanisms that distinguish highly pathogenic strains remain elusive. In this study, we focused on the early events in influenza infection, measuring the growth rate of three strains of varying pathogenicity in the mouse airway epithelium and simultaneously examining the global host transcriptional response over the first 24 hours. Although all strains replicated equally rapidly over the first viral life-cycle, their growth rates in both lung and tracheal tissue strongly diverged at later times, resulting in nearly 10-fold differences in viral load by 24 hours following infection. We identified separate networks of genes in both the lung and tracheal tissues whose rapid up-regulation at early time points by specific strains correlated with a reduced viral replication rate of those strains. The set of early-induced genes in the lung that led to viral growth restriction is enriched for both NF-κB binding site motifs and members of the TREM1 and IL-17 signaling pathways, suggesting that rapid, NF-κB –mediated activation of these pathways may contribute to control of viral replication. Because influenza infection extending into the lung generally results in severe disease, early activation of these pathways may be one factor distinguishing high- and low-pathogenicity strains.

Highlights

Despite intense research efforts, infection with influenza virus remains a significant source of morbidity and mortality world-wide
While seasonal influenza strains readily infect the upper regions of the human respiratory tract, the H5N1 viruses only establish when they penetrate more deeply, likely due to the binding specificity of their hemagglutinin molecules for α2,3-linked sialic acids which are found only in the lung [11,12,13]
At 16 hours, the replication rates started to diverge with the low pathogenicity X31 lagging behind that of the high pathogenicity PR8 and VN strains

Summary

Introduction

Infection with influenza virus remains a significant source of morbidity and mortality world-wide. Seasonal influenza strains infect three to five million people each year resulting in approximately 250,000 to 500,000 deaths [1]. In addition to yearly epidemics, influenza A viruses cause occasional pandemics when a novel strain emerges and the majority of the human population has no immunity. The 1918 influenza pandemic, which killed between 50-100 million people world-wide, was one of the most deadly events in human history [4]. While seasonal influenza strains readily infect the upper regions of the human respiratory tract, the H5N1 viruses only establish when they penetrate more deeply, likely due to the binding specificity of their hemagglutinin molecules for α2,3-linked sialic acids which are found only in the lung [11,12,13]. Infection of the bronchi and alveoli, either directly by avian viruses or by seasonal strains that spread from the upper respiratory tract, is highly correlated with severe disease [14,15,16]

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