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

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.

miR-144 attenuates the host response to influenza virus by targeting the TRAF6-IRF7 signaling axis

“…We have previously observed that lung type I alveolar epithelial cells are rapidly infected in this experimental intranasal infection model, with faster kinetics than the descending infection that occurs during natural infection [20]. We observed a significantly lower viral load in type I epithelial cells isolated from miR-144/451-deficient mice relative to wild-type cells following in vitro influenza virus infection (Fig 2A).…”

Human H7N9 and H5N1 Influenza Viruses Differ in Induction of Cytokines and Tissue Tropism

“…In spite of the differential cytokine response, no major differences in immune cell infiltration were evident between H5N1 and H7N9 viruses. Recent studies have shown that early activation of NF-Band IL-17-mediated signaling pathways may substantially contribute to the development of severe disease (28), implying that the host cytokine/chemokine response may be just as crucial to disease outcome as viral load.…”

Systems-Level Analysis of Innate Immunity

“…These whole-tissue transcriptomic analyses demonstrated that although the type I interferon transcriptional profiles of the 1918 and H5N1 viral strains were similar, genes related to the inflammatory response and cell death (including key components of the inflammasome, NLRP3, and IL-1β) were highly induced by the 1918 virus but were downregulated by the H5N1 strain (71). Similarly, we identified distinct transcriptional programs activated in the upper and lower airways by influenza strains of varying pathogenicity (72). Moreover, we determined that the induction of inflammation-related genes during swine-origin pandemic H1N1 infection in vitro is significantly delayed in comparison to infections with its parental strains (P. Dash, C.J.…”