Gene Expression Analysis of Host Innate Immune Responses during Lethal H5N1 Infection in Ferrets

Abstract

How viral and host factors contribute to the severe pathogenicity of the H5N1 subtype of avian influenza virus infection in humans is poorly understood. We identified three clusters of differentially expressed innate immune response genes in lungs from H5N1 (A/Vietnam/1203/04) influenza virus-infected ferrets by oligonucleotide microarray analysis. Interferon response genes were more strongly expressed in H5N1-infected ferret lungs than in lungs from ferrets infected with the less pathogenic H3N2 subtype. In particular, robust CXCL10 gene expression in H5N1-infected ferrets led us to test the pathogenic role of signaling via CXCL10's cognate receptor, CXCR3, during H5N1 influenza virus infection. Treatment of H5N1-infected ferrets with the drug AMG487, a CXCR3 antagonist, resulted in a reduction of symptom severity and delayed mortality compared to vehicle treatment. We contend that unregulated host interferon responses are at least partially responsible for the severity of H5N1 infection and provide evidence that attenuating the CXCR3 signaling pathway improves the clinical course of H5N1 infection in ferrets.

Gene expression changes in the host response between resistant and susceptible inbred mouse strains after influenza A infection

“…In contrast, 91, 932, 1516 and 1460 public DBA/ 2J genes were found on days 1e4. Similar amounts of regulated genes after infection with influenza A virus have been obtained in other studies (Cameron et al [16] ca. 2300 genes; Rosseau et al [17] ca.…”

“…A similar observation was made in ferrets infected with high or low pathogenic influenza virus. Interferoninduced genes were activated in both groups to a similar extent [16]. Furthermore, Zou et al [21] described the activation of genes in interferon-treated macrophages of wild type and Ubp43 mutant mice.…”

“…These genes are not activated in the susceptible strain where virus replication and tissue damage is continuing [11]. Up-regulation of genes related to cell growth and proliferation has also been observed in ferrets infected with the less virulent H3N2 virus, whereas this group of genes was down-regulated in ferrets infected with the highly pathogenic H5N1 virus [16]. From these and our observations, we speculate that the up-regulation of cell growth and proliferation genes is related to tissue repair and/or division of immune cells, whereas severe disease is indicated by absence or down-regulation of these genes.…”

Impact of Microarray Technology in Influenza Virus Research and Diagnostics

“…The genes specifically getting up-regulated in response to virus infection were interferon inducible genes, pro-inflammatory cytokines, components of JAK-STAT pathway, NF-ĸB mediated signaling and genes involved in apoptotic mechanism [32][33][34]41,42]. Interactions of these genes with various other proteins involved in signal transduction mechanism have also been elucidated in these studies.…”

“…Similar microarray based studies in ferrets showed that H5N1 infection induced severe disease that was associated with strong expression of interferon response genes including the interferon-γ-induced cytokine CXCL10. Treatment of H5N1-infected ferrets with an antagonist of the CXCL10 receptor (CXCR3) reduced the severity of the flu symptoms and the viral titers compared to the controls, clearly demonstrating the potential of biological response modifiers for the clinical management of viral infections [41].…”