title: 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.
authors.affiliation: Division of Immunology, International Institute of Infection and Immunity, Shantou University Medical College, 22 Xinling Road, Shantou, Guangdong, P. R. China.
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Cameron
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cameron
authors.forename: Jesus F
authors.initials: JF
authors.lastname: Bermejo-Martin
authors.forename: Longsi
authors.initials: L
authors.lastname: Ran
authors.forename: Luoling
authors.initials: L
authors.lastname: Xu
authors.forename: Patricia V
authors.initials: PV
authors.lastname: Turner
authors.forename: Ran
authors.initials: R
authors.lastname: Ran
authors.forename: Ali
authors.initials: A
authors.lastname: Danesh
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fang
authors.forename: Pak-Kei M
authors.initials: PK
authors.lastname: Chan
authors.forename: Nutan
authors.initials: N
authors.lastname: Mytle
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Sullivan
authors.forename: Tassie L
authors.initials: TL
authors.lastname: Collins
authors.forename: Michael G
authors.initials: MG
authors.lastname: Johnson
authors.forename: Julio C
authors.initials: JC
authors.lastname: Medina
authors.forename: Thomas
authors.initials: T
authors.lastname: Rowe
authors.forename: David J
authors.initials: DJ
authors.lastname: Kelvin
mesh_terms: D000818:Animals; D054357:Chemokine CXCL10 / Q000096:biosynthesis; D005289:Ferrets; D020869:Gene Expression Profiling; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology / Q000502:physiology; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology* / Q000502:physiology*; D008168:Lung / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D008297:Male; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors; D016019:Survival Analysis
chemical_list: D054357:Chemokine CXCL10; D054367:Receptors, CXCR3