Gene expression analysis of host innate immune responses during Lethal H5N1 infection in ferrets.
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.
Cameron
Cheryl M
CM
Division of Immunology, International Institute of Infection and Immunity, Shantou University Medical College, 22 Xinling Road, Shantou, Guangdong, P. R. China.
Cameron
Mark J
MJ
Bermejo-Martin
Jesus F
JF
Ran
Longsi
L
Xu
Luoling
L
Turner
Patricia V
PV
Ran
Ran
R
Danesh
Ali
A
Fang
Yuan
Y
Chan
Pak-Kei M
PK
Mytle
Nutan
N
Sullivan
Timothy J
TJ
Collins
Tassie L
TL
Johnson
Michael G
MG
Medina
Julio C
JC
Rowe
Thomas
T
Kelvin
David J
DJ
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
D054357:Chemokine CXCL10; D054367:Receptors, CXCR3