Differences in Cytokine Production in Human Macrophages and in Virulence in Mice Are Attributable to the Acidic Polymerase Protein of Highly Pathogenic Influenza A Virus Subtype H5N1

• Published in: The Journal of infectious diseases Vol. 207; no. 2; pp. 262 - 271
• Main Authors: Sakabe, Saori, Takano, Ryo, Nagamura-Inoue, Tokiko, Yamashita, Naohide, Nidom, Chairul A., Mai thi Quynh Le, Iwatsuki-Horimoto, Kiyoko, Kawaoka, Yoshihiro
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.01.2013
• Series: Editor's choice
• Subjects: Animals; Biological and medical sciences; Cytokines; Cytokines - biosynthesis; Cytokines - immunology; Epithelial cells; Epithelial Cells - immunology; Epithelial Cells - virology; Female; Fundamental and applied biological sciences. Psychology; Genes; H5N1 subtype influenza A virus; HEK293 Cells; Human growth; Humans; Infections; Infectious diseases; Influenza; Influenza A virus; Influenza A Virus, H5N1 Subtype - genetics; Influenza A Virus, H5N1 Subtype - pathogenicity; Influenza A Virus, H5N1 Subtype - physiology; Influenza, Human - immunology; Influenza, Human - virology; Macrophages; Macrophages - immunology; Macrophages - virology; Madin Darby Canine Kidney Cells; Major and Brief Reports; Medical sciences; Mice; Mice, Inbred BALB C; Microbiology; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - veterinary; Orthomyxoviridae Infections - virology; Reassortant Viruses - genetics; Reassortant Viruses - metabolism; Reassortant Viruses - pathogenicity; RNA Replicase - genetics; Viral Proteins - genetics; Virulence; Virulence - genetics; Viruses; Human; Infection; Influenzavirus A(H5N1); Vertebrata; Mammalia; Mouse; Acidic protein; Virulence; Rodentia; Cytokine; Subtype; Macrophage
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jis523

Background. The pathogenesis of influenza A virus subtype H5N1 (hereafter, "H5N1") infection in humans is not completely understood, although hypercytokinemia is thought to play a role. We previously reported that most H5N1 viruses induce high cytokine responses in human macrophages, whereas some H5N1 viruses induce only a low level of cytokine production similar to that induced by seasonal viruses. Methods. To identify the viral molecular determinants for cytokine induction of H5N1 viruses in human macrophages, we generated a series of reassortant viruses between the high cytokine inducer A/Vietnam/UT3028II/03 clone 2 (VN3028IIcl2) and the low inducer A/Indonesia/UT3006/05 (IDN3006) and evaluated cytokine expression in human macrophages. Results. Viruses possessing the acidic polymerase (PA) gene of VN3028IIcl2 exhibited high levels of hypercytokinemia-related cytokine expression in human macrophages, compared with IDN3006, but showed no substantial differences in viral growth in these cells. Further, the PA gene of VN3028IIcl2 conferred enhanced virulence in mice. Conclusions. These results demonstrate that the PA gene of VN3028IIcl2 affects cytokine production in human macrophages and virulence in mice. These findings provide new insights into the cytokine-mediated pathogenesis of H5N1 infection in humans.