Macaque Proteome Response to Highly Pathogenic Avian Influenza and 1918 Reassortant Influenza Virus Infections

ABSTRACT The host proteome response and molecular mechanisms that drive disease in vivo during infection by a human isolate of the highly pathogenic avian influenza virus (HPAI) and 1918 pandemic influenza virus remain poorly understood. This study presents a comprehensive characterization of the proteome response in cynomolgus macaque (Macaca fascicularis) lung tissue over 7 days of infection with HPAI (the most virulent), a reassortant virus containing 1918 hemagglutinin and neuraminidase surface proteins (intermediate virulence), or a human seasonal strain (least virulent). A high-sensitivity two-dimensional liquid chromatography-tandem mass spectroscopy strategy and functional network analysis were implemented to gain insight into response pathways activated in macaques during influenza virus infection. A macaque protein database was assembled and used in the identification of 35,239 unique peptide sequences corresponding to approximately 4,259 proteins. Quantitative analysis identified an increase in expression of 400 proteins during viral infection. The abundance levels of a subset of these 400 proteins produced strong correlations with disease progression observed in the macaques, distinguishing a “core” response to viral infection from a “high” response specific to severe disease. Proteome expression profiles revealed distinct temporal response kinetics between viral strains, with HPAI inducing the most rapid response. While proteins involved in the immune response, metabolism, and transport were increased rapidly in the lung by HPAI, the other viruses produced a delayed response, characterized by an increase in proteins involved in oxidative phosphorylation, RNA processing, and translation. Proteomic results were integrated with previous genomic and pathological analysis to characterize the dynamic nature of the influenza virus infection process.

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Recombinant Parainfluenza Virus 5 Vaccine Encoding the Influenza Virus Hemagglutinin Protects against H5N1 Highly Pathogenic Avian Influenza Virus Infection following Intranasal or Intramuscular Vaccination of BALB/c Mice

Journal of Virology ◽

10.1128/jvi.02330-12 ◽

2012 ◽

Vol 87 (1) ◽

pp. 363-371 ◽

Cited By ~ 31

Author(s):

A. J. Mooney ◽

Z. Li ◽

J. D. Gabbard ◽

B. He ◽

S. M. Tompkins

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Avian Influenza ◽

Highly Pathogenic Avian Influenza ◽

Influenza Virus Infection ◽

Parainfluenza Virus ◽

Highly Pathogenic ◽

Pathogenic Avian Influenza ◽

Influenza Virus Hemagglutinin ◽

Pathogenic Avian Influenza Virus

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Homo- and Heterosubtypic Low Pathogenic Avian Influenza Exposure on H5N1 Highly Pathogenic Avian Influenza Virus Infection in Wood Ducks (Aix sponsa)

PLoS ONE ◽

10.1371/journal.pone.0015987 ◽

2011 ◽

Vol 6 (1) ◽

pp. e15987 ◽

Cited By ~ 28

Author(s):

Taiana P. Costa ◽

Justin D. Brown ◽

Elizabeth W. Howerth ◽

David E. Stallknecht ◽

David E. Swayne

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Avian Influenza ◽

Highly Pathogenic Avian Influenza ◽

Influenza Virus Infection ◽

Aix Sponsa ◽

Highly Pathogenic ◽

Pathogenic Avian Influenza ◽

Wood Ducks ◽

Pathogenic Avian Influenza Virus

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Highly Pathogenic Avian Influenza Virus Infection in Feral Raccoons, Japan

Emerging Infectious Diseases ◽

10.3201/eid1704.101604 ◽

2011 ◽

Vol 17 (4) ◽

pp. 714-717 ◽

Cited By ~ 26

Author(s):

Taisuke Horimoto ◽

Ken Maeda ◽

Shin Murakami ◽

Maki Kiso ◽

Kiyoko Iwatsuki-Horimoto ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Highly Pathogenic Avian Influenza ◽

Influenza Virus Infection ◽

Highly Pathogenic ◽

Pathogenic Avian Influenza ◽

Pathogenic Avian Influenza Virus

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Inhibition of Reactive Oxygen Species Production Ameliorates Inflammation Induced by Influenza A Viruses via Upregulation of SOCS1 and SOCS3

Journal of Virology ◽

10.1128/jvi.03529-14 ◽

2014 ◽

Vol 89 (5) ◽

pp. 2672-2683 ◽

Cited By ~ 48

Author(s):

Siying Ye ◽

Sue Lowther ◽

John Stambas

Keyword(s):

Reactive Oxygen Species ◽

Influenza Virus ◽

Virus Infection ◽

Avian Influenza ◽

Highly Pathogenic Avian Influenza ◽

Influenza Virus Infection ◽

Reactive Oxygen ◽

Oxygen Species ◽

Highly Pathogenic ◽

Pathogenic Avian Influenza

ABSTRACTHighly pathogenic avian influenza virus infection is associated with severe mortality in both humans and poultry. The mechanisms of disease pathogenesis and immunity are poorly understood although recent evidence suggests that cytokine/chemokine dysregulation contributes to disease severity following H5N1 infection. Influenza A virus infection causes a rapid influx of inflammatory cells, resulting in increased reactive oxygen species production, cytokine expression, and acute lung injury. Proinflammatory stimuli are known to induce intracellular reactive oxygen species by activating NADPH oxidase activity. We therefore hypothesized that inhibition of this activity would restore host cytokine homeostasis following avian influenza virus infection. A panel of airway epithelial and immune cells from mammalian and avian species were infected with A/Puerto Rico/8/1934 H1N1 virus, low-pathogenicity avian influenza H5N3 virus (A/duck/Victoria/0305-2/2012), highly pathogenic avian influenza H5N1 virus (A/chicken/Vietnam/0008/2004), or low-pathogenicity avian influenza H7N9 virus (A/Anhui/1/2013). Quantitative real-time reverse transcriptase PCR showed that H5N1 and H7N9 viruses significantly stimulated cytokine (interleukin-6, beta interferon, CXCL10, and CCL5) production. Among the influenza-induced cytokines, CCL5 was identified as a potential marker for overactive immunity. Apocynin, a Nox2 inhibitor, inhibited influenza-induced cytokines and reactive oxygen species production, although viral replication was not significantly alteredin vitro. Interestingly, apocynin treatment significantly increased influenza virus-induced mRNA and protein expression of SOCS1 and SOCS3, enhancing negative regulation of cytokine signaling. These findings suggest that apocynin or its derivatives (targeting host responses) could be used in combination with antiviral strategies (targeting viruses) as therapeutic agents to ameliorate disease severity in susceptible species.IMPORTANCEHighly pathogenic avian influenza virus infection causes severe morbidity and mortality in both humans and poultry. Wide-spread antiviral resistance necessitates the need for the development of additional novel therapeutic measures to modulate overactive host immune responses after infection. Disease severity following avian influenza virus infection can be attributed in part to hyperinduction of inflammatory mediators such as cytokines, chemokines, and reactive oxygen species. Our study shows that highly pathogenic avian influenza H5N1 virus and low-pathogenicity avian influenza H7N9 virus (both associated with human fatalities) promote inactivation of FoxO3 and downregulation of the TAM receptor tyrosine kinase, Tyro3, leading to augmentation of the inflammatory cytokine response. Inhibition of influenza-induced reactive oxygen species with apocynin activated FoxO3 and stimulated SOCS1 and SOCS3 proteins, restoring cytokine homeostasis. We conclude that modulation of host immune responses with antioxidant and/or anti-inflammatory agents in combination with antiviral therapy may have important therapeutic benefits.

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