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 chromatographytandem 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.

Morphine Produces Immunosuppressive Effects in Nonhuman Primates at the Proteomic and Cellular Levels

“…The rhesus macaque's Ensemble protein list (40) (http://www.ensembl.org) was obtained from InParanoid (M.mulatta.fa 21-Apr-2009) (41)(42)(43), containing 21,905 nonredunant protein sequences (http://omics.pnl.gov), and used by SEQUEST software (Version v.27, Rev 12, Thermo Fisher Scientific, Waltham MA) to search the MS/MS spectral data. Although the genomes of AGM and PT are not fully sequenced, the Macaca mulatta protein list has previously been used in other NHP studies (44,45), and there is high sequence similarity between members of the Primate taxon. Porcine trypsin was added to the database as an expected contaminant.…”

Comparative proteome analyses of host protein expression in response to Enterovirus 71 and Coxsackievirus A16 infections

“…In recent years, focus on proteomic analysis of host cell proteins had become a popular approach to elucidate the interplay of host and viral proteins so as to devise novel ways to combat viral infections [13][14][15][16]. Proteome analysis had been used to demonstrate and characterize the cellular proteins in response to bursal disease virus (IBDV) and the membrane proteins of Mycobacterium tuberculosis [14,17].…”

The use of nonhuman primates in research on seasonal, pandemic and avian influenza, 1893–2014

“…However, the H5N1 virus was even more pathogenic, causing greater tissue damage and eliciting a stronger proinflammatory response than the 1918 reassortant virus. Three follow-up studies employing tissue samples collected in this experiment examined host gene expression in extrapulmonary tissues (Tolnay et al, 2010), the proteome response (Brown et al, 2010) and microRNA expression in lung tissues (Li et al, 2011). Each report identified distinct patterns of host responses in macaques infected with the seasonal H1N1, reassortant 1918 or H5N1 avian virus.…”