Dataset Information

The dynamic proteome of influenza A virus infection identifies M segment splicing as a host range determinant

ABSTRACT: A century ago, influenza A virus (IAV) infection caused the 1918 flu pandemic and killed an estimated 20-40 million people. Pandemic IAV outbreaks occur when strains from animal reservoirs acquire the ability to infect and spread among humans. The molecular details of this species barrier are incompletely understood. We combined metabolic pulse labeling and quantitative shotgun proteomics to globally monitor protein synthesis upon infection of human cells with a human- and a bird-adapted IAV strain. While production of host proteins was remarkably similar, we observed striking differences in the kinetics of viral protein synthesis over the course of infection. Most importantly, the matrix protein M1 was inefficiently produced by the bird-adapted strain at later stages. We show that impaired production of M1 from bird-adapted strains is caused by increased splicing of the M segment RNA to alternative isoforms. Experiments with reporter constructs and recombinant influenza viruses revealed that strain-specific M segment splicing is controlled by the 3’ splice site and functionally important for permissive infection. Independent in silico and biochemical evidence shows that avian-adapted M segments have evolved different conserved RNA structure features than human-adapted sequences. Thus, our data identifies M segment RNA splicing as a viral determinant of host range.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human) Gallus Gallus (chicken)

TISSUE(S): Embryo, Lung, Epithelial Cell, Fibroblast

DISEASE(S): Avian Influenza

SUBMITTER: Boris Bogdanow

LAB HEAD: Matthias Selbach

PROVIDER: PXD015475 | Pride | 2019-11-11

REPOSITORIES: pride

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			Action	DRS
	Animal_20190405_BB_pSILACGGHS_0_6fw.raw	Raw
	Animal_20190405_BB_pSILACGGHS_0_6fw2mic.raw	Raw
	Animal_20190405_BB_pSILACGGHS_0_6rev.raw	Raw
	Animal_20190405_BB_pSILACGGHS_5_10fw.raw	Raw
	Animal_20190405_BB_pSILACGGHS_5_10rev_20190415115438.raw	Raw

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The dynamic proteome of influenza A virus infection identifies M segment splicing as a host range determinant.

Bogdanow Boris B Wang Xi X Eichelbaum Katrin K Sadewasser Anne A Husic Immanuel I Paki Katharina K Budt Matthias M Hergeselle Martha M Vetter Barbara B Hou Jingyi J Chen Wei W Wiebusch Lüder L Meyer Irmtraud M IM Wolff Thorsten T Selbach Matthias M

Nature communications 20191204 1

Pandemic influenza A virus (IAV) outbreaks occur when strains from animal reservoirs acquire the ability to infect and spread among humans. The molecular basis of this species barrier is incompletely understood. Here we combine metabolic pulse labeling and quantitative proteomics to monitor protein synthesis upon infection of human cells with a human- and a bird-adapted IAV strain and observe striking differences in viral protein synthesis. Most importantly, the matrix protein M1 is inefficientl ...[more]

PMID: 31797923

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Project description:Influenza A virus (IAV) infection is a global respiratory disease, which annually leads to 3-5 million cases of severe illness, resulting in 290,000-650,000 deaths. Additionally, during the past century, four global IAV pandemics have claimed millions of human lives. The epithelial lining of the trachea plays a vital role during IAV infection, both as point of viral entry and replication as well as in the antiviral immune response. Tracheal tissue is generally inaccessible from human patients, which makes animal models crucial for the study of the tracheal host immune response. In this study, pigs were inoculated with swine- or human-adapted H1N1 IAV to gain insight into how host adaptation of IAV shapes the innate immune response during infection. In-depth multi-omics analysis (global proteomics and RNA sequencing) of the host response in upper and lower tracheal tissue was conducted, and results were validated by microfluidic qPCR. Additionally, a subset of samples was selected for histopathological examination. A classical innate antiviral immune response was induced in both upper and lower trachea after infection with either swine- or human-adapted IAV with upregulation of genes and higher abundance of proteins associated with viral infection and recognition, accompanied by a significant induction of interferon stimulated genes with corresponding higher proteins concentrations. Infection with the swine-adapted virus induced a much stronger immune response compared to infection with a human-adapted IAV strain in the lower trachea, which could be a consequence of a higher viral load and a higher degree of inflammation. Central components of the JAK-STAT pathway, apoptosis, pyrimidine metabolism, and the cytoskeleton were significantly altered depending on infection with swine- or human-adapted virus and might be relevant mechanisms in relation to antiviral immunity against putative zoonotic IAV. Based on our findings, we hypothesize that during host adaptation, IAV evolve to modulate important host cell elements to favor viral infectivity and replication.