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 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.3

Selective flexible packaging pathways of the segmented genome of influenza A virus

“…We have recently shown that replication of the avian A/Mallard/439/ 2004 virus in A549 cells is attenuated by three orders of magnitude at 72 h.p.i. in comparison to A/Panama/2007/99 42,43 . We were able to demonstrate that both viruses enter A549 cells with similar efficiency, and that mRNA from both virus strains accesses the translational machinery with comparable efficiency.…”

HA stabilization promotes replication and transmission of swine H1N1 gamma influenza viruses in ferrets

“…In addition to HA receptor binding and stability, other adaptive properties contributing to influenza virus transmission include polymerase activity, virus morphology, and resistance to host-based restrictions to replication ( Mänz et al, 2012 ; Bogdanow et al, 2019 ; Long et al, 2019a ). Such adaptations may also be needed for swine gamma viruses to adapt highly efficient airborne transmissibility in ferrets.…”

Addressing Non-linear System Dynamics of Single-Strand RNA Virus–Host Interaction

“…In targeting the virus–host interaction, there is an emerging need of tools that could early identify those compounds, not primarily designed for their antiviral action, identifiable by in silico approaches ( Gordon et al, 2020b ), which alone or in combination can provide clinical efficacy ( Mina et al, 2016 ; Cheng et al, 2018 ; Bogdanow et al, 2019 ; Panja et al, 2019 ; Gordon et al, 2020b ). There are known advantages of in silico modeling of the action of therapeutic agents on known diseases through agent-based modeling ( Mao et al, 2018 ).…”