Abstract
Influenza A virus carries few of its own proteins, but uses them effectively to take control of the infected cells and avoid immune responses. Over the years, host shutoff, the widespread down-regulation of host gene expression, has emerged as a key process that contributes to cellular takeover in infected cells. Interestingly, multiple mechanisms of host shutoff have been described in influenza A virus, involving changes in translation, RNA synthesis and stability. Several viral proteins, notably the non-structural protein NS1, the RNA-dependent RNA polymerase and the endoribonuclease PA-X have been implicated in host shutoff. This multitude of host shutoff mechanisms indicates that host shutoff is an important component of the influenza A virus replication cycle. Here we review the various mechanisms of host shutoff in influenza A virus and the evidence that they contribute to immune evasion and/or viral replication. We also discuss what the purpose of having multiple mechanisms may be.
Highlights
100 years after the devastating 1918 Spanish flu epidemic, influenza A virus infections remain a global problem, with only partially effective vaccines and therapeutics available for combating them.many aspects of influenza A virus infection at both the cellular and organismal level remain unclear
While the discovery of polymerase acidic (PA)-X has established that host mRNA degradation during influenza infection is a separate function from cap snatching, cap snatching may still contribute to host shutoff by altering host RNA transcription
PH1N1 strains with NS1 that bind CPSF30 replicate to similar titers as the original strains, in which NS1 does not bind CPSF30 [68]. While this result suggests that NS1 host shutoff is not involved in replication per se, these viruses presumably still carry out host shutoff through PA-X and the RNA-directed RNA polymerase complex (RdRp)
Summary
100 years after the devastating 1918 Spanish flu epidemic, influenza A virus infections remain a global problem, with only partially effective vaccines and therapeutics available for combating them. Metabolic labeling with radioactive amino acids and nucleotides showed reduced synthesis of host proteins and robust accumulation of viral proteins [1] They revealed that both the synthesis and the half-life of host mRNAs are reduced during infection [2,3,4]. 1970–1990 studies, a plethora of mechanisms have been described that underlie host shutoff and impinge on different aspects of RNA and protein expression These mechanisms involve at least six viral proteins: The trimeric RNA-directed RNA polymerase complex (RdRp), the non-structural protein NS1, and PA-X, a protein that is generated through a non-canonical translational mechanism and was only discovered in 2012 (Figure 1). We will discuss why such an extensive repertoire of tools to control gene expression may exist in such a small virus
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