Abstract
Influenza A viruses (IAV) are evolutionarily successful pathogens, capable of infecting a number of avian and mammalian species and responsible for pandemic and seasonal epidemic disease in humans. To infect new species, IAV typically must overcome a number of species barriers to entry, replication, and egress, even while virus replication is counteracted by antiviral host factors and innate immune mechanisms. A number of host factors have been found to regulate the replication of IAV by interacting with the viral RNA-dependent RNA polymerase (RdRP). The host factor PARP1, a poly-ADP ribosyl polymerase, was required for optimal functions of human, swine, and avian influenza RdRP in human 293T cells. In IAV infection, PARP1 was required for efficient synthesis of viral nucleoprotein (NP) in human lung A549 cells. Intriguingly, pharmacological inhibition of PARP1 enzymatic activity (PARylation) by 4-amino-1,8-naphthalimide led to a 4-fold increase in RdRP activity, and a 2.3-fold increase in virus titer. Exogenous expression of the natural PARylation inhibitor PARG also enhanced RdRP activity. These data suggest a virus-host interaction dynamic where PARP1 protein itself is required, but cellular PARylation has a distinct suppressive modality, on influenza A viral polymerase activity in human cells.
Highlights
Influenza viruses are segmented, negative-sense singlestranded RNA viruses in the evolutionarily diverse viral family Orthomyxoviridae
Our earlier studies indicated that poly-ADP ribosyl polymerase 1 (PARP1) interacts with and is required for activity of the influenza RNA-dependent RNA polymerase (RdRP) [20, 24]
To this end we compared knockdown of the requirement for PARP1 to knockdown of the DNA damage repair complex proteins Ku70/86 that were found to be required host factors for the influenza replication and polymerase function [24] and interact with PARP1 in DNA-damage repair (DDR) proteome network [45]
Summary
Negative-sense singlestranded RNA viruses in the evolutionarily diverse viral family Orthomyxoviridae. Annual seasonal epidemics of influenza A virus (IAV) infections are a considerable health burden in humans. The natural reservoir of IAV is in wild birds, AIV can infect poultry, and highly pathogenic avian influenza viruses (HPAIV) of H5N1, H5N6, and H7N9 hemagglutinin subtypes, among others, can spread to humans [1, 2]. Reassortment of the 8 viral gene segments in IAV genomes can result in emergence of immunologically distinct strains, capable of rapid, virulent spread in susceptible populations, gravely illustrated by the high burden of influenza and mortality of the 1918 H1N1 pandemic in humans [6]. In 2009, a novel reassortant strain of IAV (pdmH1N1), in part a genetic descendant of the
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