The N-Terminal Domain of PA from Bat-Derived Influenza-Like Virus H17N10 Has Endonuclease Activity

Abstract

e Influenza imposes a great burden on society, not only in its seasonal appearance that affects both humans and domesticated animals but also through the constant threat of potential pandemics. Migratory birds are considered to be the reservoir hosts for influenza viruses, but other animals must also be considered. The recently identified influenza-like virus genome, from H17N10 in bats, was shown to be markedly different from genomes of other known influenza viruses, as both its surface glycoproteins hemagglutinin (HA) and neuraminidase (NA) do not have canonical functions. However, no studies on other individual proteins from this particular virus have been reported until now. Here, we describe the structure of the N-terminal domain of PA from H17N10 influenza-like virus at 2.7-Å resolution and show that it has a fold similar to those of homologous PA domains present in more familiar influenza A virus strains. Moreover, we demonstrate that it possesses endonuclease activity and that the histidine residue in the active site is essential for this activity. Although this particular influenza virus subtype is probably not infectious for humans (even its virus state has not been confirmed in bats, as only the genome has been sequenced), reassortment of canonical influenza viruses with certain segments from H17N10 cannot be ruled out at this stage. Therefore, further studies are urgently needed for the sake of influenza prevention and control.

The NS1 gene from bat-derived influenza-like virus H17N10 can be rescued in influenza A PR8 backbone

“…Moreover, the crystal structure of the heterotrimeric bat-derived H17N10 polymerase, comprising PB2, PB1 and PA subunits, reveals some canonical RNA polymerase motifs and domains (Pflug et al, 2014). Besides, we also showed that the N-terminal domain of PA (PAn) from H17N10 has a similar endonuclease activity to that from categorized influenza A viruses (Tefsen et al, 2013). Although we were unable to rescue viruses containing the PAn domain from H17N10 in a PR8 background in these studies, we investigated the possibility of rescuing functional genes or domains from H17N10 in the background of a categorized influenza A virus.…”

“…Our recent finding that PAn codes for an endonuclease with activities comparable to human and avian PAn molecules (Tefsen et al, 2013) stimulated us to address the fundamental question of whether functional genes or genetic domains from H17N10 could be rescued in the background of PR8.…”

Amino acid substitutions V63I or A37S/I61T/V63I/V100A in the PA N-terminal domain increase the virulence of H7N7 influenza A virus

“…The resulted plasmids were then transformed into E. coli strain BL21 (DE3) for protein expression5051. Briefly, the bacteria were grown to an optical density of ~0.7 at 600 nm (OD600) in LB medium with 100 μg/ml ampicillin at 37 °C.…”

Learning from structure-based drug design and new antivirals targeting the ribonucleoprotein complex for the treatment of influenza

“…The structure of Nter-PA has been solved in several crystal forms with (or without) various ligands[61,62,[73][74][75][76][77][78][79]. Two years after the first structure of the PA catalytic domain…”