MAMMALIAN ADAPTATION MECHANISM OF INFLUENZA A VIRUS REPLICATION MECHINERY
Wang, Fangzheng 1993-
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ABSTRACT The incompatibility between avian influenza viruses and host factors within mammalian hosts constitutes the major host restriction on influenza A virus polymerase complex. To overcome restrictions of viral polymerase complex, the virus has evolved diverse adaptive strategies. The PB1 gene segment originated from avian strains has recurrently appeared in 1918, 1957, and 1968 pandemic viruses. Although this recurrent selection of the avian-origin PB1 segment has been correlated with enhanced viral polymerase activity in mammalian cells, the underlying mechanism behinds this phenomenon is still enigmatic. Using 2009 pH1N1 virus which naturally lacks the avian-origin PB1 segment and the canonical mammalian-signature PB2 E627K mutation, we demonstrate that the avian-origin PB1 can markedly enhance functions (both replication and transcription) of pH1N1 polymerase in human cells even in the absence of canonical PB2-associated adaptive mutations (E627K and G590S/Q591R). Mechanistically, acquisition of avian-origin PB1 does not change the interaction between polymerase subunits, or assembly of polymerase complex and viral ribonucleoprotein. In viral replication, acquisition of the avian-origin PB1 specifically facilitates the vRNA synthesis of 2009 pH1N1 polymerase by stimulating the trans-activation on cRNA-associated polymerase, thereby leading to the enhanced overall replication and polymerase activity. We extrapolate our finding to the function of acidic nuclear phosphoprotein 32 family member A (ANP32A), the major host factor underlying host restrictions on viral polymerase complex. We substantiate that the SR polymorphism (G590S/Q591R) is also deployed by viruses to accommodate the species difference in ANP32A, which is like the function of PB2 E627K. Our results also indicate that chicken ANP32A can specifically enhance vRNA synthesis of avian-like (PB2 627E) polymerase by promoting the trans-activating effect in replication without altering the genuine vRNP assembly capacity. Collectively, our results suggest that the trans-activation process in vRNA synthesis of un-adapted avian influenza polymerase is a defective step that needs to be restored via mammalian adaptation of viral polymerase complex.
DegreeMaster of Science (M.Sc.)
CommitteeHill, Janet; Wilson, Joyce; Dmitriev, Oleg
Copyright DateJanuary 2019
Influenza A virus, RNA-dependent RNA polymerase, adaptation, virus-host interactions