Abstract
ABSTRACT The human innate immune factor MxA represents an effective interspecies barrier for zoonotic influenza A viruses (IAVs) of animal origin. Accordingly, human but not avian IAVs efficiently escape the antiviral activity of MxA due to adaptive mutations in their viral nucleoprotein. Partial MxA resistance can be acquired in intermediate hosts such as swine, which possess an antivirally active Mx1 protein. Intriguingly, Mx1 of the bat Carollia perspicillata, a host of the recently discovered bat influenza A-like virus H18N11, is antivirally active against avian IAVs, thus raising the question whether H18N11 has undergone a preadaptation to human MxA. Here, by utilizing a chimeric bat influenza virus, PR8-H18N11, we demonstrate that MxA efficiently blocks viral replication in vitro as well as in MxA transgenic mice. Nevertheless, the H18N11 nucleoprotein exhibits partial MxA resistance in a polymerase reconstitution assay, suggesting that a certain degree of MxA preadaptation occurred. Together, our data indicate a currently reduced risk for H18N11 to overcome the human restriction factor MxA. Further adaptive mutations in NP are required to facilitate full MxA escape.
Highlights
Zoonotic infections with influenza A viruses (IAVs) pose a constant threat to the human population, where they can cause severe disease in individuals and potentially give rise to global pandemics [1,2,3,4,5]
In order to cross the human species barrier, avian IAVs have to acquire certain adaptive mutations in their viral nucleoprotein (NP) to overcome MxA restriction [8,9,10]. While these MxA escape amino acid patches in NP are highly conserved in all circulating human isolates, they are virtually absent in avian IAVs, suggesting that human-adapted IAVs are under constant evolutionary pressure by MxA restriction [8,11]
In the context of bat Mx1 (bMx1), both amino acid substitutions at R98 (R98 K) and K99 (K99R) had no effect on the polymerase activity, whereas the mutation E100 V decreased bMx1 resistance. Based on these results we conclude that H18N11 NP confers partial Mx resistance to C. perspicillata bMx1 and towards human MxA
Summary
Zoonotic infections with influenza A viruses (IAVs) pose a constant threat to the human population, where they can cause severe disease in individuals and potentially give rise to global pandemics [1,2,3,4,5]. The type I and III interferon (IFN)-induced large dynamin-like GTPase Mx1 (in humans commonly known as MxA) represents a potent interspecies barrier that restricts such spillover infections Despite their close phylogenetic relationship, all known avian Mx1 proteins do not exhibit any antiviral activity against IAVs [6,7]. In order to cross the human species barrier, avian IAVs have to acquire certain adaptive mutations in their viral nucleoprotein (NP) to overcome MxA restriction [8,9,10] While these MxA escape amino acid patches in NP are highly conserved in all circulating human isolates, they are virtually absent in avian IAVs, suggesting that human-adapted IAVs are under constant evolutionary pressure by MxA restriction [8,11]. As demonstrated for the 2009 pandemic H1N1 virus and more recently for a Eurasian avian-like swine IAV, MxA escape mutations in NP, and a partial MxA resistance, can be acquired in intermediate hosts like swine that express an antivirally active Mx1 protein [8,13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
