Molecular biology and spill-over potential of bat influenza A-like viruses

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The previous understanding of the influenza A virus (IAV) host range and diversity has recently been challenged by the discovery of two novel influenza subtypes in Central and South American bat species, provisionally designated H17N10 and H18N11. The surface glycoproteins of both subtypes lack the canonical receptor-binding and receptor-destroying activities of conventional hemagglutinin (HA) and neuramindase (NA) proteins, respectively.Virus isolation from infected bats or generation of recombinant viruses failed, impeding studies of their pathogenicity and zoonotic potential. We could show that bat chimeric viruses encoding HA and NA of conventional IAV fail to reassort with conventional IAV. In the first funding period, we identified the underlying mechanisms for this reassortment incompatibility, which is caused by highly conserved amino acids in the nucleoprotein (NP) of bat IAV. We were also able to generate recombinant bat IAV of both subtypes by reverse genetics after identifying highly susceptible cell lines that allowed the efficient propagation of these viruses. Furthermore, we discovered MHCII as an entry receptor for H18- and H17-mediated cell entry and could show that MHCII molecules from various bat and other species, including swine and humans, mediate cell entry. Finally, we observed that H18N11 viruses infect and replicate in various species, including mice, ferrets and bats. However, especially in mice, viral growth is associated with a deletion of the N11 head domain. In conclusion, we want to address now the following major open questions: (a) Are other cellular factors besides MHCII required for H18-mediated cell entry and endosomal release, (b) what is the function of the atypical bat flu NA-protein, (c) what is the potential of bat IAV to infect other species, and (d) are bat IAV controlled by host restriction factors of the innate immune such as MxA? With these important studies we will be able to answer the new questions from our very successful first funding period. We want to shed light onto the molecular biology of these newly discovered bat influenza viruses and also estimate their spill-over potential.