We used functional cell-based assays combined with a mutational approach to show that specific regions of MHCII and H18 are important for cell entry and probably correspond to binding sites that interact with each other. We also showed that a region in HA, distinct from the classical sugar binding region, is required for MHCII interaction. However, the affinity of this interaction is too low to be detected by standard biochemical binding assays. Therefore, we speculated that the viral particle increases the affinity by binding to multiple MHCII proteins. Using a new live imaging approach, we demonstrated that bat IAV particles bind to pre-formed clusters of MHCII molecules and subsequently induce an increase in cluster size by attracting additional molecules. Thus, these bat IAV particles compensate for the weak affinity of the individual HA/MHCII interaction by clustering MHCII molecules. MHCII is expressed on professional antigen-presenting cells (APCs). Single-cell sequencing of the intestines and associated lymph nodes of the natural bat host species infected with H18N11 revealed that enterocytes and leukocytes, particularly macrophages, become infected. Likewise, human APCs, particularly macrophages, are highly susceptible to H18N11 infection. These findings highlight that, in principle, bat IAVs have the potential to cross the human species barrier.
We also observed in H18N11-infected bats a rapid expansion of B cells during the course of infection, suggesting that antibodies might be relevant for controlling H18N11. Indeed, we showed that high neutralizing antibodies are generated in these animals after infection that were associated with no detectable viral shedding after secondary infection. These findings revisited the concept that viral infections of bats do mount significant levels of neutralizing antibodies.
During the course of the BatFLu project, we characterized the pandemic potential of bat H9N2, a recently discovered, bat-derived IAV circulating in Africa. Through a collaborative effort, we demonstrated that this virus has a greater ability than expected to cross the human species barrier due to efficient replication in human lung explants, transmission among ferrets, and escape of the human immune response. However, as with H17N10 and H18N11, there is currently no evidence of human infections with bat H9N2.
The major findings were disseminated to the public by several publications, press releases and presentations.
