Bat-borne influenza viruses enter host cells by utilizing surface exposed MHC-II molecules of various species, including humans. Now, an international research team from Germany (Medical Center—University of Freiburg and Friedrich-Loeffler-Institut, island of Riems) and the United States (Colorado State University, Fort Collins and Kansas State University, Manhattan) addressed concerns about the zoonotic spill-over potential and discovered an unexpected high genetic plasticity of the bat influenza virus H18N11 with unpredictable consequences.
An unprecedented genetic plasticity and a putative function of NA
"Influenza viruses have an inherent high mutation rate," explains Prof. Martin Schwemmle of the Medical Center—University of Freiburg and coordinator of this study. "We therefore first tested the bat flu virus' genetic stability to assess its natural mutational potential in cell culture." To their surprise, within a short period of time all isolated viruses acquired specific amino acid mutations in the viral hemagglutinin (HA) and a truncated neuraminidase (NA) surface glycoprotein. The scientists performed further experiments and showed that these amino acids changes in HA enabled an NA independent viral growth. "Using a variety of mutant viruses, we finally demonstrated that in the absence of a mutated HA, functional NA is required for viral spread." While the role of the mysterious NA protein has been unknown so far, the researchers found some evidence that its function could be to downregulate cellular MHC-II surface levels to subsequently allow efficient release of infectious viruses from infected host cells.
Potentially low risk for humans
Concerning the potential spill-over risk of the bat influenza virus to the human population, Prof. Schwemmle is cautiously optimistic as he says, "Ferrets are the best small animal model to study human pathogenicity and transmission of sialic acid dependent influenza A viruses. Assuming ferrets are also the appropriate model to study bat flu viruses that instead use MHC-II for cell entry, our study does not provide any indications that these viruses can cause or transmit disease to contact animals. Therefore, the results can be interpreted as that there is currently a low zoonotic potential. However, due to the genetic plasticity of these viruses any precise prediction is difficult."
Nevertheless, this work has raised several open questions that remain to be answered: first, is bat influenza virus NA downregulating MHC-II surface expression; and, if so, what is the underlying mechanism? Second, is it possible that bat influenza virus HA proteins can gain affinity to novel cell entry receptors due to their flexibility to accommodate amino acid mutations in HA? "We are currently looking into these questions in greater detail," says Prof. Schwemmle.
More information: Kevin Ciminski et al, Bat influenza viruses transmit among bats but are poorly adapted to non-bat species, Nature Microbiology (2019). DOI: 10.1038/s41564-019-0556-9
Journal information: Nature Microbiology
Provided by University of Freiburg