Bat flu study sheds light on zoonotic diseases
A newly discovered bat influenza virus (H18N11) has challenged assumptions about how influenza A viruses (IAVs) gain access to their host cell. This is because the surface proteins of this particular virus demonstrate unusual characteristics, when compared to conventional IAVs, the strains that cause seasonal flu in humans.
Biological mechanisms behind influenza virus
The EU-funded Bat Flu(opens in new window) project, supported by the European Research Council(opens in new window), set out to better understand the biological mechanisms at work here, and to evaluate the potential health risk that this strain could pose. “Our overarching goal was to understand how the H18 virus engages with specialised cell surface glycoproteins (MHCII) to facilitate host cell entry,” says project coordinator Martin Schwemmle from the Medical Center – University of Freiburg(opens in new window) in Germany. “However, because all biochemical assays available lacked sensitivity to prove direct interaction, we first had to develop new approaches.” This was accomplished by bringing together experts, including Jacques Neefjes (Leiden University Medical Centre), Christian Sieben (Helmholtz Centre for Infection Research) and Antoni Wrobel (University of Oxford). The new techniques that were developed enabled the team to map the H18-MHCII interaction interface and to better understand the dynamics of host cell entry.
How H18N11 binds to existing MHCII clusters
The team was able to identify the region of the MHCII molecule most likely to interact with the H18 envelope protein of bat IAVs. To clarify whether MHCII clustering is a prerequisite for viral entry, the project also developed a novel live imaging technique using photoactivated localisation microscopy (PALM) to measure receptor-ligand interactions. PALM is a super-resolution fluorescence imaging technique with a resolution in the nanometre range. Using this new technique, the team was able to demonstrate that the bat IAV H18N11 binds to existing MHCII clusters and actively recruits additional MHCII molecules to the site of attachment. Conventional IAVs typically bind to sialic acids (a type of sugar found on cell surfaces) to enter a host cell. The project team also collaborated with expert Tony Schountz (Colorado State University), who maintains a colony of Jamaican fruit bats. Single-cell RNA sequencing of infected bat tissue revealed that H18N11 primarily replicates in the white blood cells of infected bats. “The project was unique in that it was a collaboration between excellent partners from different scientific fields,” remarks Schwemmle. “This allowed us to use state-of-the-art molecular and immunological tools in a non-model species.”
Disease severity and rates of infection
The project was able to show that the interaction between H18 and MHCII is relatively weak. “Viral particles bind to MHCII clusters on the cell surface to compensate for this low affinity,” explains Schwemmle. The team also demonstrated that H18N11 replicates in human macrophages (specialised white blood cells), but without causing apparent cell death or inflammation. This is in stark contrast to the highly pathogenic avian IAVs of the H5N1 subtype, which infect macrophages and cause severe inflammatory responses. “Understanding H18N11 and its ability to prevent inflammatory responses could potentially provide new insights into the mechanisms that lead to excessive immune responses after H5N1 infection,” adds Schwemmle. This could pave the way for future research into the relationship between viruses and cell receptors, and the implications this might have for disease severity and rates of infection.
