The bat Influenza A virus subtype H18N11 induces nanoscale MHCII clustering upon host cell attachment
Posted on: 20 August 2024
Preprint posted on 12 July 2024
Sialic acid, who? Bat influenza A virus H18N11 interacts with host cells by inducing nanoscale MHCII clustering.
Selected by Mitchell Sarmie, Mohammed A. Jalloh
Categories: cell biology, genetics, immunology, microbiology, molecular biology
Why We Picked This Preprint: We chose to highlight this preprint because it reveals that bats could be intermediate hosts for influenza viruses, posing a zoonotic infection risk to humans.
Background: Unlike conventional influenza viruses (IVAs) that bind to sialic acid residues, bat influenza viruses like H18N11 use major histocompatibility complex class II (MHC-II) proteins as their cellular receptor1, challenging our understanding of the virus entry mechanism into host cells. It also highlights the unique evolutionary path of bat influenza viruses2,3. In this preprint, Osman and colleagues investigate how H18N11 induces MHC-II recruitment and clustering to facilitate viral entry upon binding to host cells (host-virus interaction).
Key Findings
“The Secrets of Bat IAV H18N11 Infection” Recent studies have shifted our understanding of how bat influenza A viruses (IAVs) interact with host cells. In this study, Osman and colleagues explored the susceptibility of cells expressing MHC-II fused with the photoconvertible fluorescent protein mEos3.2 to infection by bat influenza A virus subtype H18N11.
The researchers transduced non-permissive MDCK-II cells with a DNA cassette expressing the wildtype alpha and beta chains of human MHC-II HLA-DR15. By fusing the fluorescent protein mEos3.2 to the intracellular C-terminus of the beta chain, they visualized MHCII dynamics at the single-molecule level using photoactivated localization microscopy (PALM) (see preprint Fig1A-B). They found that cells expressing the wildtype MHCII-mEos3.2 (MHCIImEos) were susceptible to H18N11 infection, while those expressing a mutant MHC-II (MHCIImEosmut) were not. MHCIImEos supported viral entry and membrane fusion, while MHCIImEosmut did not allow endosomal release (see preprint Fig1C-E). Additionally, the soluble ectodomains of both MHCIImEos and MHCIImEosmut were tested for their ability to neutralize H18N11. Unlike MHCIImEosmut, MHCIImEos effectively neutralized the virus in a dose-dependent manner. This indicates that MHCII-mEos3.2 is suitable for further functional studies, and MHCIImEosmut is an adequate negative control.
“H18N11 Viruses and MHCII Clusters Interact on Cell Surfaces.” The secret to stopping viral entry is understanding the interaction between the virus and the host cell receptors. While trying to decipher how bat IAV subtype H18N11 binds to MHC-II clusters on the surface of host cells, Osman and colleagues hypothesized that H18N11 binds preferentially to preformed MHC-II clusters, similar to how IVAs bind to clusters of sialylated glycans. Using PALM, they observed that MHCIImEos and MHCIImEosmut form clusters on the cell surface with similar sizes. However, when exposed to H18N11, the clusters of MHCIImEos increased in size, whereas MHCIImEosmut did not— suggesting that H18N11 binds directly to pre-existing MHC-II clusters, which is indicative of a direct interaction between H18 viruses and MHC-II clusters.
“H18N11 and MHCII Dynamics on Host Cells.” The preprint authors couldn’t stop there because why would they. They decided to further examine how the interaction between H18N11 and MHC-II receptors affects their mobility on the host cell surface. Using spinning-disk confocal microscopy, they observed that H18N11 particles exhibited shorter trajectories on cells expressing MHCIImEos than MHCIImEosmut, indicating MHCII-dependent confinement of the virus (see preprint Fig4A-B). Using an “inverse infection” setup (a technique we admired) where viral particles were immobilized on glass slides, they showed that MHC-II diffuses freely in virus-free areas with reduced mobility above the viral particles– with a significant decrease in MHC-II mobility in the presence of H18N11 compared to IAV H1N1 (see preprint Fig4C-E). The interaction with H18N11 resulted in a local enrichment of MHC-II, promoting larger clusters beneath the viral particles. This suggests that the H18:MHC-II interaction specifically slows down MHC-II diffusion, contributing to the formation of larger receptor clusters.
Key Contributions:
- Unique Receptor Usage: H18N11 uses MHC-II molecules instead of the typical sialic acid receptors for cell entry.
- This study provides insights into the initial steps of the bat IAV H18N11 reproduction cycle. It shows that viral attachment and entry depend on a dynamic interaction with MHC-II, resulting in confinement of both the virus and MHC-II— critical for inducing intracellular signaling and endocytosis.
Questions and Future Directions:
- Are there any known cellular cofactors or additional receptors that work with MHC-II to facilitate bat IAV entry?
- Could the unique entry mechanism of bat IAVs be exploited to develop novel antiviral therapies or vaccines?
- How does bat IAV hemagglutinin binding affinity to MHC-II compare to that of conventional IAV hemagglutinin to sialic acid receptors?
Bibliography
- Evolutionarily conserved amino acids in MHC-II mediate bat influenza A virus entry into human cells | PLOS Biology. Accessed August 10, 2024. https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002182
- Giotis ES. Frontiers | Inferring the Urban Transmission Potential of Bat Influenza Viruses. doi:10.3389/fcimb.2020.00264
- Campos ACA, Góes LGB, Moreira-Soto A, et al. Bat Influenza A(HL18NL11) Virus in Fruit Bats, Brazil. Accessed August 10, 2024. https://wwwnc.cdc.gov/eid/article/25/2/18-1246_article
doi: https://doi.org/10.1242/prelights.38155
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