The bat Influenza A virus subtype H18N11 induces nanoscale MHCII clustering upon host cell attachment
Posted on: 20 August 2024 , updated on: 29 May 2025
Preprint posted on 12 July 2024
Article now published in Nature Communications at http://dx.doi.org/10.1038/s41467-025-58834-y
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
Updated 28 May 2025 with a postLight by Mohammed JALLOH
The preprint has now been published in Nature Communications with several significant updates and refinements. The most notable changes include expanded findings about the unique interaction between bat influenza A virus H18N11 and MHC-II receptors, particularly in the structural and functional aspects of this interaction. The authors enhanced the manuscript with more comprehensive data on the binding mechanism between the viral hemagglutinin and MHC-II. The published version includes additional structural analyses in Fig.2a-c that reveal specific interactions within the α1 domain of MHC-II, particularly in the α-helical region. These findings provide more robust support for their observations about the unique binding strategy of H18N11 compared to conventional influenza viruses. The enhanced resolution of the binding pocket structure in Fig.3b shows specific amino acid interactions that were not visible in the preprint version.
The discussion section has been substantially revised to better contextualize these findings within the broader field of viral entry mechanisms. The authors have added a more detailed comparison in Fig. 4 between the MHC-II binding mechanism and other viral entry strategies, highlighting how this unique interaction may have evolved independently in bat influenza viruses. The new data in Supp-Fig. 3 shows the role of this interaction in immune evasion, while Supp-Fig. 4 provides additional validation of the binding affinity measurements. These findings make the study more comprehensive and provide deeper insights into the evolutionary significance of this unique viral entry strategy
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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Also in the molecular biology category:
October in preprints – DevBio & Stem cell biology
Each month, preLighters with expertise across developmental and stem cell biology nominate a few recent developmental and stem cell biology (and related) preprints they’re excited about and explain in a single paragraph why. Short, snappy picks from working scientists — a quick way to spot fresh ideas, bold methods and papers worth reading in full. These preprints can all be found in the October preprint list published on the Node.
| List by | Deevitha Balasubramanian et al. |
October in preprints – Cell biology edition
Different preLighters, with expertise across cell biology, have worked together to create this preprint reading list for researchers with an interest in cell biology. This month, most picks fall under (1) Cell organelles and organisation, followed by (2) Mechanosignaling and mechanotransduction, (3) Cell cycle and division and (4) Cell migration
| List by | Matthew Davies et al. |
September in preprints – Cell biology edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading list. This month, categories include: (1) Cell organelles and organisation, (2) Cell signalling and mechanosensing, (3) Cell metabolism, (4) Cell cycle and division, (5) Cell migration
| List by | Sristilekha Nath et al. |
June in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: (1) Cell organelles and organisation (2) Cell signaling and mechanosensation (3) Genetics/gene expression (4) Biochemistry (5) Cytoskeleton
| List by | Barbora Knotkova et al. |
May in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) Biochemistry/metabolism 2) Cancer cell Biology 3) Cell adhesion, migration and cytoskeleton 4) Cell organelles and organisation 5) Cell signalling and 6) Genetics
| List by | Barbora Knotkova et al. |
Keystone Symposium – Metabolic and Nutritional Control of Development and Cell Fate
This preList contains preprints discussed during the Metabolic and Nutritional Control of Development and Cell Fate Keystone Symposia. This conference was organized by Lydia Finley and Ralph J. DeBerardinis and held in the Wylie Center and Tupper Manor at Endicott College, Beverly, MA, United States from May 7th to 9th 2025. This meeting marked the first in-person gathering of leading researchers exploring how metabolism influences development, including processes like cell fate, tissue patterning, and organ function, through nutrient availability and metabolic regulation. By integrating modern metabolic tools with genetic and epidemiological insights across model organisms, this event highlighted key mechanisms and identified open questions to advance the emerging field of developmental metabolism.
| List by | Virginia Savy, Martin Estermann |
April in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry/metabolism 2) cell cycle and division 3) cell organelles and organisation 4) cell signalling and mechanosensing 5) (epi)genetics
| List by | Vibha SINGH et al. |
Biologists @ 100 conference preList
This preList aims to capture all preprints being discussed at the Biologists @100 conference in Liverpool, UK, either as part of the poster sessions or the (flash/short/full-length) talks.
| List by | Reinier Prosee, Jonathan Townson |
February in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry and cell metabolism 2) cell organelles and organisation 3) cell signalling, migration and mechanosensing
| List by | Barbora Knotkova et al. |
Community-driven preList – Immunology
In this community-driven preList, a group of preLighters, with expertise in different areas of immunology have worked together to create this preprint reading list.
| List by | Felipe Del Valle Batalla et al. |
January in preprints – the CellBio edition
A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. This month, categories include: 1) biochemistry/metabolism 2) cell migration 3) cell organelles and organisation 4) cell signalling and mechanosensing 5) genetics/gene expression
| List by | Barbora Knotkova et al. |
2024 Hypothalamus GRC
This 2024 Hypothalamus GRC (Gordon Research Conference) preList offers an overview of cutting-edge research focused on the hypothalamus, a critical brain region involved in regulating homeostasis, behavior, and neuroendocrine functions. The studies included cover a range of topics, including neural circuits, molecular mechanisms, and the role of the hypothalamus in health and disease. This collection highlights some of the latest advances in understanding hypothalamic function, with potential implications for treating disorders such as obesity, stress, and metabolic diseases.
| List by | Nathalie Krauth |
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
| List by | Reinier Prosee |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
| List by | Alex Eve, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
| List by | Alex Eve |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
| List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
| List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
| List by | Nadja Hümpfer et al. |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
| List by | Alex Eve |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
| List by | Ana Dorrego-Rivas |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
| List by | Hiral Shah |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
| List by | Madhuja Samaddar et al. |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
| List by | Rob Hynds |
MitoList
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
| List by | Sandra Franco Iborra |