Abstract
Enteroviruses contain multiple serotypes and can cause severe neurological complications. The intricate life cycle of enteroviruses involving dynamic virus–receptor interaction hampers the development of broad therapeutics and vaccines. Here, using function-based screening, we identify a broadly therapeutic antibody h1A6.2 that potently protects mice in lethal models of infection with both enterovirus A71 and coxsackievirus A16 through multiple mechanisms, including inhibition of the virion–SCARB2 interactions and monocyte/macrophage-dependent Fc effector functions. h1A6.2 mitigates inflammation and improves intramuscular mechanics, which are associated with diminished innate immune signalling and preserved tissue repair. Moreover, cryogenic electron microscopy structures delineate an adaptive binding of h1A6.2 to the flexible and dynamic nature of the VP2 EF loop with a binding angle mimicking the SCARB2 receptor. The coordinated binding mode results in efficient binding of h1A6.2 to all viral particle types and facilitates broad neutralization of enterovirus, therefore informing a promising target for the structure-guided design of pan-enterovirus vaccine.
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Data availability
The cryo-EM density maps and corresponding atomic coordinates have been deposited in the Electron Microscopy Data Bank (EMDB) (https://www.ebi.ac.uk/emdb/) and Protein Data Bank (PDB) (https://www.rcsb.org), respectively. The accession codes are: CVA16-M:h1A6.2 (EMD-38168, PDB 8X98); CVA16-A:h1A6.2 (EMD-38169, PDB 8X99); CVA16-E:h1A6.2 (EMD-38170, PDB 8X9A); EV71-M (EMD-39572, PDB 8YTJ); EV71-E (EMD-39570, PDB 8YTB); EV71-M:h1A6.2 (EMD-38165, PDB 8X95); EV71-A:h1A6.2 (EMD-38166, PDB 8X96); EV71-E:h1A6.2 (EMD-38167, PDB 8X97); and CVA16-E:h1A6.2-local (EMD-38171, PDB 8X9B). Atomic coordinates of previously determined structures are available in the PDB under the following accession codes: 7YRF, 6LHA, 6LHB, 6LHC, 3VBS and 6I2K. The RNA-seq data have been deposited at the NCBI (https://www.ncbi.nlm.nih.gov/bioproject) under the accession code PRJNA1148760. Source data are provided with this paper.
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Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (No. 82172248 to L.X., 82272310 to T.C., 82101918 to R.Z., 82072282 to T.C., 32170942 to Q.Z. and 81991491 to N.X.), the China Postdoctoral Science Foundation (No. 2022T150550 to R.Z.). The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation. We thank H. Arase (Research Institute for Microbial Diseases and Laboratory of Immunochemistry, Osaka University) for providing 2B4 cells.
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L.X., Q.Z., R.Z., S.L., T.C. and N.X. contributed to the experimental design. L.X., Q.Z., R.Z., S.L., T.C. and N.X. contributed to the paper preparation. R.Z., Y.W., D.Z., Z.Z., H.C., Y.Z., Z.Y., X.Y., J.H., Y.Q. and M.F. contributed to the virus preparation and characteristics analysis. Y.W., Yichao Jiang, X.C., W.N., L.Z. and W.L. contributed to the preparation and in vitro characterization of the antibody. Y.W., R.Z., Z.Z., H.C., H. Yang, W.D., S.W., C.L. and H.Z. performed the animal experiments. Q.Z., Y.H., Yanan Jiang, H.S., M.H., Y.L., Z.C., J.Z. and H. Yu contributed to the structural data collection and analysis. All authors discussed the results, commented on the paper and approved the final version.
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Extended data
Extended Data Fig. 1 Construction and characterization of m1A6, h1A6 and h1A6.2-LALA.
a, The quantity of cell-bound virus RNA was determined by qRT-PCR in L929SCARB2 cell-based inhibition assay. The values (n = 3) are expressed as mean ± SD of three experiments. Significance was determined using an unpaired, two-sided Student’s t test. Symbols: ***p < 0.001, ****p < 0.0001, n.s., not significant. b, Representative fluorescence confocal images of m1A6 against EV71- or CVA16-infected RD cells. The secondary antibody (green) was Alexa Fluor 488-conjugated goat anti-mouse. The nuclei were stained with DAPI (blue). Scale bar, 25 μm. Experiments were repeated twice, and one representative result is shown. c, Western blot analysis from an experment of m1A6 against EV71-B3, B4, C2, C4 sub-genotypes and four CVA16-B1b strains. d, In vivo animal protective efficacies of six versions of humanized 1A6 (h1A6). One-day-old mice (n = 5-8) were first challenged with a lethal dose of EV71-pSVA-MP4 or CVA16-190, and then treated with 1 mg/kg of one of the h1A6 antibodies, respectively, at 24 h post-infection. Mice were monitored daily for survival after inoculation. Experiments were repeated twice, and one representative result is shown. Survival curves were compared by the log-rank (Mantel-Cox) test. Symbols: *p < 0.05, **p < 0.01, ***p < 0.001, n.s., not significant. e, SDS-PAGE analysis from an experment of h1A6.2 and h1A6.2-LALA under reducing conditions. Lane M, protein markers; Lane 1, h1A6.2; Lane 2, h1A6.2-LALA. f and g, Binding efficacies of h1A6.2 and h1A6.2-LALA to EV71 (f) or CVA16 (g) recombinant VP2 protein evaluated with binding ELISA. The values (n = 3) are expressed as mean ± SD of three experiments. EC50 values were calculated with curves generated by nonlinear regression fitted.
Extended Data Fig. 2 Characterization of h1A6.2 and h1A6.2-LALA.
a, Binding efficacies of h1A6.2 and h1A6.2-LALA to murine FcγRI, FcγRIIb, FcγRIII, FcγRIV or human FcγRI, FcγRIIa, FcγRIIb, FcγRIIIa evaluated with binding ELISA. The values (n = 2) are expressed as the mean of two experiments. b and c, Binding efficacies of h1A6.2 and h1A6.2-LALA to EV71 (b) or CVA16 (c) evaluated with binding ELISA. The values (n = 3) are expressed as mean ± SD of three experiments. EC50 values were calculated with curves generated by nonlinear regression fitted.
Extended Data Fig. 3 Fc effector functions of h1A6.2 influence the immune responses to EV71 and CVA16 infections.
a and b, H.E. staining and IHC analysis were employed for histopathological evaluations of limb muscle samples harvested at 7 dpi in EV71-infected mice (a) or CVA16-infected mice (b). Scale bars, 50 μm. Staining was performed on tissue sections from two mice per group, and representative images are shown.
Extended Data Fig. 4 Fc effector functions of h1A6.2 and monocytes/macrophages mediate protection against EV71 and CVA16 infection.
One-day-old mice were first challenged with a lethal dose of EV71-pSVA-MP4 or CVA16-190, and then treated with 10 mg/kg of h1A6.2 or h1A6.2-LALA at 2 dpi. Mice in the isotype group were virus infected with Ab-control. Naive mice were mock-infected with PBS. a, Heat-maps of cytokine levels in limb muscle samples of virus-infected mice at 7 dpi. Fold-change was calculated compared to mock-infected mice, and log2 (fold-change) was plotted in the corresponding heat-map. The experiments were performed in triplicate. b-e, Antibody-dependent cellular cytotoxicity (ADCC). A genetically engineered 2B4 reporter cell line that express mouse FcγRIV was used (b and c). Serially diluted h1A6.2 or h1A6.2-LALA was incubated with pre-coated EV71 or CVA16 particles and the mouse FcγRIV-expressing reporter cells were added. The antibody-dependent human cellular cytotoxicity (hADCC) activity against EV71 and CVA16 was also examined by using human FcγRIIIa-expressing 2B4 reporter cells (d and e). The values (n = 2) are expressed as the mean of two experiments. f and g, Antibody-dependent NK cell degranulation (ADNK). Captured EV71 (f) or CVA16 (g) particles were incubated with h1A6.2 or h1A6.2-LALA for 2 h. Human NK cells were added and incubated for 5 h at 37 °C. Cells were analyzed for CD107a expression by flow cytometry. The values (n = 3) are expressed as the mean of two experiments. h and i, Antibody-dependent cellular phagocytosis (ADCP). Cy5.5-labeled EV71 (h) or CVA16 (i) particles were pre-incubated with serially diluted h1A6.2 or h1A6.2-LALA, and added to mouse monocyte/macrophage cell lines Raw264.7, and phagocytosis was measured by flow cytometry. The values (n = 3) are expressed as the mean ± SD of three experiments. Significance was determined using an unpaired, two-sided Student’s t test. Symbols: **p < 0.01, ***p < 0.001, ****p < 0.0001.
Extended Data Fig. 5 Gating strategies of flow cytometric analysis.
a, Identification of CD107a expression on NK cells. b, Identification of internalized EV71 or CA16 particles within Raw264.7 cells. Representative images from one of two or three biologically independent samples are shown.
Extended Data Fig. 6 Cryo-EM data processing of h1A6.2 immune-complexes.
Representative 3D classification results, icosahedral refinement maps (with the sub-particles around 2-fold vertex indicated as white circle), localized sub-particles 3D classification results and localized refinement results are shown.
Extended Data Fig. 7 Global and local resolution estimation of cryo-EM reconstructions.
a–g, Global and local resolution estimation of CVA16-M:h1A6.2 (a), CVA16-A:h1A6.2 (b), CVA16-E:h1A6.2 (c), EV71-M:h1A6.2 (d), EV71-A:h1A6.2 (e), EV71-E:h1A6.2 (f) and CVA16-E:h1A6.2-local (g). Gold-standard Fourier shell correlation (FSC, threshold = 0.143 criterion) curves are shown in the right panel, the resmap analysis of density maps are shown in the left panel.
Extended Data Fig. 8 Inter-Fab interaction between the two adjacent h1A6.2 and molecular dynamics simulation of CVA16 virion.
a, The models show two adjacent h1A6.2 Fabs (showed as carton with transparent surface representation) and the 2 protomers (showed as carton and color with components) consisting the 2-fold region of CVA16 empty particles. b, close-up view shows interaction details of the two h1A6.2 Fabs. Hydrogen bonds and salt-bridges are indicated as orange and green dashed lines, respectively. c, Root mean square deviation (RMSD) of backbone atoms of CVA16-M, CVA16-E and CVA16-E:h1A6.2 (with h1A6.2 omitted). d, Root mean square fluctuation (RMSF) of viral VP2 that involved in h1A6.2 binding during the last 20 ns of the MD simulation.
Extended Data Fig. 9 Comparisons of the models of VP2 from different viral particles and their immune-complexes.
a, Comparisons of CVA16 VP2 that from CVA16 empty particle (PDB code: 6LHC), A-particle (PDB code: 6LHB) and mature virion (PDB code: 6LHA), as well as those from immune-complexes of CVA16-E:h1A6.2, CVA16-A:h1A6.2 and CVA16-M:h1A6.2. b, Comparisons of EV71 VP2 that from EV71 empty particle, A-particle and mature virion, as well as those from immune-complexes of EV71-E:h1A6.2, EV71-A:h1A6.2 and EV71-M:h1A6.2.
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Supplementary Table 1, representative cryo-EM micrographs and unprocessed scans of blots and gels.
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IFA micrographs, unprocessed western blots and gels.
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Zhu, R., Wu, Y., Huang, Y. et al. Broadly therapeutic antibody provides cross-serotype protection against enteroviruses via Fc effector functions and by mimicking SCARB2. Nat Microbiol 9, 2939–2953 (2024). https://doi.org/10.1038/s41564-024-01822-7
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DOI: https://doi.org/10.1038/s41564-024-01822-7
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