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Human FcγRIIIa activation on splenic macrophages drives dengue pathogenesis in mice

Nature Microbiology volume 8, pages 1468–1479 (2023)Cite this article

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Abstract

Although dengue virus (DENV) infection typically causes asymptomatic disease, DENV-infected patients can experience severe complications. A risk factor for symptomatic disease is pre-existing anti-DENV IgG antibodies. Cellular assays suggested that these antibodies can enhance viral infection of Fcγ receptor (FcγR)-expressing myeloid cells. Recent studies, however, revealed more complex interactions between anti-DENV antibodies and specific FcγRs by demonstrating that modulation of the IgG Fc glycan correlates with disease severity. To investigate the in vivo mechanisms of antibody-mediated dengue pathogenesis, we developed a mouse model for dengue disease that recapitulates the unique complexity of human FcγRs. In in vivo mouse models of dengue disease, we discovered that the pathogenic activity of anti-DENV antibodies is exclusively mediated through engagement of FcγRIIIa on splenic macrophages, resulting in inflammatory sequelae and mortality. These findings highlight the importance of IgG–FcγRIIIa interactions in dengue, with important implications for the design of safer vaccination approaches and effective therapeutic strategies.

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Fig. 1: In vitro ADE activity of anti-DENV IgG antibodies is dependent on the FcγR expression profile of the cell lines used in ADE assays.
Fig. 2: Development of experimental models for the study of human FcγR pathways during ADE of dengue disease.
Fig. 3: FcγRIII plays a critical role in mediating ADE of dengue infection in vitro and in enhanced antibody-mediated dengue disease in vivo.
Fig. 4: In vivo ADE of dengue disease is mediated by FcγRIIIa+ splenic macrophages.
Fig. 5: Engagement of FcγRIIIa is associated with elevated levels of inflammatory cytokines.

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Raw data for all main and extended data figures are included in the paper as source files. Source data are provided with this paper.

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Acknowledgements

We thank P. Smith, E. Lam, R. Peraza, R. Francis and J. Edgar for technical assistance; all the members of the Laboratory of Molecular Genetics and Immunology (Rockefeller University) for discussions; S. Carrasco, S. St Jean and staff from the Laboratory of Comparative Pathology for histopathology support (with funding from NIH Core Grant P30CA008748); M. Mack (University Hospital Regensburg) for providing the anti-CCR2 antibody (clone MC-21); the CRISPR and Genome Editing Center at Rockefeller University for help with the design of the Ifnar1−/− KO mice; and The Rockefeller University for continued institutional support. The following reagents were obtained through BEI Resources, NIAID, NIH: Dengue Virus Type 2 (DENV2), New Guinea C (NGC) NR-84. Research reported in this publication was supported by National Institute of Allergy and Infectious Diseases Grants R01AI137276 (to S.B.), U19AI111825 (to J.V.R., C.M.R and S.B.) and R01AI124690 (to C.M.R.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Author notes

  1. These authors contributed equally: Jeffrey V. Ravetch, Stylianos Bournazos.

Authors and Affiliations

  1. Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY, USA

    Rachel Yamin, Kevin S. Kao, Jeffrey V. Ravetch & Stylianos Bournazos

  2. Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA

    Margaret R. MacDonald & Charles M. Rice

  3. Immunology Unit, Institut Pasteur du Cambodge, Institut Pasteur International Network, Phnom Penh, Cambodia

    Tineke Cantaert

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Contributions

R.Y., J.V.R. and S.B. conceptualized the project. R.Y. and K.S.K. developed the methodology. R.Y., K.S.K. and T.C. conducted investigations and acquired resources. R.Y., J.V.R. and S.B. wrote the paper. R.Y. and S.B. performed visualization. M.R.M. and C.M.R. provided intellectual input. J.V.R. and S.B. supervised the project. J.V.R. and S.B. acquired funding.

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Correspondence to Jeffrey V. Ravetch or Stylianos Bournazos.

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Extended data

Extended Data Fig. 1 FcγR expression profile of engineered cell lines and assessment of in vitro ADE activity.

(a) FcγR expression on K562 was assessed by flow cytometry using antibodies against FcγRI, FcγRIIa, FcγRIIb, and FcγRIII (shaded histogram). Corresponding isotype control is shown in open histograms. (b,c) The in vitro ADE activity of the anti-DENV mAb C10 expressed as afucosylated (afuc) human IgG1 was assessed in U937 (black) vs U937-panFcγR (purple) cells. Percent (%) infection was assessed by flow cytometry. Area under curve (AUC) was calculated for each cell type and compared by two-tailed unpaired t-test. Figure shows one representative experiment (mean ± s.e.m) out of three performed in duplicates and normalized AUC from the three independent experiments. (d) The in vitro ADE activity of fucosylated (fuc) human IgG1, afucosylated (afuc) human IgG1, or Fc null variant was determined by multi-step viral yield on 6-, 15-, 24-, and 32-hours post-infection. Percent (%) infection was assessed by flow cytometry and compared between fucosylated and afucosylated hIgG1 by two-way ANOVA (Bonferroni post hoc analysis adjusted for multiple comparisons). Figure shows one representative experiment (mean ± s.e.m) performed in triplicates.

Source data

Extended Data Fig. 2 Characterization of Ifnar1−/−/FcγR KO and Ifnar1−/−/ FcγR humanized mice.

(a) Overview of Ifnar1 gene targeting with CRISPR/Cas9 in mice. Single guide RNA (sgRNA) was designed to target a sequence in exon 3 of the mouse Ifnar1 gene (marked in red). CRISPR-Cas9 constructs were injected to FcγR KO mouse or FcγR humanized mouse and resulted in 1 bp insertion or 1 bp deletion, respectively, that led to a premature stop codon. (b) IFNα/βR expression in various leucocyte populations (see gating strategy on the left) was assessed by flow cytometry in Ifnar1−/−/FcγR KO (grey) or Ifnar1−/−/FcγR humanized (blue) mice in comparison to FcγR humanized mice (red). (c) FcγR expression in various leucocyte populations in the blood was assessed by flow cytometry for Ifnar1−/−/FcγR KO mice (grey) and Ifnar1−/−/FcγR humanized mice (blue) and compared to FcγR expression in FcγR humanized mice. Matching isotype controls are indicated by open histograms. (d) Ifnar1−/−/FcγR KO mice were pre-treated with anti-DENV antibodies and infected with DENV. Pathological changes related to DENV infection were assessed on day 4 post-infection by H&E staining and histological evaluation of mesenteric lymph node (upper panel, 40x), lung (middle panel, 20x) and liver (lower panel, 20x). Images are representative of two infected mice.

Source data

Extended Data Fig. 3 Characterization of Fc domain variants with differential FcγR binding to assess in vivo ADE of dengue disease.

(a) Affinity of human IgG1 Fc domain variants for the various classes of human FcγRs and type II mouse FcRs. Numbers indicate the fold change in affinity compared with wild-type human IgG1. n.d.b.: no detectable binding. (b-d) Ifnar1−/−/FcγR humanized mice were administered i.v. with 20 μg or 200 μg of the ALIE variant of anti-DENV 2D22 mAb 8h before DENV2 challenge. Weight loss (b), survival (c), and platelet counts (d) were compared between the two doses by two-way ANOVA (Bonferroni post hoc analysis adjusted for multiple comparisons), log-rank (Mantel-Cox) test and two-tailed t-test, respectively. n = 6 mice per group in two independent experiments. Data are presented as mean ± s.e.m. *P<0.03; ***P<0.0008; ****P<0.0001. (e) Serum was obtained from DENV-infected mice (pre-treated with the different anti-DENV Fc variants) on day 3 post-infection and analyzed by ELISA to quantify antibody levels. IgG levels of the various Fc variants were compared to WT human IgG1 by two-way ANOVA (Bonferroni post hoc analysis adjusted for multiple comparisons). n = 7 (V11, ALIE, GAALIE), n = 8 (GA, afucosylated), n = 9 (GRLR), n = 11 (WT) mice per group from at least two independent experiments. Data are presented as mean ± s.e.m. (f) Ifnar1−/−/FcγR humanized mice were administered with 20 μg of anti-DENV mAb Fc-variants (GRLR or GAALIE) and platelet counts (mean ± s.e.m.) were measured 3 days post treatment and compared to mice that were treated with WT mAb by one-way ANOVA (Bonferroni post hoc analysis adjusted for multiple comparisons). n = 3 (WT, GRLR), n = 4 (GAALIE) mice per group from one independent experiment. NS, not significant.

Extended Data Fig. 4 Validation of antibody-mediated depletion of various cell populations.

(a-e) The efficiency of antibody-mediated depletion of NK cells, neutrophils, and the targeting of CCR2+ monocytes was determined by flow cytometry 2 days after antibody administration. The abundance of the depleted population in peripheral blood (for NK (n = 3), neutrophils (n = 3) and CCR2+ monocytes (n = 5)) or spleen (for CCR2+ monocytes (n = 5)) was calculated out of total CD45+ leucocytes and compared to matched isotype control by two-tailed unpaired t-test (one independent experiment). NK cells were defined as CD45+/CD11b−/CD3−/B220−/NK1.1+. Neutrophils were defined as CD45+/CD3−/CD11b+/SSChigh/Gr1+ (see Extended Data Fig. 2b for gating strategy). CCR2+ monocytes were defined as CD45+/CD19−/CD3−/NK1.1−/CD11b+/Ly6G−/Ly6C+. (f-i) Ifnar1−/−/FcγR humanized mice were treated with clodronate liposomes or control liposomes to deplete macrophages. Depletion of macrophages in the spleen and liver as well as efficiency of depletion on multiple myeloid subsets in the spleen (macrophages, neutrophils, and monocytes) was determined 2 days post treatment by flow cytometry. Macrophages (Mac) were defined as CD45+/CD19−/CD3−/SiglecF−/Gr1−/CD11b+/F4/80+. Red pulp macrophages (RPM) were defined as CD45+/CD19−/CD3−/SiglecF−/Gr1−/CD11blow/F4/80+. Neutrophils were defined as CD19−/CD3−/SiglecF−/SSChigh/Gr1high. Monocytes were defined as CD19−/CD3−/SiglecF−/SSClow/Gr1intermediate. Groups were compared by two-tailed unpaired t-test. n = 3 mice per group in one experiment. (j) To determine whether splenectomy affect platelet numbers in circulation, platelet counts were determined pre- and post- splenectomy and compared by two-tailed unpaired t-test (n = 5 mice per group in one experiment).

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Extended Data Fig. 5 DENV infection in splenic macrophage populations.

(a) DENV infection (DENV+) of macrophage populations in the spleen of Ifnar1−/−/FcγR humanized mice that were pre-treated with the Fc-variants (GRLR, WT or ALIE) of the anti-DENV 2D22 was determined 4 days post infection. Representative flow cytometry histograms and quantification of each population are presented. Marginal zone (MZ) macrophages were defined as CD11b+/F4/80+/Tim4high. MZ metallophilic macrophages were defined as CD11b+/F4/80+/Tim4low. Red pulp macrophages were defined as CD11blow/F4/80+. Groups were compared by one-way ANOVA (Bonferroni post hoc analysis adjusted for multiple comparisons). n = 4 mice per group. In box plots, the center line shows the median, boxes represent the middle quartiles and whiskers show the range of values (minimum to maximum).

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Yamin, R., Kao, K.S., MacDonald, M.R. et al. Human FcγRIIIa activation on splenic macrophages drives dengue pathogenesis in mice. Nat Microbiol 8, 1468–1479 (2023). https://doi.org/10.1038/s41564-023-01421-y

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