Human FcγRIIIa activation on splenic macrophages drives the in vivo pathogenesis of dengue disease
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 thein vivomechanisms of antibody-mediated dengue pathogenesis, we developed a mouse model for dengue disease that recapitulates the unique complexity of human FcγRs. Our studies reveal that thein vivopathogenic activity of anti-DENV IgG antibodies is exclusively mediated through engagement of FcγRIIIa expressed on splenic macrophages, resulting in inflammatory sequelae and mortality. These findings highlight the importance of IgG-FcγRIIIa interactions in dengue disease, with important implications in the design of safer vaccination approaches and effective therapeutic strategies..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 11. März Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yamin, Rachel [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2022.11.02.514909 |
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| PPN (Katalog-ID): |
XBI037783416 |
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| 245 | 1 | 0 | |a Human FcγRIIIa activation on splenic macrophages drives the in vivo pathogenesis of dengue disease |
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| 520 | |a 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 thein vivomechanisms of antibody-mediated dengue pathogenesis, we developed a mouse model for dengue disease that recapitulates the unique complexity of human FcγRs. Our studies reveal that thein vivopathogenic activity of anti-DENV IgG antibodies is exclusively mediated through engagement of FcγRIIIa expressed on splenic macrophages, resulting in inflammatory sequelae and mortality. These findings highlight the importance of IgG-FcγRIIIa interactions in dengue disease, with important implications in the design of safer vaccination approaches and effective therapeutic strategies. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
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| 700 | 1 | |a Kao, Kevin S. |4 aut | |
| 700 | 1 | |a MacDonald, Margaret R. |4 aut | |
| 700 | 1 | |a Cantaert, Tineke |4 aut | |
| 700 | 1 | |a Rice, Charles M. |4 aut | |
| 700 | 1 | |a Ravetch, Jeffrey V. |4 aut | |
| 700 | 1 | |a Bournazos, Stylianos |4 aut | |
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