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 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. Our studies reveal that the in vivo pathogenic 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.

Understanding antibody-dependent enhancement in dengue: Are afucosylated IgG1s a concern?

“…Using in vitro monocytic cell line, afucosylated DENV immune complexes engaged FcγRIIIa to increase immunoreceptor tyrosine-based afucosylated IgG motif (ITAM) signalling that enhanced infection [ 35 ]. In vivo studies revealed that afucosylated IgG1–FcγRIIIa interacts with splenic macrophages that promoted viral replication and anti-afucosylated IgG1 nanobodies protected against ADE pathogenicity in mice [ 36 , 37 ]. In SARS-CoV-2 infection, the uptake of afucosylated immune complexes by mononuclear cells was shown to trigger pro-inflammatory cytokine production such as TNF, IL-1β, and IL-6 [ 23 ].…”

Mechanism of glycoform specificity and protection against antibody dependent enhancement by an anti-afucosylated IgG nanobody

“…One recent study from our laboratory generated a novel mouse model of ADE that is both permissive to DENV infection and recapitulates human Fc-FcγR interactions in vivo (49) . This study identified afucosylated IgG1-FcγRIIIa interactions as the chief determinant of ADE severity.…”

“…S1A, Table 1). The loop architecture of the crystal structure for CDR1 (residues 26-34) and CDR2 (residues [46][47][48][49][50][51][52][53][54][55][56][57][58] aligned very closely with its predicted structure, however, electron density for CDR3 (residues 91-108) deviated considerably and packed closer to the globular Ig fold of the nanobody than predicted. Consistent with the previously mentioned characteristics of camelid nanobodies, the CDR3 loop protruded considerably from the main body of the molecule, indicating its inherent flexibility and potential to reach recessed epitopes, such as the N-glycans buried in the cleft of IgG molecule (33).…”