Maternal Anti-Dengue IgG Fucosylation Predicts Susceptibility to Dengue Disease in Infants

Abstract

Infant mortality from dengue disease is a devastating global health burden that could be minimized with the ability to identify susceptibility for severe disease prior to infection. Although most primary infant dengue infections are asymptomatic, maternally derived anti-dengue immunoglobulin G (IgGs) present during infection can trigger progression to severe disease through antibody-dependent enhancement mechanisms. Importantly, specific characteristics of maternal IgGs that herald progression to severe infant dengue are unknown. Here, we define R10% afucosylation of maternal anti-dengue IgGs as a risk factor for susceptibility of infants to symptomatic dengue infections. Mechanistic experiments show that afucosylation of anti-dengue IgGs promotes FcgRIIIa signaling during infection, in turn enhancing dengue virus replication in FcgRIIIa + monocytes. These studies identify a post-translational modification of anti-dengue IgGs that correlates with risk for symptomatic infant dengue infections and define a mechanism by which afucosylated antibodies and FcgRIIIa enhance dengue infections.

Proinflammatory IgG Fc structures in patients with severe COVID-19

“…modifications that are present in people with more severe dengue disease[9,10,[22][23][24][25][26]. The present findings related to antibodies in SARS-CoV-2 infections show that a specific IgG Fc structure, reduced core fucosylation, correlates with COVID-19 disease.…”

“…A striking example of this is dengue virus infections that occur in the presence of reactive, nonneutralizing IgGs. Those with severe dengue disease disproportionately produce antibodies with reduced fucosylation of the Fc; this modification enhances affinity of the Fc for the activating FcγR, FcγRIIIa which modulates dengue disease pathogenesis, likely through multiple pathways [9,10].…”

The role of IgG Fc receptors in antibody-dependent enhancement

“…However, the mechanism of ADE mediated by mAbs in vitro against SARS-CoV differs significantly from the well-established mechanisms that govern ADE in DENV infection. For example, DENV ADE relies on activating FcγRs such as FcγRIIa and FcγRIIIa 89,90 , whereas ADE mediated by SARS-CoV mAbs is dependent primarily on the inhibitory FcγRIIb and has been shown to cause preferential infection of B cell lines in vitro 146,147 . DENV exploits the FcγR pathway because of the lack of a specialized high-affinity entry receptor for DENV; however, as SARS-CoV can bind with high affinity to its entry receptor ACE2, it is questionable whether the virus utilizes low-affinity FcγRs such as FcγRIIb for infection within the lung microenvironment.…”

“…At sub-neutralizing titres, anti-DENV antibodies complex with the DENV virion and attach to the surface of FcγR-expressing leukocytes, utilizing the phagocytic FcγR pathway for entry 5 , 88 . Mechanistic studies have determined that activating FcγRs — specifically, FcγRIIa and FcγRIIIa — promote ADE during DENV infection, whereas FcγRIIb acts as a negative regulator for this process 89 , 90 . Upon internalization into the cell, antibody–virus complexes are sequestered to phagolysosomes, where low pH conditions trigger conformational changes to the structure of the DENV envelope protein (E), promoting viral fusion and infection.…”

Coming together at the hinges: Therapeutic prospects of IgG3

“… 132–134 The most compelling evidence of the relevance of ADE to infection in vivo comes from dengue, in which severity of secondary infection is associated with levels and types of virus-specific antibodies present in serum. Subneutralizing quantities, 135 but more concerningly, effective Fc γ R ligation associated with relatively high IgG1/IgG2 ratios and afucosylation 136 , 137 have been associated with disease enhancement, though correlation between IgG3 responses and severe disease has not been described.…”