Lost in post-translational modification—Dengue virus writes its own sequel

Endemic in over 100 countries, infecting approximately 400 million annually, and its breadth ever increasing, dengue virus (DENV) poses a continuing global health threat. The first infection is typically mild, but secondary infection can result in severe dengue fever and sometimes hemorrhagic fever or shock syndrome. This has been attributed to infection by an antigenically distinct variant (serotype) from the primary infection. Primary serotype antibodies form complexes with the virus in secondary infection but do not effectively neutralize it. As a result, myeloid cells become infected when they phagocytose these complexes through Fc receptor (FcR) interaction with immunoglobulin G (IgG) Fc. This unique process, termed antibody-dependent enhancement (ADE), might contribute to the severity of DENV secondary infection but does not completely explain it.

N-linked glycosylation is a form of post-translational modification of the IgG Fc. The absence of core fucose on this glycan is called afucosylation and enhances the interaction between IgG Fc with leukocyte FcRs. Therefore, IgG afucosylation could exacerbate ADE and DENV infection. To test this hypothesis, Bournazos et al. evaluated whether antibody afucosylation correlates with secondary DENV infection and is indicative of severe disease. Total anti-DENV IgG titer, although elevated in hospitalized patients, did not correlate with severe disease indicators, such as reduced platelet count or elevated hematocrit. However, they found that hospitalized patients with secondary infections had increased afucosylated anti-DENV IgG1, which did correlate with severe disease indicators. Remarkably, when measured at the time of hospital admission, elevated afucosylated IgG1 could forecast severe disease.

Intriguingly, this phenomenon did not extend to other flaviviruses: Frequency of afucosylated virus-specific IgG1 did not differ in asymptomatic vs. symptomatic or primary vs. secondary West Nile virus infection, or in acute vs. early convalescent Zika virus (ZIKV) infection. Moreover, previous DENV infection did not affect afucosylation rate of anti-ZIKV antibodies. This implies that the generation of afucosylated antibodies is incumbent on viral specificity and a unique and enigmatic property of DENV. This important work has significant implications for epidemiology and immunology by identifying a prognostic indicator for severe DENV disease and highlighting the importance of antibody glycoforms in pathophysiology.

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