Abstract
Immunity to one of the four dengue virus (DV) serotypes can increase disease severity in humans upon subsequent infection with another DV serotype. Serotype cross-reactive antibodies facilitate DV infection of myeloid cells in vitro by promoting virus entry via Fcγ receptors (FcγR), a process known as antibody-dependent enhancement (ADE). However, despite decades of investigation, no in vivo model for antibody enhancement of dengue disease severity has been described. Analogous to human infants who receive anti-DV antibodies by transplacental transfer and develop severe dengue disease during primary infection, we show here that passive administration of anti-DV antibodies is sufficient to enhance DV infection and disease in mice using both mouse-adapted and clinical DV isolates. Antibody-enhanced lethal disease featured many of the hallmarks of severe dengue disease in humans, including thrombocytopenia, vascular leakage, elevated serum cytokine levels, and increased systemic viral burden in serum and tissue phagocytes. Passive transfer of a high dose of serotype-specific antibodies eliminated viremia, but lower doses of these antibodies or cross-reactive polyclonal or monoclonal antibodies all enhanced disease in vivo even when antibody levels were neutralizing in vitro. In contrast, a genetically engineered antibody variant (E60-N297Q) that cannot bind FcγR exhibited prophylactic and therapeutic efficacy against ADE-induced lethal challenge. These observations provide insight into the pathogenesis of antibody-enhanced dengue disease and identify a novel strategy for the design of therapeutic antibodies against dengue.
Highlights
The four serotypes of dengue virus (DV) are mosquito-borne flaviviruses responsible for 50–100 million human infections annually
While no mortality was observed in naıve mouse serum (NMS)-recipient mice infected with 106 pfu or less of DV2, 92–100% of anti-DV1 recipients died after inoculation with
Increased infection of Fcc receptors (FccR)-bearing cells during antibodydependent enhancement (ADE) ADE is predicted to facilitate infection of FccR-bearing cell types such as tissue macrophages and dendritic cells [4]; we examined the cellular tropism of DV2 in mice by immunostaining for the viral NS3 protein, which is only present during active replication of the virus
Summary
The four serotypes of dengue virus (DV) are mosquito-borne flaviviruses responsible for 50–100 million human infections annually. Primary infection in individuals over the age of one year with any DV serotype is usually asymptomatic or results in self-limited dengue fever (DF), but secondary infection with another DV serotype carries an increased risk of severe disease, including life-threatening dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) [1,2]. The increased severity of secondary infections is believed to result, at least in part, from antibodydependent enhancement (ADE) of DV infection, in which FccR engagement by antibody-virus immune complexes facilitates virus entry into susceptible myeloid cell types [4]. A role for ADE in human dengue pathogenesis is supported by observations that maternally-derived anti-DV antibodies increase the risk of DHF in infants during primary infection with DENV2 [5,6]. Fundamental questions about the immunology and pathogenesis of ADE have remained unanswered, and small animal models for testing antiviral interventions in the context of ADE have not been available
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