Abstract
Approximately 500,000 people are hospitalized with severe dengue illness annually. Antibody-dependent enhancement (ADE) of dengue virus (DENV) infection is believed to contribute to the pathogenic cytokine storm described in severe dengue patients, but the precise signaling pathways contributing to elevated cytokine production are not elucidated. IL-1β is a potent inflammatory cytokine that is frequently elevated during severe dengue, and the unique dual regulation of IL-1β provides an informative model to study ADE-induced cytokines. This work utilizes patient-derived anti-DENV mAbs and primary human monocytes to study ADE-induced IL-1β and other cytokines. ADE of DENV serotype 2 (DENV-2) elevates mature IL-1β secretion by monocytes independent of DENV replication by 4 h postinoculation (hpi). Prior to this, DENV immune complexes activate spleen tyrosine kinase (Syk) within 1 hpi. Syk induces elevated IL1B, TNF, and IL6 mRNA by 2 hpi. Syk mediates elevated IL-1β secretion by activating ERK1/2, and both Syk and ERK1/2 inhibitors ablated ADE-induced IL-1β secretion. Maturation of pro-IL-1β during ADE requires caspase-1 and NLRP3, but caspase-1 is suboptimally increased by ADE and can be significantly enhanced by a typical inflammasome agonist, ATP. Importantly, this inflammatory Syk-ERK signaling axis requires DENV immune complexes, because DENV-2 in the presence of serotype-matched anti-DENV-2 mAb, but not anti-DENV-1 mAb, activates Syk, ERK, and IL-1β secretion. This study provides evidence that DENV-2 immune complexes activate Syk to mediate elevated expression of inflammatory cytokines. Syk and ERK may serve as new therapeutic targets for interfering with ADE-induced cytokine expression during severe dengue.
Highlights
Insights into the mechanisms of elevated cytokine production during severe dengue disease are needed
Antibody-dependent Enhancement of Dengue Virus Infection Increases Viral Replication in Primary Human Monocytes— Purified CD14ϩ monocytes were inoculated with mosquito cell-derived supernatant containing an multiplicity of infection (MOI) of 50 dengue virus (DENV)-2 16681 Vero cell ffu/monocyte. 1 h prior to inoculation, DENV serotype 2 (DENV-2) was incubated with 2 g/ml anti-DENV prM human mAb 5G22 to form DENV-2 immune complexes or with control medium for non-Antibody-dependent enhancement (ADE) conditions
We confirm that ADE of DENV infection elevates secretion of IL-1 by primary human monocytes and provide insight into the modulation of cytokine induction by ADE
Summary
Insights into the mechanisms of elevated cytokine production during severe dengue disease are needed. Results: Dengue virus immune complexes induce inflammatory cytokine expression by activating spleen tyrosine kinase (Syk) during antibody-dependent enhancement of infection. This is informative because DENV does not cause relevant disease in immunocompetent mice unless extremely high inoculums are used [43,44,45,46,47,48,49,50,51] Using these valuable antibodies in ADE studies with primary human monocytes allows identification of important signaling pathways that represent potential therapeutic targets for the treatment of severe dengue disease. Activation of ERK1/2 by Syk is required for an IL-1 response to DENV immune complexes, identifying two potential points of intervention for interfering with ADE-induced cytokine production
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