Hyperinflammatory syndrome, natural killer cell function and genetic polymorphisms in the pathogenesis of severe dengue.

BackgroundSevere dengue, characterized by shock and organ dysfunction is driven by an excessive host immune response. We investigated the role of hyperinflammation in dengue pathogenesis.MethodsPatients recruited into an observational study were divided into three plasma leak severity grades. Hyperinflammatory biomarkers were measured at 4 time-points. Frequencies, activation and cytotoxic potential of NK cells were analysed by flow cytometry. RNA was extracted from sorted CD56+ NK cells and libraries prepared using SMART-Seq and sequenced using HiSeq3000 (Illumina).Results69 patients were included (grade 0: 42, grade 1: 19, grade 2: 8 patients). Patients with grade 2 leakage had higher biomarkers than grade 0, including higher peak ferritin levels (83.3% vs 45.2%) and H scores (median 148.5 vs 105.5). NK cells from grade 2 patients exhibited decreased expression of perforin and granzyme B and activation markers. RNA sequencing revealed three SNPs in NK cell functional genes associated with more severe leakage; NK cell lectin-like receptor K1 gene (KLRK1) and PRF1 gene.ConclusionsFeatures of hyperinflammation are associated with dengue severity, including higher biomarkers, impaired NK cell function and polymorphisms in genes NK cell cytolyitc function genes (KLRK1 and PRF-1). Trials of immunomodulatory therapy in these patients is now warranted.