Hyperinflammatory Syndrome, Natural Killer Cell Function, and Genetic Polymorphisms in the Pathogenesis of Severe Dengue . (10th March 2022) - Vuong, Nguyen Lam
Abstract: Background: Severe dengue, characterized by shock and organ dysfunction, is driven by an excessive host immune response. We investigated the role of hyperinflammation in dengue pathogenesis. Methods: Patients recruited into an observational study were divided into 3 plasma leak severity grades. Hyperinflammatory biomarkers were measured at 4 time points. Frequencies, activation, and cytotoxic potential of natural killer (NK) cells were analyzed by flow cytometry. RNA was extracted from sorted CD56 + NK cells and libraries were prepared using SMART-Seq and sequenced using HiSeq3000 (Illumina). Results: Sixty-nine patients were included (grade 0, 42 patients; grade 1, 19 patients; 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 3 single-nucleotide polymorphisms in NK cell functional genes associated with more severe leakage—NK cell lectin-like receptor K1 gene ( KLRK1 ) and perforin 1 ( PRF1 ). Conclusions: Features of hyperinflammation are associated with dengue severity, including higher biomarkers, impaired NK cell function, and polymorphisms in NK cell cytolytic function genes ( KLRK1 and PRF1 ). Trials of immunomodulatory therapy in these patients is now warranted. Abstract : Patients with severe dengue have higher inflammatory biomarkers, impaired natural killer (NK) cell activation/cytotoxic potential, and polymorphisms in genes involved in NK cell cytolytic function.