Hyperinflammatory Syndrome, Natural Killer Cell Function, and Genetic Polymorphisms in the Pathogenesis of Severe Dengue . (10th March 2022)

• Record Type: Journal Article
• Authors: Vuong, Nguyen Lam; Cheung, Ka Wai; Periaswamy, Balamurugan; Vi, Tran Thuy; Duyen, Huynh Thi Le; Leong, Yan Shan; Binte Hamis, Zayanah Noor; Gregorova, Michaela; Ooi, Eng Eong; Sessions, October; Rivino, Laura; Yacoub, Sophie
• Is Part Of: Journal of infectious diseases. Volume 226:Number 8(2022)
• Page Start: 1338
• Page End: 1347
• Publication Date: 2022-03-10
• Subjects: dengue -- hyperinflammation -- macrophage activation syndrome -- single-nucleotide polymorphisms -- immunomodulation; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jiac093
• Languages: English
• ISSNs: 0022-1899

Abstract

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.