Nguyen Lam Vuong1,2, Ka Wai Cheung3, Balamurugan Periaswamy4, Tran Thuy Vi1, Huynh Thi Le Duyen1, Yan Shan Leong3, Zayanah Noor Binte Hamis3, Michaela Gregorova5, Eng Eong Ooi3,6, October Sessions3,6,7, Laura Rivino3,5, Sophie Yacoub1,8. 1. Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam. 2. University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam. 3. Duke-National University of Singapore Medical School, Singapore. 4. Genome Institute of Singapore, Singapore. 5. School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom. 6. Saw Swee Hock School of Public Health, National University of Singapore, Singapore. 7. Department of Pharmacy, National University of Singapore, Singapore. 8. Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, United Kingdom.
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.
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.
Authors: Cornelia A M van de Weg; Ralph M H G Huits; Cláudio S Pannuti; Rosalba M Brouns; Riemsdijk W A van den Berg; Henk-Jan van den Ham; Byron E E Martina; Albert D M E Osterhaus; Mihai G Netea; Joost C M Meijers; Eric C M van Gorp; Esper G Kallas Journal: PLoS Negl Trop Dis Date: 2014-10-09
Authors: Puja Mehta; Daniel F McAuley; Michael Brown; Emilie Sanchez; Rachel S Tattersall; Jessica J Manson Journal: Lancet Date: 2020-03-16 Impact factor: 79.321