Global and cell type-specific immunological hallmarks of severe dengue progression

Abstract

Severe dengue (SD) is a major cause of morbidity and mortality impacting approximately 5 million out of 400 million people infected with dengue virus (DENV) annually. To define DENV target cells and immunological hallmarks of SD progression in children's blood, we integrated virus-inclusive single cell RNA-Seq 2 (viscRNA-Seq 2) with functional assays. Beyond myeloid cells, in natural infection, B cells harbor replicating DENV capable of infecting permissive cells. Alterations in cell type abundance, gene and protein expression and secretion, and cell-cell communications point towards increased migration and inflammation in SD progressors (SDp). Concurrently, antigen presenting cells from SDp demonstrate intact uptake, yet impaired interferon responses and antigen presentation, in part DENV-modulated. Increased activation, regulation, and exhaustion of effector responses and expansion of HLA-DR-expressing, possibly compensatory, adaptive-like NK cells also characterize SDp. These findings reveal DENV target cells in the human blood and provide insight into SD pathogenesis beyond antibody-mediated enhancement.

Systems immunology of transcriptional responses to viral infection identifies conserved antiviral pathways across macaques and humans

“…Data from Ghita et al. 137 was generously shared. Both datasets were processed via Seurat and scanpy for QC, dimension reduction, clustering, and cell type classification.…”

Dengue NS1 interaction with lipids alters its pathogenic effects on monocyte derived macrophages

“…The reasons for occurrence of symptomatic and severe disease in some individuals remain incompletely understood. Many factors appear to be involved such as presence of host comorbidities (diabetes, cardiovascular disease and obesity), heterologous infections, the magnitude, breadth and the specificity of DENV specific antibody and T cell responses, the virulence of the infecting DENV strain, the extent viraemia and an altered dysfunctional immune responses [7,16,25,37].…”

“…The DENV infects many different cell types including monocytes, macrophages, hepatocytes and B cells causing disease pathogenesis [16,25]. However, in addition to the virus, dengue NS1 independently has shown to contribute to disease pathogenesis by disrupting the endothelial glycocalyx [4,32], inducing cytokine production from immune cells [26], activating phospholipase A2 enzymes [34] and immune evasion by interfering with complement activation [3], based on in vitro experiments and in dengue mouse models.…”