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

Dengue virus (DENV) causes widespread mosquito-borne infection. While most symptomatic patients experience mild disease, a fraction progresses to severe dengue (SD)--a life-threatening condition whose pathogenesis remains largely unknown. We integrated virus-inclusive single cell RNA-Seq 2 (viscRNA-Seq 2) with functional assays to determine the immunological hallmarks of SD progression in children's blood. We show that beyond myeloid cells, in natural infection, B cells harbor replicating DENV capable of infecting permissive cells. Alterations in cell abundance, gene and protein expression and secretion, and cell-cell communications suggesting increased migration and inflammation in SD progressors, yet concurrent: i) impaired interferon responses and antigen presentation, in part DENV-modulated, by antigen presenting cells (APCs) in face of intact uptake; ii) activation, regulation, and exhaustion of effector responses, enhanced IFN?-responses, and appearance of HLA-DR-expressing NK cells possibly compensating for APCs impairments. These observations reveal the target cells of DENV in human blood and provide insight into SD pathogenesis beyond antibody-mediated enhancement. Overall design: PBMCs derived from 20 DENV-infected children and 4 healthy controls were isolated by magnetic separation and analyzed via a optimized viscRNA-Seq 2 approach