Dengue virus co-opts innate type 2 pathways to escape early control of viral replication

Journal article

Mast cell products and high levels of type 2 cytokines are associated with severe dengue disease. Group 2 innate lymphoid cells (ILC2) are type-2 cytokine-producing cells that are activated by epithelial cytokines and mast cell-derived lipid mediators. Through ex vivo RNAseq analysis, we observed that ILC2 are activated during acute dengue viral infection, and show an impaired type I-IFN signature in severe disease. We observed that circulating ILC2 are permissive for dengue virus infection in vivo and in vitro, particularly when activated through prostaglandin D₂ (PGD₂). ILC2 underwent productive dengue virus infection, which was inhibited through CRTH2 antagonism. Furthermore, exogenous IFN-β induced expression of type I-IFN responsive anti-viral genes by ILC2. PGD₂ downregulated type I-IFN responsive gene and protein expression; and urinary prostaglandin D₂ metabolite levels were elevated in severe dengue. Moreover, supernatants from activated ILC2 enhanced monocyte infection in a GM-CSF and mannan-dependent manner. Our results indicate that dengue virus co-opts an innate type 2 environment to escape early type I-IFN control and facilitate viral dissemination. PGD₂ downregulates type I-IFN induced anti-viral responses in ILC2. CRTH2 antagonism may be a therapeutic strategy for dengue-associated disease.

Authors: Fonseka, CL; Hardman, CS; Woo, J; Singh, R; Nahler, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Communications Biology
• Volume: 5
• Issue: 1
• Pages: 735-735
• Article number: 735
• Publication date: 2022-07-22
• DOI: 10.1038/s42003-022-03682-5
• EISSN: 2399-3642
• ISSN: 2399-3642
• Language: English
• Keywords: Interferon; Immunology; Virology; Dengue virus; Innate immune system; Biology; Viral replication; Immune system; Virus; Dengue fever; Innate lymphoid cell