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

• Published in: Communications biology Vol. 5; no. 1; p. 735
• Main Authors: Fonseka, Chathuranga L., Hardman, Clare S., Woo, Jeongmin, Singh, Randeep, Nahler, Janina, Yang, Jiahe, Chen, Yi-Ling, Kamaladasa, Achala, Silva, Tehani, Salimi, Maryam, Gray, Nicki, Dong, Tao, Malavige, Gathsaurie N., Ogg, Graham S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.07.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/21; 38/77; 45/91; 631/250/2504/2506; 631/326/596/1413; 692/4017; 96/106; Antiviral agents; Biology; Biomedical and Life Sciences; Cytokines; Cytokines - metabolism; Dengue fever; Dengue hemorrhagic fever; Dengue Virus - metabolism; Granulocyte-macrophage colony-stimulating factor; Humans; Immunity, Innate; Infections; Life Sciences; Lymphocytes - metabolism; Lymphoid cells; Mannan; Monocytes; Prostaglandin D2; Prostaglandins - metabolism; Protein expression; Severe Dengue - metabolism; Viral infections; Virus Replication; Viruses; β-Interferon
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-022-03682-5

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 D 2 (PGD 2 ). 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. PGD 2 downregulated type I-IFN responsive gene and protein expression; and urinary prostaglandin D 2 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. PGD 2 downregulates type I-IFN induced anti-viral responses in ILC2. CRTH2 antagonism may be a therapeutic strategy for dengue-associated disease. Group 2 innate lymphoid cells are activated during acute dengue viral infection in human, downregulate type I-IFN responsive gene and protein expression through Prostaglandin D2, and are permissive for productive dengue viral infection.