| 总结: | <p>Dengue is a mosquito borne tropical infection caused by the dengue virus with a dramatic global spread over the last few decades. Dengue infection can present as dengue fever (DF) or the severe forms such as dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS). There is a recognised clinical link between asthma and other allergies associating with severe dengue. Furthermore, mast cells are known to be activated in dengue infection and high levels of type 2 cytokines are known to be associated with DHF. Group 2 Innate Lymphoid Cells (ILC2) are type 2 cytokine secreting cells that respond to different stimuli including lipid mediators such as prostaglandin D2 (PGD2) and leukotrienes. Here, the hypothesis was tested that ILC2 contribute to dengue pathogenesis. First, increased peripheral blood ILC2 frequency was observed in dengue-infected individuals compared to healthy controls (HC). From ex vivo RNA sequencing data of ILC2 sorted from peripheral blood mononuclear cells (PBMC) of patients with DF and DHF, it was found that ILC2 were activated and infected, supporting viral dissemination. In vitro, ILC2 were permissive to infection particularly when activated and led to productive viral replication. From ex vivo RNA sequencing data it was evident that in DF the type I interferon related genes were highly expressed by ILC2 and in DHF this response was impaired.</p>
<p>Blockade of CRTH2, a PGD2 receptor, reduced dengue viral infection in ILC2 by inhibiting action of both exogenous and endogenously produced PGD2; and PGD2 reduced the ability of ILC2 to respond to type I IFN. Moreover, LTE4, another lipid mediator in the group of leukotrienes produced by mast cells increased infectivity of ILC2, and this could be inhibited by leukotriene receptor blockade. It was found that activated ILC2 supernatants promoted differentiation of monocytes to monocyte-derived dendritic cells (MoDCs) and could upregulate expression of DC-SIGN and MMR, which are key receptors facilitating attachment of dengue virus. Additionally, activated ILC2 supernatants increased dengue virus infection in differentiating monocytes in a GM-CSF dependent mechanism. Lastly, urinary PGD2 metabolites were elevated in severe dengue when reaching the ‘critical phase’ of the disease.</p>
<p>In summary, ILC2 are highly activated during acute dengue infection and can be infected by dengue virus ex vivo and in vitro. Dengue virus co-opts the innate type 2 pathways to escape protective type I interferon responses. We propose CRTH2 inhibition could be a novel mechanism to reduce viral replication in dengue infection.</p>
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