Generation and Characterization of Human-Mouse STING Chimeras That Allow DENV Replication in Mouse Cells.

Our group was the first to describe direct antagonism of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway by dengue virus (DENV) in human cells, and here, we report new findings on the characterization of the interaction between the DENV nonstructural protein 2B (NS2B)-NS3 (NS2B3) protease complex and STING. We demonstrate interactions between NS2B and the transmembrane domains of human STING and between NS3 and a portion of the cytoplasmic C-terminal domain of human STING. One significant obstacle we face today in the DENV field is the lack of small animal models available that can effectively recapitulate DENV pathogenesis in the early events of infection. The existing mouse models are either immunocompromised mice lacking interferon (IFN) receptors or "humanized" mice reconstituted with human stem cells. However, both approaches fail to capture important aspects of human pathogenesis because they lack critical innate immunity components or have deficiencies in immune cell development or maintenance. As an important step toward developing an immunocompetent mouse model for DENV, we have generated two chimeric human-mouse STING constructs that have promise in retaining both cleavability by NS2B3 and signaling capacity in the mouse.