Dengue poses a continued global health thread and climate change has contributed to an expanding habitat of the mosquitos that spread the Dengue virus (DENV). While first infections generally result in mild flu-like symptoms, future DENV infections with a different serotype can lead to severe hemorrhagic fever or in rarer cases Dengue shock syndrome. Secondary infection is enhanced by the presence of antibodies from primary infection that are non-neutralizing against other DENV serotypes. This antibody-dependent enhancement has hampered vaccine development and raised concerns about the broad employment of the first approved Dengue vaccine. To develop alternative antiviral strategies, we focus on host cell processes that are required for Dengue infection and replication, and that are also commonly employed by related flaviviruses, such as Zika, Yellow Fever, West Nile or Hepatitis C virus. Flavivirus replication and assembly occurs at the endoplasmic reticulum (ER) membrane, and the virus extensively remodels this organelle through the unfolded protein response (UPR). In particular, infection results in the activation of the ATF6 and IRE/XBP1s arm of the UPR, inducing expression of distinct ER chaperones and protein folding factors that maintain protein homeostasis. To probe the individual roles of the UPR branches in the context of DENV infection, we take advantage of recently developed pharmacologic agents that specifically activate or inhibit the ATF6 or IRE/XBP1s pathways. In particular, we discover that treatment with a small-molecule ATF6 activator results in significant reduction in viral propagation. Using chemoproteomics for target identification, we define that the molecule activates ATF6 through perturbation of ER redox signaling processes. We also discuss results from proteomics profiling to determine other host cell pathways that are impacted by the small molecule, as well as our ongoing efforts to characterize how modulation of these redox processes is involved in regulating DENV replication and the ability to assembly and secrete new virions. These efforts will enable the development of new therapeutic strategies centered on the host cells, which can also be explored against other flaviviruses.

Targeting Dengue virus replication through pharmacologic modulation of ER proteostasis pathways

2019 Fall National Meeting

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