Characterization of STING mediated innate immune sensing in the context of pathology

Thesis Type: Postgraduate

Institution Of The Thesis: Orta Doğu Teknik Üniversitesi, Faculty of Arts and Sciences, Department of Biology, Turkey

Approval Date: 2018


Consultant: MAYDA GÜRSEL


Type I interferonopathies are a group of diseases characterized by excess type I interferon production. Here, we examined the intracellular signal transduction pathways of two interferonopathies, STING-associated vasculopathy with Onset in Infancy (SAVI) and Aicardi-Goutières syndrome (AGS) using in vitro cell line models. SAVI is characterized by constitutive STING activation. M155V and N154S gain-of-function mutations in STING can cause disease in humans. We expressed the M155V mutant STING in STING-knocked out B16 Blue interferon reporter cell line. The effect of STING in tumor progression was investigated in mice using wild type, STING-/- or STINGM155V expressing B16 melanoma cells, with no significant differences between these groups. Using the STINGM155V expressing cells, we investigated type I IFN secretion profile to delineate the mechanism behind the cold-induced exacerbation of inflammation observed in SAVI patients. Similarly, TREX1 KO THP cells were used as a model of Aicardi-Goutières syndrome. Exposure to cold upregulated both p-STING and total STING levels in B16 cells, which may account for cold-temperature associated increase in inflammation in patients. Next, we analyzed the type I IFN suppressing activity of various inhibitors in our cell-line disease models. Results indicated that TBK1/IKK inhibitors Amlexanox and BX-795 were more effective in controlling chronic type I IFN production than the JAK/STAT inhibitors ruxolitinib and tofacitinib. Finally, we also investigated whether or not cGAS/STING signaling is regulated by circadian rhythms. Preliminary data showed that cGAS/STING-dependent type I IFN production oscillated over time, suggesting that this signaling pathway might indeed be under circadian regulation.