Gamma interferon-inducible lysosomal thioreductase (GILT) ablation renders mouse fibroblasts sensitive to dengue virus replication

Dengue viruses (DENV), members of mosquito-borne Flaviviruses, are human pathogens of global significance. The virus enters the host cell through endocytosis and uncoating subsequent to a low pH-triggered conformational change of E protein in endosomes. The endosomes are active in antigen processing and the key enzyme involved is the gamma interferon-inducible lysosomal thiol reductase (GILT). Here, we sought to address the role of GILT in DENV2 entry using fibroblasts from wild type (WT) and GILT knockout (GILT−/−) mice (MFs) with defective antigen processing. Our results obtained using DENV2 infectious and Renilla luciferase reporter replicon RNAs show that WT MFs are relatively resistant and GILT−/− MFs are susceptible to DENV2 translation and replication. We show that DENV2 infection of WT MEFs induced autophagy based on an increased LC3-II/LC3-I ratio that is further enhanced in GILT−/− cells. The increased susceptibility of DENV2 infection in the GILT−/−MFs strongly correlates with increased autophagy.