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Toll-like receptors (TLRs) are important sensors that recognize pathogen-associated molecular patterns. Generally, TLR9 is known to recognize bacterial or viral DNA but not viral RNA and initiate an immune response. Herein, we demonstrate that infection with dengue virus (DENV), an RNA virus, activates TLR9 in human dendritic cells (DCs). DENV infection induces release of mitochondrial DNA (mtDNA) into the cytosol and activates TLR9 signaling pathways, leading to production of interferons (IFNs). The DENV-induced mtDNA release involves reactive oxygen species generation and inflammasome activation. DENV infection disrupts the association between transcription factor A mitochondria (TFAM) and mtDNA and activates the mitochondrial permeability transition pores. The side-by-side comparison of TLR9 and cyclic GMP-AMP synthase (cGAS) knockdown reveals that both cGAS and TLR9 comparably contribute to DENV-induced immune activation. The significance of TLR9 in DENV-induced immune response is also confirmed in examination with the bone marrow-derived DCs prepared from -knockout mice. Our study unravels a previously unrecognized phenomenon in which infection with an RNA virus, DENV, activates TLR9 signaling by inducing mtDNA release in human DCs.

Infection with hepatitis C virus (HCV) is a leading risk factor for chronic liver disease progression, including steatosis, cirrhosis, and hepatocellular carcinoma. With approximately 3% of the human population infected worldwide, HCV infection remains a global public health challenge. The efficacy of current therapy is still limited in many patients infected with HCV, thus a greater understanding of pathogenesis in HCV infection is desperately needed. Emerging lines of evidence indicate that HCV triggers a wide range of cellular stress responses, including cell cycle arrest, apoptosis, endoplasmic reticulum (ER) stress/unfolded protein response (UPR), and autophagy. Also, recent studies suggest that these HCV-induced cellular responses may contribute to chronic liver diseases by modulating cell proliferation, altering lipid metabolism, and potentiating oncogenic pathways. However, the molecular mechanism underlying HCV infection in the pathogenesis of chronic liver diseases still remains to be determined. Here, we review the known stress response activation in HCV infection in vitro and in vivo, and also explore the possible relationship of a variety of cellular responses with the pathogenicity of HCV-associated diseases. Comprehensive knowledge of HCV-mediated disease progression shall shed new insights into the discovery of novel therapeutic targets and the development of new intervention strategy.