TNF-α induced by Hepatitis C Virus via TLR7 and TLR8 in hepatocytes supports interferon signaling via an autocrine mechanism

Jiyoung Lee, Yongjun Tian, Stephanie Tze Chan, Ja Yeon Kim, Cecilia Cho, Jing-hsiung James Ou

PLOS Pathogens. (2015)

Speaker: Hsin-Hsin Chen (陳亲亲)                              Time: 14:00~15:00, Oct. 14, 2015

Commentator: Dr. Shun-Hua Chen (陳舜華 老師)    Place: Room 601

Abstract:

Hepatitis C virus (HCV) is a small, enveloped, single-stranded, positive-sense RNA virus belonging to the family Flaviviridae. The cytokine responses from host cells can provide the initial host defense mechanism during infectious pathogens invasion. Multiple studies indicate that the blood level of TNF-α which is a pro-inflammatory cytokine produced in response to infectious pathogens is increased in HCV patients whereas its level is positively correlated with HCV pathogenesis and the severity of liver diseases [1,2].Yet, the major source of TNF-α in response to HCV infection is unclear. Here, the author demonstrated that TNF-α can be induced by HCV-infected host cells in a biphasic manner. The author, to show the first phase of induction used HCV E2 envelope protein antibody that has blocked the expression of TNF-α at early time point of infection. Moreover, the chemicals induced to prevent the endocytosis of HCV also reduced the expression of TNF-α at 24 hours, the second phase of induction. The initial induction of TNF-α by HCV In addition, they found that supression of the downstream effectors of TLR7/8 signaling pathway including MyD88, IRAK1, TRAF6, TAK1 and p65 NF-κB by antisense RNA could inhibit the expression of TNF-α. Further studies showed that TNF-α induced by HCV could activate its own receptor TNFR1 on hepatocytes to suppress HCV replication and supports interferon signaling via an autocrine mechanism. TNF-α suppression, lead to the loss of IFNAR2, impaired interferon signaling and also the induction of interferon-stimulated genes. In conclusion, this study provides evidences to demonstrate that hepatocytes can sense HCV infection via TLR7/8 to induce the expression of TNF-α, which in turn inhibits HCV replication via an autocrine mechanism to support interferon signaling and restore the expression of IFNAR2.

References:

1.         Itoh Y, D. et al. (1999). Serum levels of soluble tumor necrosis factor receptors and effects of interferon therapy in patients with chronic hepatitis C virus infection. American Journal of Gastroenterology 94, 1332–1340.

2.         Kallinowski B. et al. (1998). Induction of tumour necrosis factor (TNF) receptor type p55 and p75 in patients with chronic hepatitis C virus (HCV) infection. Clinical and Experimental Immunology 111, 269–277.