Relationship between sex hormones and RIG-I signaling in peripheral blood mononuclear cells of patients infected with hepatitis C virus

Abstract

Abstract. It has previously been suggested that men and women demonstrate differing immune responses to hepatitis C virus (HCV) infection, resulting in the investigation of the role of sex hormones and if they influence the anti-HCV response. The present study aimed to examine if hormone levels were associated with interferon (IFN) signaling pathways in peripheral blood mononuclear cells of 131 patients infected with HCV and 113 healthy controls. HCV infection was diagnosed based on the presence of anti-HCV antibodies and HCV RNA in serum. Expression of testosterone and estrogen was measured at the protein level using a competitive chemiluminescence immunoassay, and at the mRNA level using reverse transcription-quantitative polymerase chain reaction. HCV-infected males had increased levels of estrogen and a decreased ratio of testosterone to estrogen compared with healthy male controls (all P<0.001). HCV-infected patients demonstrated a significantly decreased expression of IFN and retinoic acid-induced gene protein I (RIG-I), RIG-I mRNA compared with controls. Pearson correlation analysis revealed that among males, levels of RIG-I correlated with levels of IFN-β mRNA (r=0.460), testosterone (r=-0.500), and the ratio of testosterone to estrogen (r=-0.477; all P<0.001). However, levels of RIG-I did not correlate with levels of IFN-α mRNA (r=0.158) or estrogen (r=0.173; both P>0.05). These results suggested that testosterone or the ratio of testosterone to estrogen may inhibit RIG-I signaling and thereby influence immune responses to HCV infection. IntroductionHepatitis C virus (HCV), a single-strand RNA virus of the Flaviviridae family, infects approximately 170 million people worldwide (1). HCV replication in infected individuals triggers an innate immune response that is often ineffective: As many as 80% of HCV-infected patients cannot eliminate the virus and develop chronic hepatitis, cirrhosis, and even liver cancer (2). Innate immune responses to HCV infection differ between men and women (3-5), leading to the question of whether sex hormones may influence these responses.Innate immune responses are induced when pattern recognition receptors (PRRs), which are expressed on immune cells, especially antigen-presenting cells, recognize viral genetic material (6). PRRs include Rig-like helicase receptors, NOD-nucleotide binding oligomerization domain-like receptors and Toll-like receptors. PRRs trigger signaling pathways that induce the production and release of cytokines such as the type I interferons IFN-α and IFN-βThe central PRR activated in response to RNA virus infection is retinoic acid-induced gene protein I (RIG-I), a 5'-triphosphorylated, uncapped RNA-binding DexD/H-box helicase (7). After binding to viral RNA, RIG-I induces a host response in which the amino-caspase activation and recruitment domains (CARDs) interact with the amino-terminal CARD of the IFN-β promoter-stimulator 1 (IPS-1) (7).The present study explored whether differences in sex hormone levels between men and women may lead to differenc...

Consequences of sex differences in Type I IFN responses for the regulation of antiviral immunity

“…For instance, RIG-I is an IFN-stimulated gene that, due to overall enhanced Type I IFN responses in females, might increase its expression faster in female than male cells. Indeed, RIG-I signaling has been shown to be targeted in viral infections, suggesting a viral mechanisms to avoid detection during hepatitis C virus (HCV) infection (66). HCV also disrupts STING signaling complexes, cleaves MAVS and TRIF proteins, all of them limiting IFN induction (64).…”