Hepatitis C virus (HCV) is the most common blood-borne infection in the United States, with an overall prevalence of ~2%, and an estimated 200 million chronically infected people worldwide. A substantial body of evidence, including work from our laboratory, supports the concept that early events in the coordination and nature of multi-cellular immune responses are critical in determining whether the virus is cleared or whether persistence is established. However, despite the fact that approximately 40,000 pregnancies occur each year in HCV-infected women, little is known about the immunopathogenesis or correlates of protective immunity in this setting, in part because pregnant women with chronic HCV have hitherto been excluded from studies of immunity. For the first time, we present evidence that trophoblasts, specialized cells of the placenta that play important roles in embryo implantation and interaction with decidualized maternal uterus, can take up HCV proteins as well as respond to a viral product of hepatitis C (known as a pathogen-associated molecular pattern or PAMP) by producing high levels of Type III IFNs. These intriguing results corroborate the recent studies demonstrating genetic associations with single nucleotide polymorphisms that encode interferon lambda 3 and spontaneous recovery from HCV. Furthermore, we have identified HCV-specific CD8+ T cells within the maternal-fetal interface that we hypothesize demonstrate versatile functional attributes that prevent transmission in the majority of cases. We will also study how antigen-presenting cells in the decidua cross- present HCV antigens from trophoblasts and prime CD8+ T cells within the maternal fetal interface. Thus, our proposal seeks to mechanistically understand the different cells and signals that underpin HCV transmission versus protection.

Public Health Relevance

Hepatitis C is an RNA virus that infects approximately 200 million throughout the world. In the U.S. alone, it is estimated that approximately 40,000 births occur annually in HCV-positive pregnant women. HCV infection is associated with an increased risk for pre-term delivery, perinatal mortality, intrauterine growth restriction, and other complications;furthermore, vertical transmission accounts for the majority of pediatric HCV cases. Remarkably little is known about the mechanisms that govern transmission or protection for the fetus. We propose to study the integration and nature of multi-cellular immune responses within the maternal-fetal interface.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Reddy, Uma M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Golden-Mason, Lucy; Rosen, Hugo R (2017) Galectin-9: Diverse roles in hepatic immune homeostasis and inflammation. Hepatology 66:271-279
Sheiko, Melissa A; Golden-Mason, Lucy; Giugliano, Silvia et al. (2016) CD4+ and CD8+ T Cell Activation in Children with Hepatitis C. J Pediatr 170:142-8.e1
Spear, Timothy T; Riley, Timothy P; Lyons, Gretchen E et al. (2016) Hepatitis C virus-cross-reactive TCR gene-modified T cells: a model for immunotherapy against diseases with genomic instability. J Leukoc Biol 100:545-57
Giugliano, Silvia; Petroff, Margaret G; Warren, Bryce D et al. (2015) Hepatitis C Virus Sensing by Human Trophoblasts Induces Innate Immune Responses and Recruitment of Maternal NK Cells: Potential Implications for Limiting Vertical Transmission. J Immunol 195:3737-47
Rosen, Hugo R (2013) Emerging concepts in immunity to hepatitis C virus infection. J Clin Invest 123:4121-30