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 of HCV in this setting, in part because pregnant women with chronic HCV have hitherto been excluded from studies of immunity. For the first time, 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. Furthermore, wepresent evidence that trophoblasts, specialized cells of the placenta that play important roles in embryo implantation and interaction with decidualized maternal uterus, can 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 (interferon lambda 3). These intriguing results corroborate the recent studies demonstrating genetic associations with single nucleotide polymorphisms that encode interferon lambda 3 and spontaneous recovery from HCV. We will also characterize how the HCV PAMP affects apoptosis signaling and differentiation of trophoblasts. In the third aim, building on strong preliminary data that ? T cells are significantly expanded within the placentas of HCV-positive mothers who do not transmit virus to their infants, we will characterize the phenotype, function, and restriction of these cells, implicated in other models as a first line of defense against viral infections. Thus, our proposal seeks to mechanistically understand the different cells and signals at the maternal-fetal interface that underpin transmission versus protection and cause detrimental effects within the placenta. Although focused on HCV infection, the results generated will have far-reaching implications for other viral pathogens that affect pregnancy.

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 including: conventional and homeostatically-driven CTLs, innate Type I and III interferon signaling within trophoblasts and downstream effector functions, and the role of unconventional ?? T cells. Moreover, several of the in vitro models are designed to recapitulate the in vivo setting. We believe completion of the objectives-based on extensive preliminary data and conceptual insights--will provide novel information about viral pathogenesis and direct approaches to intervene therapeutically.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI100991-01
Application #
8535990
Study Section
Special Emphasis Panel (ZAI1-BDP-M (M1))
Program Officer
Koshy, Rajen
Project Start
2012-09-20
Project End
2014-02-28
Budget Start
2012-09-20
Budget End
2014-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$531,913
Indirect Cost
$181,832
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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