Hepatitis C Virus Sensing by Human Trophoblasts Induces Innate Immune Responses and Recruitment of Maternal NK Cells: Potential Implications for Limiting Vertical Transmission.
Hepatitis C virus (HCV) is the world's most common blood-borne viral infection for which there is no vaccine. The rates of vertical transmission range between 3 and 6% with odds 90% higher in the presence of HIV coinfection. Prevention of vertical transmission is not possible because of lack of an approved therapy for use in pregnancy or an effective vaccine. Recently, HCV has been identified as an independent risk factor for preterm delivery, perinatal mortality, and other complications. In this study, we characterized the immune responses that contribute to the control of viral infection at the maternal-fetal interface (MFI) in the early gestational stages. In this study, we show that primary human trophoblast cells and an extravillous trophoblast cell line (HTR8), from first and second trimester of pregnancy, express receptors relevant for HCV binding/entry and are permissive for HCV uptake. We found that HCV-RNA sensing by human trophoblast cells induces robust upregulation of type I/III IFNs and secretion of multiple chemokines that elicit recruitment and activation of decidual NK cells. Furthermore, we observed that HCV-RNA transfection induces a proapoptotic response within HTR8 that could affect the morphology of the placenta. To our knowledge, for the first time, we demonstrate that HCV-RNA sensing by human trophoblast cells elicits a strong antiviral response that alters the recruitment and activation of innate immune cells at the MFI. This work provides a paradigm shift in our understanding of HCV-specific immunity at the MFI as well as novel insights into mechanisms that limit vertical transmission but may paradoxically lead to virus-related pregnancy complications.
Division of Gastroenterology and Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, CO 80045;
Silvia
S
Giugliano
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160;
Margaret G
MG
Petroff
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160;
Bryce D
BD
Warren
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160;
Susmita
S
Jasti
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160;
Caitlin
C
Linscheid
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160;
Ashley
A
Ward
Department of Obstetrics and Gynecology, University of Colorado, Aurora, CO 80045;
Anita
A
Kramer
Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, CO 80045;
Evgenia
E
Dobrinskikh
Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO 80045;
Melissa A
MA
Sheiko
Department of Immunology, University of Washington, School of Medicine, Seattle, WA 98109;
Michael
M
Gale
Division of Gastroenterology and Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, CO 80045;
Lucy
L
Golden-Mason
Department of Obstetrics and Gynecology, Stanford University, Palo Alto, CA 94304; and.
Virginia D
VD
Winn
Division of Gastroenterology and Hepatology, Hepatitis C Center, Department of Medicine, University of Colorado Denver, Aurora, CO 80045; Eastern Colorado Veteran's Affairs Medical Center, Denver, CO 80220 Hugo.Rosen@ucdenver.edu.
Hugo R
HR
Rosen
D000328:Adult; D005260:Female; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology* / Q000473:pathology / Q000635:transmission; D006801:Humans; D007113:Immunity, Innate; D007112:Immunity, Maternally-Acquired; D018445:Infectious Disease Transmission, Vertical; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology* / Q000821:virology; D014327:Trophoblasts / Q000276:immunology* / Q000473:pathology