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Abstract
Vertical transmission accounts for the majority of pediatric cases of hepatitis C viral (HCV) infection. In contrast to the adult population who develop persistent viremia in ∼80% of cases following exposure, the rate of mother-to-child transmission (2–6%) is strikingly low. Protection from vertical transmission likely requires the coordination of multiple components of the immune system. Placenta and decidua provide a direct connection between mother and infant. We hypothesized that innate immune responses would differ across the three compartments (decidua, placenta and cord blood) and that hepatitis C exposure would modify innate immunity in these tissues. The study was comprised of HCV-infected and healthy control mother and infant pairs from whom cord blood, placenta and decidua were collected with isolation of mononuclear cells. Multiparameter flow cytometry was performed to assess the phenotype, intracellular cytokine production and cytotoxicity of the cells. In keeping with a model where the maternal-fetal interface provides antiviral protection, we found a gradient in proportional frequencies of NKT and γδ-T cells being higher in placenta than cord blood. Cytotoxicity of NK and NKT cells was enhanced in placenta and placental NKT cytotoxicity was further increased by HCV infection. HCV exposure had multiple effects on innate cells including a decrease in activation markers (CD69, TRAIL and NKp44) on NK cells and a decrease in plasmacytoid dendritic cells in both placenta and cord blood of exposed infants. In summary, the placenta represents an active innate immunological organ that provides antiviral protection against HCV transmission in the majority of cases; the increased incidence in preterm labor previously described in HCV-seropositive mothers may be related to enhanced cytotoxicity of NKT cells.
Highlights
Hepatitis C virus (HCV) is the most common blood borne infection in the United States (US), with an overall prevalence of 1.8% [1] that varies according to racial and ethnic groups
In order to define the role placental immune function plays in protection from vertical transmission of HCV infection, we performed the first thorough characterization of innate cells on term placenta paired with cord blood (CB) and decidua using multiparameter flow cytometry
The differences in innate immune composition include increased natural killer T cells (NKTs) cells in placenta compared to cord blood, in keeping with previous studies documenting increased NKT cells in maternal decidua compared to maternal peripheral blood [20]
Summary
Hepatitis C virus (HCV) is the most common blood borne infection in the United States (US), with an overall prevalence of 1.8% [1] that varies according to racial and ethnic groups. In light of the high rate of chronic infection developed in the non-pregnant state and the significant rate (15–35%) in HIV, the remarkably low rate of HCV infection following exposure in utero and at delivery, warrants further study [8,9]. A placental infection that elicits the production of inflammatory cytokines such as IFN-c and TNF-a could activate the maternal immune system, leading to placental damage and preterm labor [10]. In this regard, infection with HCV is a newly identified independent risk factor for preterm delivery, perinatal mortality, intrauterine growth restriction, and other complications [11,12,13]
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