HHV-6A infection of endometrial epithelial cells affects immune profile and trophoblast invasion

Daria Bortolotti; Valentina Gentili; Antonella Rotola; Rosario Cultrera; Roberto Marci; Dario Di Luca; Roberta Rizzo

doi:10.1111/aji.13174

HHV-6A infection of endometrial epithelial cells affects immune profile and trophoblast invasion

Am J Reprod Immunol. 2019 Oct;82(4):e13174. doi: 10.1111/aji.13174. Epub 2019 Aug 17.

Authors

Daria Bortolotti¹, Valentina Gentili¹, Antonella Rotola¹, Rosario Cultrera², Roberto Marci^{3

4}, Dario Di Luca⁵, Roberta Rizzo¹

Affiliations

¹ Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
² Department of Medical Sciences, Section of Dermathology and Infective Medicine, University of Ferrara, Ferrara, Italy.
³ Department of Morphology, Surgery and Experimental Medicine, Section of Orthopedics, Obstetrics and Gynecology and Anesthesiology and Reanimation Ferrara, University of Ferrara, Ferrara, Italy.
⁴ School of Medicine, University of Geneva, Geneva, Switzerland.
⁵ Department of Medical Sciences, University of Ferrara, Ferrara, Italy.

PMID: 31338899
DOI: 10.1111/aji.13174

Abstract

Problem: We first reported human herpesvirus (HHV)-6A DNA presence in 43% of endometrial cells from women with idiopathic infertility, whereas no fertile control women harbored the virus. We investigated the effect of HHV-6A infection on the immunological status of the endometrium.

Method of study: Endometrial biopsies, uterine flushing, and whole blood samples were collected from 67 idiopathic infertile women (mid-secretory phase). We analyzed the endometrial immunological status evaluating: (a) the effect of HHV-6A infection on endometrial immune profile analyzing the ratio of interleukin (IL)-15/ fibroblast growth factor-inducible 14 (Fn-14) and IL-18/ TNF-related weak inducer of apoptosis (TWEAK) mRNA as a biomarker of endometrial (e)natural killer activation/maturation, angiogenesis, and Th1/Th2 balance; (b) endometrial receptivity to trophoblasts in endometrial 3D in vitro model; (c) natural killer (NK) cells and T cells percentage and subpopulations by flow cytometry.

Results: We confirmed the presence of HHV-6A infection in a 40% of idiopathic infertile women, characterized by an immune profile reflecting eNK cell cytotoxic activation and a decrease in CD4+ CD25+ CD127dim/^- regulatory T cells. The co-culture of endometrial epithelial cells with spheroids generated from the extravillous trophoblast-derived cell line JEG3 showed a twofold expansion of spheroids on endometrial epithelial-stromal cells (ESC) culture surface from HHV-6A negative women while no expansion was observed on the surface of ESC from HHV-6A positive women.

Conclusion: The identification of an effect of HHV-6A infection on endometrial immune status opens new perspectives in idiopathic infertile women care management. In addition, it would be possible to select antiviral therapies as novel, non-hormonal therapeutic approaches to those idiopathic infertile women characterized by the presence of endometrial HHV-6A infection, to increase their pregnancy rate.

Keywords: HLA-G; NK cells; T cells; idiopathic female infertility.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Cell Movement
DNA, Viral
Endometrium / immunology*
Endometrium / virology
Epithelial Cells / immunology*
Epithelial Cells / virology
Female
Herpesvirus 6, Human*
Humans
Infertility / immunology*
Infertility / virology
Killer Cells, Natural / immunology
Roseolovirus Infections / immunology*
Roseolovirus Infections / virology
Stromal Cells / immunology
Stromal Cells / virology
T-Lymphocytes / immunology
Trophoblasts / physiology*
Young Adult

Substances

DNA, Viral

Abstract

Publication types

MeSH terms

Substances

Grants and funding