Fetal Inheritance of Chromosomally Integrated Human Herpesvirus 6 Predisposes the Mother to Pre-eclampsia

Overview

Journal Nat Microbiol

Specialties Microbiology
Parasitology

Date 2020 May 6

PMID 32367053

Citations 17

Authors

Francesca Gaccioli

Susanne Lager

Marcus C de Goffau

Ulla Sovio

Justyna Dopierala

Sungsam Gong

Emma Cook

Andrew Sharkey

Ashley Moffett

Wai Kwong Lee

Christian Delles

Cristina Venturini

Judith Breuer

Julian Parkhill

Sharon J Peacock

D Stephen Charnock-Jones

Gordon C S Smith

Affiliations

Soon will be listed here.

Abstract

Pre-eclampsia (typically characterized by new-onset hypertension and proteinuria in the second half of pregnancy) represents a major determinant of the global burden of disease. Its pathophysiology involves placental dysfunction, but the mechanism is unclear. Viral infection can cause organ dysfunction, but its role in placentally related disorders of human pregnancy is unknown. We addressed this using RNA sequencing metagenomics of placental samples from normal and complicated pregnancies. Here, we show that human herpesvirus 6 (HHV-6, A or B) RNA was detected in 6.1% of cases of pre-eclampsia and 2.2% of other pregnancies. Fetal genotyping demonstrated that 70% of samples with HHV-6 RNA in the placenta exhibited inherited, chromosomally integrated HHV-6 (iciHHV-6). We genotyped 467 pre-eclampsia cases and 3,854 controls and found an excess of iciHHV-6 in the cases (odds ratio of 2.8, 95% confidence intervals of 1.4-5.6, P = 0.008). We validated this finding by comparing iciHHV-6 in a further 740 cases with controls from large-scale population studies (odds ratio of 2.5, 95% confidence intervals of 1.4-4.4, P = 0.0013). We conclude that iciHHV-6 results in the transcription of viral RNA in the human placenta and predisposes the mother to pre-eclampsia.

Citing Articles

Blood DNA virome associates with autoimmune diseases and COVID-19.

Sasa N, Kojima S, Koide R, Hasegawa T, Namkoong H, Hirota T Nat Genet. 2025; 57(1):65-79.

PMID: 39753770 PMC: 11735405. DOI: 10.1038/s41588-024-02022-z.

Fetal cord plasma herpesviruses and preeclampsia: an observational cohort study.

Hakkinen I, Yazgeldi Gunaydin G, Pyoria L, Kojima S, Parrish N, Perdomo M Sci Rep. 2024; 14(1):14605.

PMID: 38918446 PMC: 11199493. DOI: 10.1038/s41598-024-65386-6.

Deep metagenomic characterization of the gut virome in pregnant women with preeclampsia.

Lv L, Wen J, Zhang Y, Guo R, Li H, Yi Z mSphere. 2024; 9(4):e0067623.

PMID: 38506520 PMC: 11036803. DOI: 10.1128/msphere.00676-23.

The immediate-early protein 1 of human herpesvirus 6B interacts with NBS1 and inhibits ATM signaling.

Collin V, Biquand E, Tremblay V, Lavoie E, Blondeau A, Gravel A EMBO Rep. 2024; 25(2):725-744.

PMID: 38177923 PMC: 10897193. DOI: 10.1038/s44319-023-00035-z.

Noninvasive Prenatal Testing Using Circulating DNA and RNA: Advances, Challenges, and Possibilities.

Moufarrej M, Bianchi D, Shaw G, Stevenson D, Quake S Annu Rev Biomed Data Sci. 2023; 6:397-418.

PMID: 37196360 PMC: 10528197. DOI: 10.1146/annurev-biodatasci-020722-094144.

References

McClure E, Garces A, Saleem S, Moore J, Bose C, Esamai F . Global Network for Women's and Children's Health Research: probable causes of stillbirth in low- and middle-income countries using a prospectively defined classification system. BJOG. 2017; 125(2):131-138. PMC: 5537043. DOI: 10.1111/1471-0528.14493. View

Brosens I, Pijnenborg R, Vercruysse L, Romero R . The "Great Obstetrical Syndromes" are associated with disorders of deep placentation. Am J Obstet Gynecol. 2010; 204(3):193-201. PMC: 3369813. DOI: 10.1016/j.ajog.2010.08.009. View

Gardy J, Loman N . Towards a genomics-informed, real-time, global pathogen surveillance system. Nat Rev Genet. 2017; 19(1):9-20. PMC: 7097748. DOI: 10.1038/nrg.2017.88. View

Houldcroft C, Beale M, Breuer J . Clinical and biological insights from viral genome sequencing. Nat Rev Microbiol. 2017; 15(3):183-192. PMC: 7097211. DOI: 10.1038/nrmicro.2016.182. View

Depledge D, Palser A, Watson S, Lai I, Gray E, Grant P . Specific capture and whole-genome sequencing of viruses from clinical samples. PLoS One. 2011; 6(11):e27805. PMC: 3220689. DOI: 10.1371/journal.pone.0027805. View

Gravel A, Hall C, Flamand L . Sequence analysis of transplacentally acquired human herpesvirus 6 DNA is consistent with transmission of a chromosomally integrated reactivated virus. J Infect Dis. 2013; 207(10):1585-9. DOI: 10.1093/infdis/jit060. View

Huang Y, Hidalgo-Bravo A, Zhang E, Cotton V, Mendez-Bermudez A, Wig G . Human telomeres that carry an integrated copy of human herpesvirus 6 are often short and unstable, facilitating release of the viral genome from the chromosome. Nucleic Acids Res. 2013; 42(1):315-27. PMC: 3874159. DOI: 10.1093/nar/gkt840. View

Tanaka-Taya K, Sashihara J, Kurahashi H, Amo K, Miyagawa H, Kondo K . Human herpesvirus 6 (HHV-6) is transmitted from parent to child in an integrated form and characterization of cases with chromosomally integrated HHV-6 DNA. J Med Virol. 2004; 73(3):465-73. DOI: 10.1002/jmv.20113. View

Miura H, Kawamura Y, Hattori F, Kozawa K, Ihira M, Ohye T . Chromosomally integrated human herpesvirus 6 in the Japanese population. J Med Virol. 2018; 90(10):1636-1642. DOI: 10.1002/jmv.25244. View

10.

Gravel A, Dubuc I, Morissette G, Sedlak R, Jerome K, Flamand L . Inherited chromosomally integrated human herpesvirus 6 as a predisposing risk factor for the development of angina pectoris. Proc Natl Acad Sci U S A. 2015; 112(26):8058-63. PMC: 4491735. DOI: 10.1073/pnas.1502741112. View

11.

Sovio U, Gaccioli F, Cook E, Hund M, Charnock-Jones D, Smith G . Prediction of Preeclampsia Using the Soluble fms-Like Tyrosine Kinase 1 to Placental Growth Factor Ratio: A Prospective Cohort Study of Unselected Nulliparous Women. Hypertension. 2017; 69(4):731-738. PMC: 5344177. DOI: 10.1161/HYPERTENSIONAHA.116.08620. View

12.

Sultana Z, Maiti K, Dedman L, Smith R . Is there a role for placental senescence in the genesis of obstetric complications and fetal growth restriction?. Am J Obstet Gynecol. 2017; 218(2S):S762-S773. DOI: 10.1016/j.ajog.2017.11.567. View

13.

Broady A, Loichinger M, Ahn H, Davy P, Allsopp R, Bryant-Greenwood G . Protective proteins and telomere length in placentas from patients with pre-eclampsia in the last trimester of gestation. Placenta. 2017; 50:44-52. PMC: 5654626. DOI: 10.1016/j.placenta.2016.12.018. View

14.

Sano R, Reed J . ER stress-induced cell death mechanisms. Biochim Biophys Acta. 2013; 1833(12):3460-3470. PMC: 3834229. DOI: 10.1016/j.bbamcr.2013.06.028. View

15.

Burton G, Yung H, Cindrova-Davies T, Charnock-Jones D . Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia. Placenta. 2008; 30 Suppl A:S43-8. PMC: 2684656. DOI: 10.1016/j.placenta.2008.11.003. View

16.

Racicot K, Mor G . Risks associated with viral infections during pregnancy. J Clin Invest. 2017; 127(5):1591-1599. PMC: 5409792. DOI: 10.1172/JCI87490. View

17.

Zhang E, Bell A, Wilkie G, Suarez N, Batini C, Veal C . Inherited Chromosomally Integrated Human Herpesvirus 6 Genomes Are Ancient, Intact, and Potentially Able To Reactivate from Telomeres. J Virol. 2017; 91(22). PMC: 5660504. DOI: 10.1128/JVI.01137-17. View

18.

Peddu V, Dubuc I, Gravel A, Xie H, Huang M, Tenenbaum D . Inherited Chromosomally Integrated Human Herpesvirus 6 Demonstrates Tissue-Specific RNA Expression That Correlates with an Increased Antibody Immune Response. J Virol. 2019; 94(1). PMC: 6912112. DOI: 10.1128/JVI.01418-19. View

19.

Marci R, Gentili V, Bortolotti D, Monte G, Caselli E, Bolzani S . Presence of HHV-6A in Endometrial Epithelial Cells from Women with Primary Unexplained Infertility. PLoS One. 2016; 11(7):e0158304. PMC: 4930213. DOI: 10.1371/journal.pone.0158304. View

20.

Caselli E, Bortolotti D, Marci R, Rotola A, Gentili V, Soffritti I . HHV-6A Infection of Endometrial Epithelial Cells Induces Increased Endometrial NK Cell-Mediated Cytotoxicity. Front Microbiol. 2018; 8:2525. PMC: 5736868. DOI: 10.3389/fmicb.2017.02525. View