Immune rebalancing at the maternal-fetal interface of maternal SARS-CoV-2 infection during early pregnancy
Chenxiang Xi, Zihui Yan, Dandan Bai, Yalin Zhang, Beiying Wang, Xiaoxiao Han, Li Wu, Xiaohui Shi, Zhiyi Hu, Ming Tang, Zhongqu Su, Yingdong Liu, Binya Liu, Jiqing Yin, Hong Wang, Xiaocui Li, Yanping Zhang, Shaorong Gao, Wenqiang Liu
Immune rebalancing at the maternal-fetal interface of maternal SARS-CoV-2 infection during early pregnancy
The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) remains a threat to pregnant women. However, the impact of early pregnancy SARS-CoV-2 infection on the maternal-fetal interface remains poorly understood. Here, we present a comprehensive analysis of single-cell transcriptomics and metabolomics in placental samples infected with SARS-CoV-2 during early pregnancy. Compared to control placentas, SARS-CoV-2 infection elicited immune responses at the maternal-fetal interface and induced metabolic alterations in amino acid and phospholipid profiles during the initial weeks post-infection. However, subsequent immune cell activation and heightened immune tolerance in trophoblast cells established a novel dynamic equilibrium that mitigated the impact on the maternal-fetal interface. Notably, the immune response and metabolic alterations at the maternal-fetal interface exhibited a gradual decline during the second trimester. Our study underscores the adaptive immune tolerance mechanisms and establishment of immunological balance during the first two trimesters following maternal SARS-CoV-2 infection.
maternal / immune / rebalancing / fetal / interface / SARS
[1] |
Abu-Raya B, Kollmann TR, Marchant A et al. The immune system of HIV-exposed uninfected infants. Front Immunol 2016;7:383.
CrossRef
Google scholar
|
[2] |
Adebayo A, Varzideh F, Wilson S et al. l-Arginine and COVID-19: an update. Nutrients 2021;13:3951.
CrossRef
Google scholar
|
[3] |
Amiot L, Vu N, Samson M. Immunomodulatory properties of HLA-G in infectious diseases. J Immunol Res 2014;2014:298569.
CrossRef
Google scholar
|
[4] |
Ashkar AA, Croy BA. Interferon-gamma contributes to the normalcy of murine pregnancy. Biol Reprod 1999;61:493–502.
CrossRef
Google scholar
|
[5] |
Bailey CC, Zhong G, Huang IC et al. IFITM-family proteins: the cell’s first line of antiviral defense. Annu Rev Virol 2014;1:261–283.
CrossRef
Google scholar
|
[6] |
Bergen V, Lange M, Peidli S et al. Generalizing RNA velocity to transient cell states through dynamical modeling. Nat Biotechnol 2020;38:1408–1414.
CrossRef
Google scholar
|
[7] |
Busnadiego I, Fernbach S, Pohl MO et al. Antiviral activity of Type I, II, and III interferons counterbalances ACE2 inducibility and restricts SARS-CoV-2. mBio 2020;11:e01928–e01920.
CrossRef
Google scholar
|
[8] |
Butler A, Hoffman P, Smibert P et al. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol 2018;36:411–420.
CrossRef
Google scholar
|
[9] |
Chen J, Du L, Wang F et al. Cellular and molecular atlas of the placenta from a COVID-19 pregnant woman infected at midgestation highlights the defective impacts on foetal health. Cell Prolif 2022;55:e13204.
CrossRef
Google scholar
|
[10] |
Chen X, Shi H, Li C et al. The effect of SARS-CoV-2 infection on human embryo early development: a multicenter prospective cohort study. Sci China Life Sci 2023;66:1697–1700.
CrossRef
Google scholar
|
[11] |
Chumbley G, King A, Robertson K et al. Resistance of HLA-G and HLA-A2 transfectants to lysis by decidual NK cells. Cell Immunol 1994;155:312–322.
CrossRef
Google scholar
|
[12] |
Clark DA, Chaouat G, Wong K et al. Tolerance mechanisms in pregnancy: a reappraisal of the role of class I paternal MHC antigens. Am J Reprod Immunol 2010;63:93–103.
CrossRef
Google scholar
|
[13] |
Co EC, Gormley M, Kapidzic M et al. Maternal decidual macrophages inhibit NK cell killing of invasive cytotrophoblasts during human pregnancy. Biol Reprod 2013;88:155.
CrossRef
Google scholar
|
[14] |
Dashraath P, Wong J LJ, Lim M XK et al. Coronavirus disease 2019 (COVID-19) pandemic and pregnancy. Am J Obstet Gynecol 2020;222:521–531.
CrossRef
Google scholar
|
[15] |
Garcia-Flores V, Romero R, Xu Y et al. Maternal-fetal immune responses in pregnant women infected with SARS-CoV-2. Nat Commun 2022;13:320.
CrossRef
Google scholar
|
[16] |
Geiger R, Rieckmann JC, Wolf T et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 2016;167:829–842.e13.
CrossRef
Google scholar
|
[17] |
Guo C, Cai P, Jin L et al. Single-cell profiling of the human decidual immune microenvironment in patients with recurrent pregnancy loss. Cell Discov 2021;7:1.
CrossRef
Google scholar
|
[18] |
Hanna J, Goldman-Wohl D, Hamani Y et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med 2006;12:1065–1074.
CrossRef
Google scholar
|
[19] |
Hojyo S, Uchida M, Tanaka K et al. How COVID-19 induces cytokine storm with high mortality. Inflamm Regen 2020;40:37.
CrossRef
Google scholar
|
[20] |
Jabrane-Ferrat N. Features of human Decidual NK cells in healthy pregnancy and during viral infection. Front Immunol 2019;10:1397.
CrossRef
Google scholar
|
[21] |
Jia H, Liu C, Li D et al. Metabolomic analyses reveal new stage-specific features of COVID-19. Eur Respir J 2022;59:2100284.
CrossRef
Google scholar
|
[22] |
Jin S, Guerrero-Juarez CF, Zhang L et al. Inference and analysis of cell-cell communication using CellChat. Nat Commun 2021;12:1088.
CrossRef
Google scholar
|
[23] |
La Manno G, Soldatov R, Zeisel A et al. RNA velocity of single cells. Nature 2018;560:494–498.
CrossRef
Google scholar
|
[24] |
Lee CQ, Gardner L, Turco M et al. What Is trophoblast? A combination of criteria define human first-trimester trophoblast. Stem Cell Rep 2016;6:257–272.
CrossRef
Google scholar
|
[25] |
Li X, Zhou J, Fang M et al. Pregnancy immune tolerance at the maternal-fetal interface. Int Rev Immunol 2020;39:247–263.
CrossRef
Google scholar
|
[26] |
Liberzon A, Birger C, Thorvaldsdottir H et al. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst 2015;1:417–425.
CrossRef
Google scholar
|
[27] |
Liu C, Wu T, Fan F, Liu Y et al. A portable and cost-effective microfluidic system for massively parallel single-cell transcriptome profiling. 2019.
CrossRef
Google scholar
|
[28] |
Masoodi M, Peschka M, Schmiedel S et al. Disturbed lipid and amino acid metabolisms in COVID-19 patients. J Mol Med (Berl) 2022;100:555–568.
CrossRef
Google scholar
|
[29] |
McGinnis CS, Murrow LM, Gartner ZJ. DoubletFinder: doublet detection in single-cell RNA sequencing data using artificial nearest neighbors. Cell Syst 2019;8:329–337.e4.
CrossRef
Google scholar
|
[30] |
McInnes L, Healy J, Melville J J a p a. Umap: Uniform manifold approximation and projection for dimension reduction. 2018.
CrossRef
Google scholar
|
[31] |
Pereira L. Congenital viral infection: traversing the uterine-placental interface. Annu Rev Virol 2018;5:273–299.
CrossRef
Google scholar
|
[32] |
Pijnenborg R, Dixon G, Robertson WB et al. Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy. Placenta 1980;1:3–19.
CrossRef
Google scholar
|
[33] |
Que H, Chen L, Wei X. SARS-CoV-2 variants, immune escape, COVID-19 vaccine, and therapeutic strategies. Sci China Life Sci 2023;66:406–410.
CrossRef
Google scholar
|
[34] |
Schust DJ, Hill AB, Ploegh HL. Herpes simplex virus blocks intracellular transport of HLA-G in placentally derived human cells. J Immunol 1996;157:3375–3380.
CrossRef
Google scholar
|
[35] |
Shen T, Wang T. Metabolic reprogramming in COVID-19. Int J Mol Sci 2021;22:11475.
CrossRef
Google scholar
|
[36] |
Shen B, Yi X, Sun Y et al. Proteomic and metabolomic characterization of COVID-19 patient sera. Cell 2020;182:59–72.e15.
CrossRef
Google scholar
|
[37] |
Slatter TL, Hung NG, Clow WM et al. A clinicopathological study of episomal papillomavirus infection of the human placenta and pregnancy complications. Mod Pathol 2015;28:1369–1382.
CrossRef
Google scholar
|
[38] |
Sureshchandra S, Zulu MZ, Doratt BM et al. Single-cell RNA sequencing reveals immunological rewiring at the maternal-fetal interface following asymptomatic/mild SARS-CoV-2 infection. Cell Rep 2022;39:110938.
CrossRef
Google scholar
|
[39] |
Suryawanshi H, Morozov P, Straus A et al. A single-cell survey of the human first-trimester placenta and decidua. Sci Adv 2018;4:eaau4788.
CrossRef
Google scholar
|
[40] |
Tang AW, Alfirevic Z, Quenby S. Natural killer cells and pregnancy outcomes in women with recurrent miscarriage and infertility: a systematic review. Hum Reprod 2011;26:1971–1980.
CrossRef
Google scholar
|
[41] |
Thellin O, Coumans B, Zorzi W et al. Tolerance to the foeto-placental ‘graft’: ten ways to support a child for nine months. Curr Opin Immunol 2000;12:731–737.
CrossRef
Google scholar
|
[42] |
Vento-Tormo R, Efremova M, Botting RA et al. Single-cell reconstruction of the early maternal-fetal interface in humans. Nature 2018;563:347–353.
CrossRef
Google scholar
|
[43] |
Wang X, Wang D, He S. The role of a cytokine storm in severe coronavirus disease 2019 in pregnancy. Am J Obstet Gynecol 2020;223:780–782.
CrossRef
Google scholar
|
[44] |
Wei J, Liu X, Xiao W et al. Phospholipid remodeling and its derivatives are associated with COVID-19 severity. J Allergy Clin Immunol 2023;151:1259–1268.
CrossRef
Google scholar
|
[45] |
Xu X, Xu J, Wu J et al. Phosphorylation-mediated IFN-gammaR2 membrane translocation is required to activate macrophage innate response. Cell 2018;175:1336–1351.e17.
CrossRef
Google scholar
|
[46] |
Yi S, Wang L, Wang M et al. Effect of SARS-CoV-2 infection in early pregnancy on placental development. Sci China Life Sci 2023;67:622–625.
CrossRef
Google scholar
|
[47] |
Zhou Y, Zhou B, Pache L et al. Metascape provides a biologist-oriented resource for the analysis of systemslevel datasets. Nat Commun 2019;10:1523.
CrossRef
Google scholar
|
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