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Schistosomiasis Induces Persistent DNA Methylation and Tuberculosis-Specific Immune Changes

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Schistosomiasis Induces Persistent DNA Methylation and Tuberculosis-Specific Immune Changes This information is current as Andrew R. DiNardo, Tomoki Nishiguchi, Emily M. Mace, of October 5, 2021. Kimal Rajapakshe, Godwin Mtetwa, Alexander Kay, Gugu Maphalala, W. Evan Secor, Rojelio Mejia, Jordan S. Orange, Cristian Coarfa, Kapil N. Bhalla, Edward A. Graviss, Anna M. Mandalakas and George Makedonas J Immunol 2018; 201:124-133; Prepublished online 11 May 2018; Downloaded from doi: 10.4049/jimmunol.1800101 http://www.jimmunol.org/content/201/1/124 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2018/05/10/jimmunol.180010 Material 1.DCSupplemental References This article cites 76 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/201/1/124.full#ref-list-1 Why The JI? Submit online. by guest on October 5, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Schistosomiasis Induces Persistent DNA Methylation and Tuberculosis-Specific Immune Changes Andrew R. DiNardo,* Tomoki Nishiguchi,* Emily M. Mace,†,‡ Kimal Rajapakshe,x Godwin Mtetwa,{ Alexander Kay,{ Gugu Maphalala,‖ W. Evan Secor,# Rojelio Mejia,** Jordan S. Orange,†,‡ Cristian Coarfa,x Kapil N. Bhalla,†† Edward A. Graviss,‡‡ Anna M. Mandalakas,*,1 and George Makedonas†,‡,1 Epigenetic mechanisms, such as DNA methylation, determine immune cell phenotype. To understand the epigenetic alterations induced by helminth coinfections, we evaluated the longitudinal effect of ascariasis and schistosomiasis infection on CD4+ T cell DNA methylation and the downstream tuberculosis (TB)–specific and bacillus Calmette–Gue´rin–induced immune pheno- type. All experiments were performed on human primary immune cells from a longitudinal cohort of recently TB-exposed children. Compared with age-matched uninfected controls, children with active Schistosoma haematobium and Ascaris lumbri- Downloaded from coides infection had 751 differentially DNA-methylated genes, with 72% hypermethylated. Gene ontology pathway analysis identified inhibition of IFN-g signaling, cellular proliferation, and the Th1 pathway. Targeted real-time quantitative PCR after methyl-specific endonuclease digestion confirmed DNA hypermethylation of the transcription factors BATF3, ID2, STAT5A, IRF5, PPARg, RUNX2, IRF4, and NFATC1 and cytokines or cytokine receptors IFNGR1, TNFS11, RELT (TNF receptor), IL12RB2, and IL12B (p < 0.001; Sidak–Bonferroni). Functional blockage of the IFN-g signaling pathway was confirmed, with helminth-infected individuals having decreased upregulation of IFN-g–inducible genes (Mann–Whitney p < 0.05). Hypomethylation of the IL-4 pathway http://www.jimmunol.org/ and DNA hypermethylation of the Th1 pathway was confirmed by Ag-specific multidimensional flow cytometry demonstrating decreased TB-specific IFN-g and TNF and increased IL-4 production by CD4+ T cells (Wilcoxon signed-rank p <0.05).In S. haematobium–infected individuals, these DNA methylation and immune phenotypic changes persisted at least 6 mo after successful deworming. This work demonstrates that helminth infection induces DNA methylation and immune perturbations that inhibit TB- specific immune control and that the duration of these changes are helminth specific. The Journal of Immunology, 2018, 201: 124–133. he immune system has multiple mechanisms to remain subsets (Th1, Th2, Th9, Th17, T regulatory cells [Tregs], Th22, and T responsive to changing environments. It is now clear that follicular helper cells) (4–6). To differentiate into a Th1 CD4+ T cell, by guest on October 5, 2021 T both the innate and adaptive immune response use epi- the IFNG promoter is demethylated and the IL4 locus undergoes genetic mechanisms of gene regulation to maintain long-term repressive histone modifications (7–9). Although previously thought phenotypes. For example, monocytes “trained” with b-glucan or to be immutable, epigenetic mechanisms have recently been de- bacillus Calmette–Gue´rin (BCG) undergo epigenetic chromatin al- scribed that allow T cells to shift between Th1 and Th2 phenotypes terations that alter TNF and IL-6 production and improve Staphylo- depending on environmental stimuli (10). Understanding the duration coccus, Candida, and mycobacterial killing (1, 2). Long-term and mechanisms of epigenetic-mediated immune polarization is phenotypic changes in adaptive immunity are similarly epigenetically critical to predicting and reversing detrimental immune perturbations. mediated. The RAG-mediated TCR rearrangement requires hypo- Helminths are a heterogeneous group of parasites estimated to methylation of RAG and other critical genes (3). After TCR rear- affect a quarter of the world’s population (11, 12). Although most rangement, T cells remain responsive to changing environments via infections are subclinical, they can induce growth retardation, epigenetic modifications that polarize CD4+ T cells into phenotypic nutritional deficiencies, and profoundly perturb immunogenicity *The Global Tuberculosis Program, Immigrant and Global Health, Department of This work was supported by a Burroughs Wellcome Fund/American Society of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX Tropical Medicine and Hygiene Postdoctoral Fellowship in Tropical Infectious Dis- 77030; †Department of Pathology, Baylor College of Medicine, Houston, TX eases (early career grant), the Thrasher Research Fund (early career grant), and 77030; ‡Texas Children’s Hospital Center for Human Immunobiology, Department National Institutes of Health Grant T-32 AI 55413–11 (to A.R.D.). of Pediatrics, Texas Children’s Hospital Center for Human Immunobiology, Baylor x The findings and conclusions in this report are those of the authors and do not College of Medicine, Houston, TX 77030; Dan L Duncan Comprehensive Cancer { necessarily represent the views of the Centers for Disease Control and Prevention. Center, Baylor College of Medicine, Houston, TX 77030; Baylor–Swaziland Children’s Foundation, Mbabane H100, Swaziland; ‖Ministry of Health, Mbabane Address correspondence and reprint requests to Dr. Andrew R. DiNardo, Baylor H100, Swaziland; #Parasitic Diseases Branch, Division of Parasitic Diseases and College of Medicine, Feigin Center, Suite 630, 1102 Bates Avenue, Houston, TX Malaria, Centers for Disease Control and Prevention, Atlanta, GA 30333; 77030. E-mail address: [email protected] **Department of Pediatrics, National School of Tropical Medicine, Texas The online version of this article contains supplemental material. Children’s Hospital Center for Human Immunobiology, Houston, TX 77030; ††Department of Leukemia, MD Anderson Cancer Center, Houston, TX 77030; Abbreviations used in this article: BCG, bacillus Calmette–Gue´rin; gDNA, genomic and ‡‡Department of Pathology and Genomic Medicine, Houston Methodist DNA; GO, gene ontology; IQR, interquartile range; MF, macrophage; MDMF, Hospital Research Institute, Houston, TX 77030 monocyte-derived MF; MSMD, Mendelian susceptibility to mycobacterial disease; O&P, ova and parasite microscopy; qPCR, quantitative PCR; SEA, S. mansoni– 1A.M.M. and G.M. are colast authors and contributed equally to this work. soluble egg Ag; TB, tuberculosis; Treg, T regulatory cell. ORCIDs: 0000-0003-2172-1491 (G. Mtetwa); 0000-0002-3635-8405 (G. Maphalala); 0000- 0003-0584-5961 (W.E.S.); 0000-0003-4134-4558 (R.M.); 0000-0003-1024-5813 (E.A.G.). Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 Received for publication January 23, 2018. Accepted for publication April 9, 2018. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800101 The Journal of Immunology 125 (12–14). The helminth-induced immune response is characterized real-time PCR were performed. Schistosomiasis serology was performed by tolerance and a type 2 immune polarization (15, 16) with de- by standard ELISA. In brief, 96-well ELISA plates were coated with 2 mg/ml creased IFN-g, IL-12, and IL-17 (17) and increased Tregs (18), S. mansoni–soluble egg Ag (SEA) in 0.1 M sodium bicarbonate buffer (pH 9.6) for 2 h, followed by washing with PBS plus 0.3% Tween 20 and blocking IL-4, IL-5, IL-10 (19), and TGF-b (20). This profound type 2 and with PBS/Tween containing 5% dry milk powder. Plates were again washed immune-tolerant phenotype undermines the type 1 immune re- and incubated with a 1:50 dilution of participant plasma in PBS/Tween/milk sponse to cholera, Salmonella, tetanus, and BCG (21–25) and is for 30 min. Plates were again washed and incubated with a 1:50,000 dilution the suspected rationale for increased TB disease progression of HRP-conjugated mouse anti-human IgG (SouthernBiotech, Birmingham, AL) for 30 min. After a final wash, SureBlue TMB (Kirkegaard & Perry among helminth-infected
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