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Mrna Biogenesis in Tuberculosis Hugh Salamon, Yaming Qiao, Jeff C

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Mrna Biogenesis in Tuberculosis Hugh Salamon, Yaming Qiao, Jeff C Evidence for Postinitiation Regulation of mRNA Biogenesis in Tuberculosis Hugh Salamon, Yaming Qiao, Jeff C. Cheng, Ken D. Yamaguchi, Patricia Soteropoulos, Michael Weiden, Maria This information is current as Laura Gennaro and Richard Pine of October 1, 2021. J Immunol 2013; 190:2747-2755; Prepublished online 1 February 2013; doi: 10.4049/jimmunol.1202185 http://www.jimmunol.org/content/190/6/2747 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2013/02/01/jimmunol.120218 Material 5.DC1 References This article cites 61 articles, 26 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/190/6/2747.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 1, 2021 • 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 © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Evidence for Postinitiation Regulation of mRNA Biogenesis in Tuberculosis Hugh Salamon,* Yaming Qiao,† Jeff C. Cheng,‡,1 Ken D. Yamaguchi,* Patricia Soteropoulos,† Michael Weiden,x Maria Laura Gennaro,†,{ and Richard Pine†,{ Mycobacterium tuberculosis infection alters macrophage gene expression and macrophage response to IFN-g, a critical host defense cytokine. However, regulation of these changes is poorly understood. We report discordance of changes in nascent transcript and total nuclear RNA abundance for the transcription factors STAT1 and IRF1, together with lack of effect on their RNA half-lives, in human THP-1 cells infected with M. tuberculosis and stimulated with IFN-g. The results indicate that negative postinitiation regulation of mRNA biogenesis limits the expression of these factors, which mediate host defense against M. tuberculosis through the cellular response to IFN-g. Consistent with the results for STAT1 and IRF1, transcriptome analysis reveals downregulation of postinitiation mRNA biogenesis processes and pathways by infection, with and without IFN-g stimulation. Clinical relevance for Downloaded from regulation of postinitiation mRNA biogenesis is demonstrated by studies of donor samples showing that postinitiation mRNA biogenesis pathways are repressed in latent tuberculosis infection compared with cured disease and in active tuberculosis compared with ongoing treatment or with latent tuberculosis. For active disease and latent infection donors from two populations (London, U.K., and The Gambia), each analyzed using a different platform, pathway-related gene expression differences were highly correlated, demonstrating substantial specificity in the effect. Collectively, the molecular and bioinformatic analyses point toward downregulation of postinitiation mRNA biogenesis pathways as a means by which M. tuberculosis infection limits expression of http://www.jimmunol.org/ immunologically essential transcription factors. Thus, negative regulation of postinitiation mRNA biogenesis can constrain the macrophage response to infection and overall host defense against tuberculosis. The Journal of Immunology, 2013, 190: 2747–2755. orbidity and mortality from tuberculosis are extremely latent infection; reviewed in 5). Determining effects of M. tu- high, with ∼8 million new cases of active disease per berculosis infection on host macrophage gene expression and M year and ∼2 million deaths (1); in the absence of ef- relating those effects to differences in gene expression between fective treatment, mortality is ∼50% (2). Increased failure of anti- individuals who maintain latent tuberculosis infection (LTBI) and those who develop pulmonary tuberculosis (PTB) should facilitate tuberculous chemotherapy (3, 4) with the emergence of multidrug by guest on October 1, 2021 and extensively drug-resistant strains of Mycobacterium tubercu- efforts to apply host immune pressure against tuberculosis. losis has added urgency to the goal of developing effective vac- The interaction between macrophages infected with M. tuber- cines and immunotherapies. Macrophages are the immune cells culosis and the host immune mediator IFN-g is a major determi- predominantly targeted by M. tuberculosis. Bacterial replication nant of host response to M. tuberculosis (6). The host transcription occurs in macrophages at two points in the immunologic life cycle factors STAT1 and IRF1 are essential mediators of the response of tuberculosis: during the innate immune response to infection to IFN-g and of host defense against M. tuberculosis (7–10). In (before adaptive immunity forces a transition to latent infection) humans, mutations in STAT1 confer susceptibility to normally and during reactivation (when adaptive immunity fails to maintain nonpathogenic mycobacterial infections (11, 12); in mice, a de- ficiency of STAT1 or IRF1 abolishes immune control of M. tu- berculosis growth, which leads to a fatal fulminant infection *Knowledge Synthesis, Inc., Berkeley, CA 94716; †Public Health Research Institute Center, New Jersey Medical School, University of Medicine and Dentistry of New rather than a chronic illness with slow disease progression (13, Jersey, Newark, NJ 07103; ‡Department of Biological Sciences, New Jersey Institute x 14). The consequences of deficiencies in these transcription of Technology, Newark, NJ 07102; Division of Pulmonary and Critical Care Med- factors emphasize that their regulation is essential for an effec- icine, Department of Medicine, New York University School of Medicine, New York, NY 10016; and {Department of Medicine, New Jersey Medical School, University of tive host response to M. tuberculosis. Moreover, both are induced Medicine and Dentistry of New Jersey, Newark, NJ 07103 by M. tuberculosis infection and by IFN-g stimulation (15–21). 1Current address: Early Clinical Development Statistics, Merck Research Laborato- IFN-g induction of STAT1 and IRF1 and M. tuberculosis in- ries, Rahway, NJ. duction of IRF1 are attributable at least in part to increased Received for publication August 7, 2012. Accepted for publication January 1, 2013. transcription. However, little is known about whether mecha- This work was supported by National Institutes of Health Grants AI37877 and nisms other than regulation of transcription initiation control their HL68517 (to R.P.) and HL106788 (to M.L.G. and R.P.) and by the Foundation of the University of Medicine and Dentistry of New Jersey (to R.P.). expression, or any other transcriptome changes, with or without IFN-g stimulation in cells infected with M. tuberculosis. Address correspondence and reprint requests to Dr. Richard Pine, New Jersey Med- ical School–University of Medicine and Dentistry of New Jersey, 225 Warren Street, Postinitiation steps in mRNA biogenesis (59 end capping, elon- Newark, NJ 07103. E-mail: [email protected] gation, splicing, 39 end cleavage and polyadenylation) allow reg- The online version of this article contains supplemental material. ulation of gene expression in addition to control of transcription Abbreviations used in this article: CERNO, Coincident Extreme Ranks in Numerical initiation (22–25). Alternative splicing and polyadenylation can Observations; GO, gene ontology; LTBI, latent tuberculosis infection; PTB, pulmo- determine tissue-specific or signal-mediated levels of transcript nary tuberculosis. isoform expression (reviewed in Refs. 26, 27). For example, in Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 patients with chronic granulomatous disease, increased levels of www.jimmunol.org/cgi/doi/10.4049/jimmunol.1202185 2748 REGULATION OF mRNA BIOGENESIS IN TUBERCULOSIS functional NADPH (phagocyte) oxidase as a response to IFN-g Quantitative RT-PCR therapy result from mutations that alter CYBB gene exon usage Reverse transcription reactions, quantitative PCR reactions using molecular (28, 29). In other examples, stimulation of TLRs by bacteria- beacons for amplicon detection, and calculation of target abundance were derived ligands alters transcripts through effects on alternative performed as described previously for IRF1. The results were normalized to splicing and polyadenylation (30–36). With M. tuberculosis in- the level of GAPDH exon 9 for the respective samples (21). Mock reverse fection, alternatively spliced transcripts of IL12Rb are produced transcription samples for each RNA preparation demonstrated negligible DNA contamination. The specificity of assays for introns and exon junc- (37). Even without alternative mRNA processing, changing the tions was confirmed with genomic DNA and cDNA templates. Data are rate of a single processing event can control gene expression from four to six independent experiments; not all genes were assayed in level, as demonstrated for glucocorticoid-mediated repression of some experiments. RNA half-life was calculated as the average of values gonadotropin-releasing hormone expression through inhibition determined
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