Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Stress-caused anergy of leukocytes towards Staphylococcal enterotoxin B and exposure transcriptome signatures

Genes & Immunity volume 16, pages 330–346 (2015)Cite this article

Subjects

Abstract

Leucocytes from soldiers exposed to battlefield-like stress (RASP: Rangers Assessment and Selection Program) were exposed in vitro to Staphylococcal enterotoxin B (SEB). We assayed SEB-induced regulation of gene expression, both in the presence and absence of severe stress, to generate two sets of gene profiles. One set of transcripts and microRNAs were specific to post-RASP SEB exposure, and another set were signatures of SEB exposure common to both the pre- and post-RASP leucocytes. Pathways and upstream regulatory analyses indicated that the post-RASP SEB-signature transcripts were manifestation of the anergic state of post-RASP leucocytes. These were further verified using expression-based predictions of cellular processes and literature searches. Specificity of the second set of transcripts to SEB exposure was verified using machine-learning algorithms on our and four other (Gene Expression Omnibus) data sets. Cell adhesion, coagulation, hypoxia and vascular endothelial growth factor-mediated vascular leakage were SEB-specific pathways even under the background of severe stress. Hsa-miR-155-3p was the top SEB exposure predictor in our data set, and C-X-C motif chemokine ligand 9 was SEB specific in all the analyzed data sets. The SEB-signature transcripts (which also showed distinct expression signatures from Yersinia pestis and dengue virus) may serve as potential biomarkers of SEB exposure even under the background of stress.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11

Similar content being viewed by others

References

  1. Muhie S, Hammamieh R, Cummings C, Yang D, Jett M . Transcriptome characterization of immune suppression from battlefield-like stress. Genes Immun 2013; 14: 19–34.

    Article  CAS  Google Scholar 

  2. Lindsay CD, Griffiths GD . Addressing bioterrorism concerns: options for investigating the mechanism of action of Staphylococcus aureus enterotoxin B. Hum Exp Toxicol 2013; 32: 606–619.

    Article  CAS  Google Scholar 

  3. Cook E, Wang X, Robiou N, Fries BC . Measurement of staphylococcal enterotoxin B in serum and culture supernatant with a capture enzyme-linked immunosorbent assay. Clin Vaccine Immunol 2007; 14: 1094–1101.

    Article  CAS  Google Scholar 

  4. Krakauer T . Cell adhesion molecules are co-receptors for staphylococcal enterotoxin B-induced T-cell activation and cytokine production. Immunol Lett 1994; 39: 121–125.

    Article  CAS  Google Scholar 

  5. Faulkner L, Cooper A, Fantino C, Altmann DM, Sriskandan S . The mechanism of superantigen-mediated toxic shock: not a simple Th1 cytokine storm. J Immunol 2005; 175: 6870–6877.

    Article  CAS  Google Scholar 

  6. Di Stefano A, Paulesu L, Niccolai N, Scarselli M, Soldani P, Neri P . Identification of critical residues of staphylococcal enterotoxin B for lymphomonocyte proliferation and cytokine production. J Pept Res 1998; 52: 130–136.

    Article  CAS  Google Scholar 

  7. Hong SC, Waterbury G, Janeway CA Jr . Different superantigens interact with distinct sites in the Vbeta domain of a single T cell receptor. J Exp Med 1996; 183: 1437–1446.

    Article  CAS  Google Scholar 

  8. Hayball JD, O'Hehir RE, Lamb JR, Lake RA . The domain structure and functional relationships in the bacterial superantigen, SEB. Biol Chem Hoppe Seyler 1995; 376: 303–309.

    Article  CAS  Google Scholar 

  9. Tokura Y, Heald PW, Yan SL, Edelson RL . Stimulation of cutaneous T-cell lymphoma cells with superantigenic staphylococcal toxins. J Invest Dermatol 1992; 98: 33–37.

    Article  CAS  Google Scholar 

  10. Sadegh-Nasseri S, Dalai SK, Ferris LCK, Mirshahidi S . Suboptimal engagement of the T-cell receptor by a variety of peptide-MHC ligands triggers T-cell anergy. Immunology 2010; 129: 1–7.

    Article  CAS  Google Scholar 

  11. Kriegel MA, Adam-Klages S, Gabler C, Blank N, Schiller M, Scheidig C et al. Anti-HLA-DR-triggered monocytes mediate in vitro T cell anergy. Int Immunol 2008; 20: 601–613.

    Article  CAS  Google Scholar 

  12. Tochiki N, Narita M, Zheng Z, Lu C, Saitoh A, Watanabe N et al. Induction of recipient cell-specific donor T-cell anergy by UV-C-irradiated recipient immature monocyte-derived dendritic cells. Bone Marrow Transplant 2008; 41: 1037–1045.

    Article  CAS  Google Scholar 

  13. Zambricki E, Zal T, Yachi P, Shigeoka A, Sprent J, Gascoigne N et al. In vivo anergized T cells form altered immunological synapses in vitro. Am J Transplant 2006; 6: 2572–2579.

    Article  CAS  Google Scholar 

  14. Watson ARO, Mittler JN, Lee WT . Staphylococcal enterotoxin B induces anergy to conventional peptide in memory T cells. Cell Immunol 2003; 222: 144–155.

    Article  CAS  Google Scholar 

  15. Watson AR, Lee WT . Defective T cell receptor-mediated signal transduction in memory CD4 T lymphocytes exposed to superantigen or anti-T cell receptor antibodies. Cell Immunol 2006; 242: 80–90.

    Article  CAS  Google Scholar 

  16. Coppola MA, Blackman MA . Bacterial superantigens reactivate antigen-specific CD8+ memory T cells. Int Immunol 1997; 9: 1393–1403.

    Article  CAS  Google Scholar 

  17. Ge RT, Mo LH, Wu R, Liu JQ, Zhang HP, Liu Z et al. Insulin-like growth factor-1 endues monocytes with immune suppressive ability to inhibit inflammation in the intestine. Sci Rep 2015; 5: 7735.

    Article  CAS  Google Scholar 

  18. Breiman L . Random forest. Mach Learn 2001; 45: 5–32.

    Article  Google Scholar 

  19. Sharma P, Sahni NS, Tibshirani R, Skaane P, Urdal P, Berghagen H et al. Early detection of breast cancer based on gene-expression patterns in peripheral blood cells. Breast Cancer Res 2005; 7: R634–R644.

    Article  CAS  Google Scholar 

  20. Tibshirani R, Hastie T, Narasimhan B, Chu G . Diagnosis of multiple cancer types by shrunken centroids of gene expression. Proc Natl Acad Sci USA 2002; 99: 6567–6572.

    Article  CAS  Google Scholar 

  21. Arad G, Levy R, Nasie I, Hillman D, Rotfogel Z, Barash U et al. Binding of superantigen toxins into the CD28 homodimer interface is essential for induction of cytokine genes that mediate lethal shock. PLoS Biol 2011; 9: e1001149.

    Article  CAS  Google Scholar 

  22. Tzachanis D, Freeman GJ, Hirano N, van Puijenbroek AA, Delfs MW, Berezovskaya A et al. Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells. Nat Immunol 2001; 2: 1174–1182.

    Article  CAS  Google Scholar 

  23. Gorak-Stolinska P, Kemeny DM, Noble A . Activation-induced cell death in human T cells is a suicidal process regulated by cell density but superantigen induces T cell fratricide. Cell Immunol 2002; 219: 98–107.

    Article  CAS  Google Scholar 

  24. Kulhankova K, King J, Salgado-Pabon W . Staphylococcal toxic shock syndrome: superantigen-mediated enhancement of endotoxin shock and adaptive immune suppression. Immunol Res 2014; 59: 182–187.

    Article  CAS  Google Scholar 

  25. Jin J, Chang DY, Kim SH, Rha KS, Mo JH, Shin EC et al. Role of hypoxia-inducible factor-1alpha expression in regulatory T cells on nasal polypogenesis. Laryngoscope 2014; 124: E151–E159.

    Article  CAS  Google Scholar 

  26. Uchakina ON, Castillejo CM, Bridges CC, McKallip RJ . The role of hyaluronic acid in SEB-induced acute lung inflammation. Clin Immunol 2013; 146: 56–69.

    Article  CAS  Google Scholar 

  27. Krakauer T . Update on staphylococcal superantigen-induced signaling pathways and therapeutic interventions. Toxins 2013; 5: 1629–1654.

    Article  CAS  Google Scholar 

  28. Groom JR, Luster AD . CXCR3 in T cell function. Exp Cell Res 2011; 317: 620–631.

    Article  CAS  Google Scholar 

  29. Tallent SM, Degrasse JA, Wang N, Mattis DM, Kranz DM . Novel platform for the detection of Staphylococcus aureus enterotoxin B in foods. Appl Environ Microbiol 2013; 79: 1422–1427.

    Article  CAS  Google Scholar 

  30. Maere S, Heymans K, Kuiper M . BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics 2005; 21: 3448–3449.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Julia Scheerer and Allison Hoke for editing the manuscript and for their invaluable comments. We are grateful to The Defense Threat Reduction Agency for funding.

Human subjects protection

Research was conducted in compliance with IRB-approved human subjects protocol—no.1014 for initial collection of samples and A-16815 for continuation of data evaluation. The human use approval was obtained from the local Protection of Human subjects Office and further approved by the Human Research Protection Office, Office of Research Protections, US Army Medical Research and Materiel Command, Fort Detrick, MD, USA.

Disclaimer

The views, opinions, and/or findings contained in this report are those of the authors and should not be construed as official Department of the Army position, policy or decision, unless so designated by other official documentation. Citations of commercial organizations or trade names in this report do not constitute an official Department of the Army endorsement or approval of the products or services of these organizations.

Author information

Authors and Affiliations

  1. Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    S Muhie

  2. Integrative Systems Biology Program, US Army Center for Environmental Health Research, Frederick, MD, USA

    R Hammamieh & M Jett

  3. College Park, MD, USA

    C Cummings

  4. Department of Chemistry, Georgetown University, Washington, DC, USA

    D Yang

Authors
  1. S Muhie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Hammamieh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Cummings
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Jett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Jett.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on Genes and Immunity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Muhie, S., Hammamieh, R., Cummings, C. et al. Stress-caused anergy of leukocytes towards Staphylococcal enterotoxin B and exposure transcriptome signatures. Genes Immun 16, 330–346 (2015). https://doi.org/10.1038/gene.2015.16

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2015.16

Search

Advanced search

Quick links