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.

  • Research Article
  • Published:

Mast cells as rapid innate sensors of cytomegalovirus by TLR3/TRIF signaling-dependent and -independent mechanisms

Abstract

The succinct metaphor, ‘the immune system's loaded gun', has been used to describe the role of mast cells (MCs) due to their storage of a wide range of potent pro-inflammatory and antimicrobial mediators in secretory granules that can be released almost instantly on demand to fight invaders. Located at host–environment boundaries and equipped with an arsenal of pattern recognition receptors, MCs are destined to be rapid innate sensors of pathogens penetrating endothelial and epithelial surfaces. Although the importance of MCs in antimicrobial and antiparasitic defense has long been appreciated, their role in raising the alarm against viral infections has been noted only recently. Work on cytomegalovirus (CMV) infection in the murine model has revealed MCs as players in a novel cross-talk axis between innate and adaptive immune surveillance of CMV, in that infection of MCs, which is associated with MC degranulation and release of the chemokine CCL5, enhances the recruitment of protective CD8 T cells to extravascular sites of virus replication, specifically to lung interstitium and alveolar epithelium. Here, we have expanded on these studies by investigating the conditions for MC activation and the consequent degranulation in response to host infection. Surprisingly, the data revealed two temporally and mechanistically distinct waves of MC activation: an almost instant indirect activation that depended on TLR3/TRIF signaling and delayed activation by direct infection of MCs that did not involve TLR3/TRIF signaling. Cell type-specific Cre-recombination that yielded eGFP-expressing reporter virus selectively originating from MCs identified MC as a new in vivo, first-hit target cell of productive murine CMV infection.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Abraham SN, St John AL . Mast cell-orchestrated immunity to pathogens. Nat Rev Immunol 2010; 10: 440–452.

    Article  CAS  Google Scholar 

  2. Collington SJ, Williams TJ, Weller CL . Mechanisms underlying the localisation of mast cells in tissues. Trends Immunol 2011; 32: 478–485.

    Article  CAS  Google Scholar 

  3. Wernersson S, Pejler G . Mast cell secretory granules: armed for battle. Nat Rev Immunol 2014; 14: 478–494.

    Article  CAS  Google Scholar 

  4. Rodewald HR, Feyerabend TB . Widespread immunological functions of mast cells: fact or fiction? Immunity 2012; 37: 13–24.

    Article  CAS  Google Scholar 

  5. Galli SJ, Tsai M . IgE and mast cells in allergic disease. Nat Med 2012; 18: 693–704.

    Article  CAS  Google Scholar 

  6. Pennock JL, Grencis RK . The mast cell and gut nematodes: damage and defence. Chem Immunol Allergy 2006; 90: 128–140.

    CAS  PubMed  Google Scholar 

  7. Galli SJ, Maurer M, Lantz CS . Mast cells as sentinels of innate immunity. Curr Opin Immunol 1999; 11: 53–59.

    Article  CAS  Google Scholar 

  8. Stassen M, Hültner L, Schmitt E . Classical and alternative pathways of mast cell activation. Crit Rev Immunol 2002; 22: 115–140.

    Article  CAS  Google Scholar 

  9. Matsushima H, Yamada N, Matsue H, Shimada S . TLR3-, TLR7-, and TLR9-mediated production of proinflammatory cytokines and chemokines from murine connective tissue type skin-derived mast cells but not from bone marrow-derived mast cells. J Immunol 2004; 173: 531–541.

    Article  CAS  Google Scholar 

  10. Kulka M, Metcalfe DD . TLR3 activation inhibits human mast cell attachment to fibronectin and vitronectin. Mol Immunol 2006; 43: 1579–1586.

    Article  CAS  Google Scholar 

  11. Sandig H, Bulfone-Paus S . TLR signaling in mast cells: common and unique features. Front Immunol 2012; 3: 185.

    Article  Google Scholar 

  12. Galli SJ, Kalesnikoff J, Grimbaldeston MA, Piliponsky AM, Williams CM, Tsai M . Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu Rev Immunol 2005; 23: 749–786.

    Article  CAS  Google Scholar 

  13. Hershko AY, Rivera J . Mast cell and T cell communication; amplification and control of adaptive immunity. Immunol Lett 2010; 128: 98–104.

    Article  CAS  Google Scholar 

  14. Valitutti S, Espinosa E . Cognate interactions between mast cells and helper T lymphocytes. Self Nonself 2010; 1: 114–122.

    Article  Google Scholar 

  15. Orinska Z, Bulanova E, Budagian V, Metz M, Maurer M, Bulfone-Paus S . TLR3-induced activation of mast cells modulates CD8+ T-cell recruitment. Blood 2005; 106: 978–987.

    Article  CAS  Google Scholar 

  16. St John AL, Rathore AP, Yap H, Ng ML, Metcalfe DD, Vasudevan SG et al. Immune surveillance by mast cells during dengue infection promotes natural killer (NK) and NKT-cell recruitment and viral clearance. Proc Natl Acad Sci USA 2011; 108: 9190–9195.

    Article  CAS  Google Scholar 

  17. McAlpine SM, Issekutz TB, Marshall JS . Virus stimulation of human mast cells results in the recruitment of CD56+ T cells by a mechanism dependent on CCR5 ligands. FASEB J 2012; 26: 1280–1289.

    Article  CAS  Google Scholar 

  18. Ebert S, Becker M, Lemmermann NA, Büttner JK, Michel A, Taube C et al. Mast cells expedite control of pulmonary murine cytomegalovirus infection by enhancing the recruitment of protective CD8 T cells to the lungs. PLoS Pathog 2014; 10: e1004100.

    Article  Google Scholar 

  19. Oschatz C, Maas C, Lecher B, Jansen T, Bjorkqvist J, Tradler T et al. Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo. Immunity 2011; 34: 258–268.

    Article  CAS  Google Scholar 

  20. Kambayashi T, Allenspach EJ, Chang JT, Zou T, Shoag JE, Reiner SL et al. Inducible MHC class II expression by mast cells supports effector and regulatory T cell activation. J Immunol 2009; 182: 4686–4695.

    Article  CAS  Google Scholar 

  21. Stelekati E, Bahri R, D'Orlando O, Orinska Z, Mittrucker HW, Langenhaun R et al. Mast cell-mediated antigen presentation regulates CD8+ T cell effector functions. Immunity 2009; 31: 665–676.

    Article  CAS  Google Scholar 

  22. Wang Z, Lai Y, Bernard JJ, Macleod DT, Cogen AL, Moss B et al. Skin mast cells protect mice against vaccinia virus by triggering mast cell receptor S1PR2 and releasing antimicrobial peptides. J Immunol 2012; 188: 345–357.

    Article  CAS  Google Scholar 

  23. Aoki R, Kawamura T, Goshima F, Ogawa Y, Nakae S, Nakao A et al. Mast cells play a key role in host defense against herpes simplex virus infection through TNF-alpha and IL-6 production. J Invest Dermatol 2013; 133: 2170–2179.

    Article  CAS  Google Scholar 

  24. Davison AJ, Holton M, Dolan A, Dargan DJ, Gatherer D, Hayward GS . Comparative genomics of primate cytomegaloviruses. In: Reddehase MJ (ed.) Cytomegaloviruses: From Molecular Pathogenesis to Intervention. Vo. I. Norfolk: Caister Academic Press, 2013: 1–22.

    Google Scholar 

  25. Redwood AJ, Shellam GR, Smith LM . Molecular evolution of murine cytomegalovirus genomes. In: Reddehase MJ (ed.) Cytomegaloviruses: From Molecular Pathogenesis to Intervention. Vol. I. Norfolk: Caister Academic Press, 2013: 23–37.

    Google Scholar 

  26. Ho M . The history of cytomegalovirus and its diseases. Med Microbiol Immunol 2008; 197: 65–73.

    Article  Google Scholar 

  27. Boppana SB, Britt WJ . Synopsis of clinical aspects of human cytomegalovirus disease. In: Reddehase MJ (ed.) Cytomegaloviruses: From Molecular Pathogenesis to Intervention. Vol. II. Norfolk: Caister Academic Press, 2013: 1–25.

    Google Scholar 

  28. Lyon MF, Glenister PH . A new allele sash (Wsh) at the W-locus and a spontaneous recessive lethal in mice. Genet Res 1982; 39: 315–322.

    Article  CAS  Google Scholar 

  29. Grimbaldeston MA, Chen CC, Piliponsky AM, Tsai M, Tam SY, Galli SJ . Mast cell-deficient W-sash c-kit mutant Kit W-sh/W-sh mice as a model for investigating mast cell biology in vivo. Am J Pathol 2005; 167: 835–848.

    Article  CAS  Google Scholar 

  30. Scholten J, Hartmann K, Gerbaulet A, Krieg T, Muller W, Testa G et al. Mast cell-specific Cre/loxP-mediated recombination in vivo. Transgenic Res 2008; 17: 307–315.

    Article  CAS  Google Scholar 

  31. Mallen-St Clair J, Pham CT, Villalta SA, Caughey GH, Wolters PJ . Mast cell dipeptidyl peptidase I mediates survival from sepsis. J Clin Invest 2004; 113: 628–634.

    Article  CAS  Google Scholar 

  32. Podlech J, Holtappels R, Grzimek NK, Reddehase MJ . Animal models: murine cytomegalovirus. In: Kaufmann SHE, Kabelitz D (eds.) Methods in Microbiology: Immunology of Infection. 2nd ed. London: Academic Press, 2002: 493–525.

    Chapter  Google Scholar 

  33. Lemmermann NA, Podlech J, Seckert CK, Kropp KA, Grzimek NK, Reddehase MJ et al. CD8 T-cell immunotherapy of cytomegalovirus disease in the murine model. In: Kabelitz D, Kaufmann SHE (eds.) Methods in Microbiology: Immunology of Infection. 3rd ed. London: Academic Press, 2010: 369–420.

    Chapter  Google Scholar 

  34. Wagner M, Jonjic S, Koszinowski UH, Messerle M . Systematic excision of vector sequences from the BAC-cloned herpesvirus genome during virus reconstitution. J Virol 1999; 73: 7056–7060.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Bubic I, Wagner M, Krmpotic A, Saulig T, Kim S, Yokoyama WM et al. Gain of virulence caused by loss of a gene in murine cytomegalovirus. J Virol 2004; 78: 7536–7544.

    Article  CAS  Google Scholar 

  36. Angulo A, Ghazal P, Messerle M . The major immediate-early gene ie3 of mouse cytomegalovirus is essential for viral growth. J Virol 2000; 74: 11129–11136.

    Article  CAS  Google Scholar 

  37. Sacher T, Podlech J, Mohr CA, Jordan S, Ruzsics Z, Reddehase MJ et al. The major virus-producing cell type during murine cytomegalovirus infection, the hepatocyte, is not the source of virus dissemination in the host. Cell Host Microbe 2008; 3: 263–272.

    Article  CAS  Google Scholar 

  38. Erlach KC, Böhm V, Knabe M, Deegen P, Reddehase MJ, Podlech J . Activation of hepatic natural killer cells and control of liver-adapted lymphoma in the murine model of cytomegalovirus infection. Med Microbiol Immunol 2008; 197: 167–178.

    Article  CAS  Google Scholar 

  39. Kurz S, Steffens HP, Mayer A, Harris JR, Reddehase MJ . Latency versus persistence or intermittent recurrences: evidence for a latent state of murine cytomegalovirus in the lungs. J Virol 1997; 71: 2980–2987.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Tabeta K, Georgel P, Janssen E, Du X, Hoebe K, Crozat K et al. Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc Natl Acad Sci USA 2004; 101: 3516–3521.

    Article  CAS  Google Scholar 

  41. Dalod M, Biron CA . Immunoregulatory cytokine networks discovered and characterized during murine cytomegalovirus infections. In: Reddehase MJ (ed.) Cytomegaloviruses: From Molecular Pathogenesis to Intervention. Vol. II. Norfolk: Caister Academic Press, 2013: 131–257.

    Google Scholar 

  42. Vidal S, Krmpotic A, Pyzik M, Jonjic S . Innate immunity to cytomegalovirus in the murine model. In: Reddehase MJ (ed.) Cytomegaloviruses: From Molecular Pathogenesis to Intervention. Vol. II. Norfolk: Caister Academic Press, 2013: 191–213.

    Google Scholar 

  43. Arase H, Mocarski ES, Campbell AE, Hill AB, Lanier LL . Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 2002; 296: 1323–1326.

    Article  CAS  Google Scholar 

  44. Smith HR, Heusel JW, Mehta IK, Kim S, Dorner BG, Naidenko OV et al. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc Natl Acad Sci USA 2002; 99: 8826–8831.

    Article  CAS  Google Scholar 

  45. Stoddart CA, Cardin RD, Boname JM, Manning WC, Abenes GB, Mocarski ES . Peripheral blood mononuclear phagocytes mediate dissemination of murine cytomegalovirus. J Virol 1994; 68: 6243–6253.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Sacher T, Jordan S, Mohr CA, Vidy A, Weyn AM, Ruszics Z et al. Conditional gene expression systems to study herpesvirus biology in vivo. Med Microbiol Immunol 2008; 197: 269–276.

    Article  CAS  Google Scholar 

  47. Lunderius-Andersson C, Enokson M, Nilsson G . Mast cells respond to cell injury through the recognition of IL-33. Front Immunol 2012; 3: 82.

    Article  Google Scholar 

  48. Delale T, Paquin A, Asselin-Paturel C, Dalod M, Brizard G, Bates EE et al. MyD88-dependent and -independent murine cytomegalovirus sensing for IFN-alpha release and initiation of immune responses in vivo. J Immunol 2005; 175: 6723–6732.

    Article  CAS  Google Scholar 

  49. Yung S, Chan TM . Pathophysiological changes to the peritoneal membrane during PD-related peritonitis: the role of mesothelial cells. Mediators Inflamm 2012; 2012: 484167.

    Article  Google Scholar 

  50. Edelmann KH, Richardson-Burns S, Alexopoulou L, Tyler KL, Flavell RA, Oldstone MB . Does Toll-like receptor 3 play a biological role in virus infections? Virology 2004; 322: 231–238.

    Article  CAS  Google Scholar 

  51. Gilfillan AM, Beaven MA . Regulation of mast cell responses in health and disease. Crit Rev Immunol 2011; 31: 475–529.

    Article  CAS  Google Scholar 

  52. Schäfer T, Starkl P, Allard C, Wolf RM, Schweighoffer T . A granular variant of CD63 is a regulator of repeated human mast cell degranulation. Allergy 2010; 65: 1242–1255.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft, Clinical Research Group KFO 183 (NAWL, SE and MJR) and Priority Program SPP1394, individual project STA 984/4-1 (MS). NAWL received intramural funding from the young investigator program MAIFOR of the University Medical Center Mainz. Supplementary Information accompanies the paper on Cellular & Molecular Immunology's website. (http://www.nature.com/cmi).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Matthias J Reddehase.

Additional information

Supplementary Information accompanies the paper on Cellular & Molecular Immunology's website (http://www.nature.com/cmi).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Becker, M., Lemmermann, N., Ebert, S. et al. Mast cells as rapid innate sensors of cytomegalovirus by TLR3/TRIF signaling-dependent and -independent mechanisms. Cell Mol Immunol 12, 192–201 (2015). https://doi.org/10.1038/cmi.2014.73

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2014.73

Keywords

This article is cited by

Search

Quick links