Skip to main content

Stromal Cell Responses in Infection

  • Chapter
  • First Online:
Stromal Immunology

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1060))

Abstract

Stromal cells and the immune functions that they regulate underpin multiple aspects of host defence, but the study of stromal cells as targets of infection and as regulators of anti-infective immunity is in its infancy and still limited to a few well-worked examples. In this review, the role of stromal cells at each sequential stage of infection is discussed, with examples drawn from across the spectrum of infectious agents, from prions to the parasitic helminths. Gaps in knowledge are identified, the challenges in studying stromal cell biology in the context of infection are highlighted, and the potential for stromal cell-targeted therapeutics is briefly discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Donjacour AA, Cunha GR. Stromal regulation of epithelial function. Cancer Treat Res. 1991;53:335–64.

    Article  CAS  PubMed  Google Scholar 

  2. Zhang X, Martinez D, Koledova Z, Qiao G, Streuli CH, Lu P. FGF ligands of the postnatal mammary stroma regulate distinct aspects of epithelial morphogenesis. Development. 2014;141(17):3352–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Espinosa-Cantellano M, Martinez-Palomo A. Pathogenesis of intestinal amebiasis: from molecules to disease. Clin Microbiol Rev. 2000;13(2):318–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Artis D, Grencis RK. The intestinal epithelium: sensors to effectors in nematode infection. Mucosal Immunol. 2008;1(4):252–64.

    Article  CAS  PubMed  Google Scholar 

  5. Hiemstra IH, Klaver EJ, Vrijland K, Kringel H, Andreasen A, Bouma G, Kraal G, van Die I, den Haan JM. Excreted/secreted Trichuris suis products reduce barrier function and suppress inflammatory cytokine production of intestinal epithelial cells. Mol Immunol. 2014;60(1):1–7.

    Article  CAS  PubMed  Google Scholar 

  6. Kaye P, Scott P. Leishmaniasis: complexity at the host-pathogen interface. Nat Rev Microbiol. 2011;9(8):604–15.

    Article  CAS  PubMed  Google Scholar 

  7. Barrias ES, de Carvalho TM, De Souza W. Trypanosoma cruzi: entry into mammalian host cells and parasitophorous vacuole formation. Front Immunol. 2013;4:186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bogdan C, Donhauser N, Doring R, Rollinghoff M, Diefenbach A, Rittig MG. Fibroblasts as host cells in latent leishmaniosis. J Exp Med. 2000;191(12):2121–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Svensson M, Maroof A, Ato M, Kaye PM. Stromal cells direct local differentiation of regulatory dendritic cells. Immunity. 2004;21(6):805–16.

    Article  CAS  PubMed  Google Scholar 

  10. Hsu KM, Pratt JR, Akers WJ, Achilefu SI, Yokoyama WM. Murine cytomegalovirus displays selective infection of cells within hours after systemic administration. J Gen Virol. 2009;90(Pt 1):33–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Baldwin J, Park PJ, Zanotti B, Maus E, Volin MV, Shukla D, Tiwari V. Susceptibility of human iris stromal cells to herpes simplex virus 1 entry. J Virol. 2013;87(7):4091–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Valyi-Nagy T, Sheth V, Clement C, Tiwari V, Scanlan P, Kavouras JH, Leach L, Guzman-Hartman G, Dermody TS, Shukla D. Herpes simplex virus entry receptor nectin-1 is widely expressed in the murine eye. Curr Eye Res. 2004;29(4–5):303–9.

    Article  CAS  PubMed  Google Scholar 

  13. Keele BF, Tazi L, Gartner S, Liu Y, Burgon TB, Estes JD, Thacker TC, Crandall KA, McArthur JC, Burton GF. Characterization of the follicular dendritic cell reservoir of human immunodeficiency virus type 1. J Virol. 2008;82(11):5548–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Smith BA, Gartner S, Liu Y, Perelson AS, Stilianakis NI, Keele BF, Kerkering TM, Ferreira-Gonzalez A, Szakal AK, Tew JG, Burton GF. Persistence of infectious HIV on follicular dendritic cells. J Immunol. 2001;166(1):690–6.

    Article  CAS  PubMed  Google Scholar 

  15. Spiegel H, Herbst H, Niedobitek G, Foss HD, Stein H. Follicular dendritic cells are a major reservoir for human immunodeficiency virus type 1 in lymphoid tissues facilitating infection of CD4+ T-helper cells. Am J Pathol. 1992;140(1):15–22.

    PubMed  PubMed Central  CAS  Google Scholar 

  16. Thacker TC, Zhou X, Estes JD, Jiang Y, Keele BF, Elton TS, Burton GF. Follicular dendritic cells and human immunodeficiency virus type 1 transcription in CD4+ T cells. J Virol. 2009;83(1):150–8.

    Article  CAS  PubMed  Google Scholar 

  17. Baud J, Varon C, Chabas S, Chambonnier L, Darfeuille F, Staedel C. Helicobacter pylori initiates a mesenchymal transition through ZEB1 in gastric epithelial cells. PLoS One. 2013;8(4):e60315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Reilkoff RA, Bucala R, Herzog EL. Fibrocytes: emerging effector cells in chronic inflammation. Nat Rev Immunol. 2011;11(6):427–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Macedo-Silva RM, Santos Cde L, Diniz VA, Carvalho JJ, Guerra C, Corte-Real S. Peripheral blood fibrocytes: new information to explain the dynamics of Leishmania infection. Mem Inst Oswaldo Cruz. 2014;109(1):61–9.

    Article  PubMed  Google Scholar 

  20. Allahverdiyev AM, Bagirova M, Elcicek S, Koc RC, Baydar SY, Findikli N, Oztel ON. Adipose tissue-derived mesenchymal stem cells as a new host cell in latent leishmaniasis. Am J Trop Med Hyg. 2011;85(3):535–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Schilling JD, Martin SM, Hung CS, Lorenz RG, Hultgren SJ. Toll-like receptor 4 on stromal and hematopoietic cells mediates innate resistance to uropathogenic Escherichia coli. Proc Natl Acad Sci U S A. 2003;100(7):4203–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Spanier J, Lienenklaus S, Paijo J, Kessler A, Borst K, Heindorf S, Baker DP, Kroger A, Weiss S, Detje CN, Staeheli P, Kalinke U. Concomitant TLR/RLH signaling of radioresistant and radiosensitive cells is essential for protection against vesicular stomatitis virus infection. J Immunol. 2014;193(6):3045–54.

    Article  CAS  PubMed  Google Scholar 

  23. Tomalka J, Ganesan S, Azodi E, Patel K, Majmudar P, Hall BA, Fitzgerald KA, Hise AG. A novel role for the NLRC4 inflammasome in mucosal defenses against the fungal pathogen Candida albicans. PLoS Pathog. 2011;7(12):e1002379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Schneider K, Loewendorf A, De Trez C, Fulton J, Rhode A, Shumway H, Ha S, Patterson G, Pfeffer K, Nedospasov SA, Ware CF, Benedict CA. Lymphotoxin-mediated crosstalk between B cells and splenic stroma promotes the initial type I interferon response to cytomegalovirus. Cell Host Microbe. 2008;3(2):67–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Verma S, Wang Q, Chodaczek G, Benedict CA. Lymphoid-tissue stromal cells coordinate innate defense to cytomegalovirus. J Virol. 2013;87(11):6201–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Andersson U, Tracey KJ. HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol. 2011;29:139–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chan JK, Roth J, Oppenheim JJ, Tracey KJ, Vogl T, Feldmann M, Horwood N, Nanchahal J. Alarmins: awaiting a clinical response. J Clin Invest. 2012;122(8):2711–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, Garner H, Trouillet C, de Bruijn MF, Geissmann F, Rodewald HR. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature. 2015;518(7540):547–51.

    Article  CAS  PubMed  Google Scholar 

  29. Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K, Prinz M, Wu B, Jacobsen SE, Pollard JW, Frampton J, Liu KJ, Geissmann F. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science. 2012;336(6077):86–90.

    Article  CAS  PubMed  Google Scholar 

  30. Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M, Strauss-Ayali D, Viukov S, Guilliams M, Misharin A, Hume DA, Perlman H, Malissen B, Zelzer E, Jung S. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013;38(1):79–91.

    Article  CAS  PubMed  Google Scholar 

  31. Onder L, Narang P, Scandella E, Chai Q, Iolyeva M, Hoorweg K, Halin C, Richie E, Kaye P, Westermann J, Cupedo T, Coles M, Ludewig B. IL-7-producing stromal cells are critical for lymph node remodeling. Blood. 2012;120(24):4675–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cohen JN, Guidi CJ, Tewalt EF, Qiao H, Rouhani SJ, Ruddell A, Farr AG, Tung KS, Engelhard VH. Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J Exp Med. 2010;207(4):681–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Fletcher AL, Lukacs-Kornek V, Reynoso ED, Pinner SE, Bellemare-Pelletier A, Curry MS, Collier AR, Boyd RL, Turley SJ. Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J Exp Med. 2010;207(4):689–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Baptista AP, Roozendaal R, Reijmers RM, Koning JJ, Unger WW, Greuter M, Keuning ED, Molenaar R, Goverse G, Sneeboer MM, den Haan JM, Boes M, Mebius RE. Lymph node stromal cells constrain immunity via MHC class II self-antigen presentation. eLife. 2014; 3:e04433

    Google Scholar 

  35. Dubrot J, Duraes FV, Potin L, Capotosti F, Brighouse D, Suter T, LeibundGut-Landmann S, Garbi N, Reith W, Swartz MA, Hugues S. Lymph node stromal cells acquire peptide-MHCII complexes from dendritic cells and induce antigen-specific CD4(+) T cell tolerance. J Exp Med. 2014;211(6):1153–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Peduto L, Dulauroy S, Lochner M, Spath GF, Morales MA, Cumano A, Eberl G. Inflammation recapitulates the ontogeny of lymphoid stromal cells. J Immunol. 2009;182(9):5789–99.

    Article  CAS  PubMed  Google Scholar 

  37. Despars G, Tan J, Periasamy P, O’Neill HC. The role of stroma in hematopoiesis and dendritic cell development. Curr Stem Cell Res Ther. 2007;2(1):23–9.

    Article  CAS  PubMed  Google Scholar 

  38. O’Neill HC, Griffiths KL, Periasamy P, Hinton RA, Petvises S, Hey YY, Tan JK. Spleen stroma maintains progenitors and supports long-term hematopoiesis. Curr Stem Cell Res Ther. 2014;9(4):354–63.

    Article  PubMed  Google Scholar 

  39. Tan JK, Periasamy P, O'Neill HC. Delineation of precursors in murine spleen that develop in contact with splenic endothelium to give novel dendritic-like cells. Blood. 2010;115(18):3678–85.

    Article  CAS  PubMed  Google Scholar 

  40. Nguyen Hoang AT, Liu H, Juarez J, Aziz N, Kaye PM, Svensson M. Stromal cell-derived CXCL12 and CCL8 cooperate to support increased development of regulatory dendritic cells following Leishmania infection. J Immunol. 2010;185(4):2360–71.

    Article  CAS  PubMed  Google Scholar 

  41. Li Q, Guo Z, Xu X, Xia S, Cao X. Pulmonary stromal cells induce the generation of regulatory DC attenuating T-cell-mediated lung inflammation. Eur J Immunol. 2008;38(10):2751–61.

    Article  CAS  PubMed  Google Scholar 

  42. Tang H, Guo Z, Zhang M, Wang J, Chen G, Cao X. Endothelial stroma programs hematopoietic stem cells to differentiate into regulatory dendritic cells through IL-10. Blood. 2006;108(4):1189–97.

    Article  CAS  PubMed  Google Scholar 

  43. Xia S, Guo Z, Xu X, Yi H, Wang Q, Cao X. Hepatic microenvironment programs hematopoietic progenitor differentiation into regulatory dendritic cells, maintaining liver tolerance. Blood. 2008;112(8):3175–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Xu X, Yi H, Guo Z, Qian C, Xia S, Yao Y, Cao X. Splenic stroma-educated regulatory dendritic cells induce apoptosis of activated CD4 T cells via Fas ligand-enhanced IFN-gamma and nitric oxide. J Immunol. 2012;188(3):1168–77.

    Article  CAS  PubMed  Google Scholar 

  45. Zhang M, Tang H, Guo Z, An H, Zhu X, Song W, Guo J, Huang X, Chen T, Wang J, Cao X. Splenic stroma drives mature dendritic cells to differentiate into regulatory dendritic cells. Nat Immunol. 2004;5(11):1124–33.

    Article  CAS  PubMed  Google Scholar 

  46. Li L, Liu S, Zhang T, Pan W, Yang X, Cao X. Splenic stromal microenvironment negatively regulates virus-activated plasmacytoid dendritic cells through TGF-beta. J Immunol. 2008;180(5):2951–6.

    Article  CAS  PubMed  Google Scholar 

  47. Hussaarts L, van der Vlugt LE, Yazdanbakhsh M, Smits HH. Regulatory B-cell induction by helminths: implications for allergic disease. J Allergy Clin Immunol. 2011;128(4):733–9.

    Article  CAS  PubMed  Google Scholar 

  48. Turner JD, Narang P, Coles MC, Mountford AP. Blood flukes exploit Peyer’s Patch lymphoid tissue to facilitate transmission from the mammalian host. PLoS Pathog. 2012;8(12):e1003063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wood GS. The immunohistology of lymph nodes in HIV infection: a review. Prog AIDS Pathol. 1990;2:25–32.

    PubMed  CAS  Google Scholar 

  50. Wood GS, Garcia CF, Dorfman RF, Warnke RA. The immunohistology of follicle lysis in lymph node biopsies from homosexual men. Blood. 1985;66(5):1092–7.

    PubMed  CAS  Google Scholar 

  51. Rosenberg YJ, Lewis MG, Greenhouse JJ, Cafaro A, Leon EC, Brown CR, Bieg KE, Kosco-Vilbois MH. Enhanced follicular dendritic cell function in lymph nodes of simian immunodeficiency virus-infected macaques: consequences for pathogenesis. Eur J Immunol. 1997;27(12):3214–22.

    Article  CAS  PubMed  Google Scholar 

  52. Smelt SC, Engwerda CR, McCrossen M, Kaye PM. Destruction of follicular dendritic cells during chronic visceral leishmaniasis. J Immunol. 1997;158(8):3813–21.

    PubMed  CAS  Google Scholar 

  53. Zeng M, Paiardini M, Engram JC, Beilman GJ, Chipman JG, Schacker TW, Silvestri G, Haase AT. Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution. Blood. 2012;120(9):1856–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zeng M, Southern PJ, Reilly CS, Beilman GJ, Chipman JG, Schacker TW, Haase AT. Lymphoid tissue damage in HIV-1 infection depletes naive T cells and limits T cell reconstitution after antiretroviral therapy. PLoS Pathog. 2012;8(1):e1002437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ato M, Stager S, Engwerda CR, Kaye PM. Defective CCR7 expression on dendritic cells contributes to the development of visceral leishmaniasis. Nat Immunol. 2002;3(12):1185–91.

    Article  CAS  PubMed  Google Scholar 

  56. Graw F, Regoes RR. Influence of the fibroblastic reticular network on cell-cell interactions in lymphoid organs. PLoS Comput Biol. 2012;8(3):e1002436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Scandella E, Bolinger B, Lattmann E, Miller S, Favre S, Littman DR, Finke D, Luther SA, Junt T, Ludewig B. Restoration of lymphoid organ integrity through the interaction of lymphoid tissue-inducer cells with stroma of the T cell zone. Nat Immunol. 2008;9(6):667–75.

    Article  CAS  PubMed  Google Scholar 

  58. Benedict CA, De Trez C, Schneider K, Ha S, Patterson G, Ware CF. Specific remodeling of splenic architecture by cytomegalovirus. PLoS Pathog. 2006;2(3):e16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Engwerda CR, Ato M, Cotterell SE, Mynott TL, Tschannerl A, Gorak-Stolinska PM, Kaye PM. A role for tumor necrosis factor-alpha in remodeling the splenic marginal zone during Leishmania donovani infection. Am J Pathol. 2002;161(2):429–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Beattie L, Engwerda CR, Wykes M, Good MF. CD8+ T lymphocyte-mediated loss of marginal metallophilic macrophages following infection with Plasmodium chabaudi chabaudi AS. J Immunol. 2006;177(4):2518–26.

    Article  CAS  PubMed  Google Scholar 

  61. Yurdakul P, Dalton J, Beattie L, Brown N, Erguven S, Maroof A, Kaye PM. Compartment-specific remodeling of splenic micro-architecture during experimental visceral leishmaniasis. Am J Pathol. 2011;179(1):23–9.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Dalton JE, Maroof A, Owens BM, Narang P, Johnson K, Brown N, Rosenquist L, Beattie L, Coles M, Kaye PM. Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice. J Clin Invest. 2010;120(4):1204–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Grewal JS, Pilgrim MJ, Grewal S, Kasman L, Werner P, Bruorton ME, London SD, London L. Salivary glands act as mucosal inductive sites via the formation of ectopic germinal centers after site-restricted MCMV infection. FASEB J. 2011;25(5):1680–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. GeurtsvanKessel CH, Willart MA, Bergen IM, van Rijt LS, Muskens F, Elewaut D, Osterhaus AD, Hendriks R, Rimmelzwaan GF, Lambrecht BN. Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice. J Exp Med. 2009;206(11):2339–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Slight SR, Rangel-Moreno J, Gopal R, Lin Y, Fallert Junecko BA, Mehra S, Selman M, Becerril-Villanueva E, Baquera-Heredia J, Pavon L, Kaushal D, Reinhart TA, Randall TD, Khader SA. CXCR5(+) T helper cells mediate protective immunity against tuberculosis. J Clin Invest. 2013;123(2):712–26.

    PubMed  PubMed Central  CAS  Google Scholar 

  66. Moore JW, Beattie L, Dalton JE, Owens BM, Maroof A, Coles MC, Kaye PM. B cell: T cell interactions occur within hepatic granulomas during experimental visceral leishmaniasis. PLoS One. 2012;7(3):e34143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Barone F, Nayar S, Buckley CD. The role of non-hematopoietic stromal cells in the persistence of inflammation. Front Immunol. 2012;3:416.

    PubMed  Google Scholar 

  68. Serhan CN, Brain SD, Buckley CD, Gilroy DW, Haslett C, O’Neill LA, Perretti M, Rossi AG, Wallace JL. Resolution of inflammation: state of the art, definitions and terms. FASEB J. 2007;21(2):325–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Russell CD, Schwarze J. The role of pro-resolution lipid mediators in infectious disease. Immunology. 2014;141(2):166–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Rajasagi NK, Reddy PB, Suryawanshi A, Mulik S, Gjorstrup P, Rouse BT. Controlling herpes simplex virus-induced ocular inflammatory lesions with the lipid-derived mediator resolvin E1. J Immunol. 2011;186(3):1735–46.

    Article  CAS  PubMed  Google Scholar 

  71. Zeng M, Haase AT, Schacker TW. Lymphoid tissue structure and HIV-1 infection: life or death for T cells. Trends Immunol. 2012;33(6):306–14.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author thanks his numerous colleagues who have contributed to the study of stromal cell biology in his laboratory and the Medical Research Council and the Wellcome Trust for providing long-term research support. The author also apologizes to the many investigators whose work has been omitted for the sake of brevity but who have set the scene for future studies of the role of stromal cells in infection.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Paul M. Kaye .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Kaye, P.M. (2018). Stromal Cell Responses in Infection. In: Owens, B., Lakins, M. (eds) Stromal Immunology. Advances in Experimental Medicine and Biology, vol 1060. Springer, Cham. https://doi.org/10.1007/978-3-319-78127-3_2

Download citation

Publish with us

Policies and ethics