Regulation of macrophage activity by surface receptors contained within Borrelia burgdorferi-enriched phagosomal fractions

Autoři: Ana Carreras-González aff001;  Diego Barriales aff001;  Ainhoa Palacios aff001;  Marta Montesinos-Robledo aff001;  Nicolás Navasa aff001;  Mikel Azkargorta aff002;  Ainize Peña-Cearra aff001;  Julen Tomás-Cortázar aff001;  Iraide Escobes aff002;  Miguel Angel Pascual-Itoiz aff001;  Jana Hradiská aff003;  Jan Kopecký aff003;  David Gil-Carton aff004;  Rafael Prados-Rosales aff001;  Leticia Abecia aff001;  Estíbaliz Atondo aff001;  Itziar Martín aff001;  Aize Pellón aff001;  Félix Elortza aff002;  Héctor Rodríguez aff001;  Juan Anguita aff001
Působiště autorů: Inflammation and Macrophage Plasticity Laboratory, CIC bioGUNE, Derio, Bizkaia, Spain aff001;  Proteomics Platform, CIBERehd, ProteoRed-ISCIII, CIC bioGUNE, Derio, Bizkaia, Spain aff002;  Faculty of Science, University of South Bohemia, Branišovská, České Budějovice, Czech Republic aff003;  Structural Biology Unit, CIC bioGUNE, Derio, Bizkaia, Spain aff004;  Ikerbasque, Basque Foundation for Science, Bilbao, Bizkaia, Spain aff005
Vyšlo v časopise: Regulation of macrophage activity by surface receptors contained within Borrelia burgdorferi-enriched phagosomal fractions. PLoS Pathog 15(11): e32767. doi:10.1371/journal.ppat.1008163
Kategorie: Research Article


Macrophages mediate the elimination of pathogens by phagocytosis resulting in the activation of specific signaling pathways that lead to the production of cytokines, chemokines and other factors. Borrelia burgdorferi, the causative agent of Lyme disease, causes a wide variety of pro-inflammatory symptoms. The proinflammatory capacity of macrophages is intimately related to the internalization of the spirochete. However, most receptors mediating this process are largely unknown. We have applied a multiomic approach, including the proteomic analysis of B. burgdorferi-containing phagosome-enriched fractions, to identify surface receptors that are involved in the phagocytic capacity of macrophages as well as their inflammatory output. Sucrose gradient protein fractions of human monocyte-derived macrophages exposed to B. burgdorferi contained the phagocytic receptor, CR3/CD14 highlighting the major role played by these proteins in spirochetal phagocytosis. Other proteins identified in these fractions include C-type lectins, scavenger receptors or Siglecs, of which some are directly involved in the interaction with the spirochete. We also identified the Fc gamma receptor pathway, including the binding receptor, CD64, as involved both in the phagocytosis of, and TNF induction in response to B. burgdorferi in the absence of antibodies. The common gamma chain, FcγR, mediates the phagocytosis of the spirochete, likely through Fc receptors and C-type lectins, in a process that involves Syk activation. Overall, these findings highlight the complex array of receptors involved in the phagocytic response of macrophages to B. burgdorferi.

Klíčová slova:

Borrelia burgdorferi – Cell binding – Macrophages – Phagocytosis – Fc receptors – Spirochetes – Phagosomes – Complement receptors


1. EC. Parliament calls for “alarming” spread of Lyme disease to be tackled | News | European Parliament. 2018 (Nov 29). Available from:

2. Schotthoefer AM, Frost HM. Ecology and Epidemiology of Lyme Borreliosis. Clin Lab Med. 2015;35:723–43. doi: 10.1016/j.cll.2015.08.003 26593254

3. Murray TS, Shapiro ED. Lyme disease. Clin Lab Med. 2010;30:311–28. doi: 10.1016/j.cll.2010.01.003 20513553

4. Chomel B. Lyme disease. Rev Sci Tech. 2015;34:569–76. doi: 10.20506/rst.34.2.2380 26601457

5. Lelovas P, Dontas I, Bassiakou E, Xanthos T. Cardiac implications of Lyme disease, diagnosis and therapeutic approach. Int J Cardiol. 2008;129:15–21. doi: 10.1016/j.ijcard.2008.01.044 18508142

6. Aucott JN, Seifter A, Rebman AW. Probable late lyme disease: a variant manifestation of untreated Borrelia burgdorferi infection. BMC Infect Dis. 2012;12:173. doi: 10.1186/1471-2334-12-173 22853630

7. Schwan TG, Karstens RH, Schrumpf ME, Simpson WJ. Changes in antigenic reactivity of Borrelia burgdorferi, the Lyme disease spirochete, during persistent infection in mice. Can J Microbiol. 1991;37:450–4. doi: 10.1139/m91-074 1913349

8. Aslam B, Nisar MA, Khurshid M, Farooq Salamat MK. Immune escape strategies of Borrelia burgdorferi. Future Microbiol. 2017;12:1219–37. doi: 10.2217/fmb-2017-0013 28972415

9. Montgomery RR, Booth CJ, Wang X, Blaho VA, Malawista SE, Brown CR. Recruitment of macrophages and polymorphonuclear leukocytes in Lyme carditis. Infect Immun. 2007;75:613–20. doi: 10.1128/IAI.00685-06 17101663

10. Hovius JW, Bijlsma MF, van der Windt GJ, Wiersinga WJ, Boukens BJ, Coumou J, et al. The urokinase receptor (uPAR) facilitates clearance of Borrelia burgdorferi. PLoS Pathog. 2009;5:e1000447. doi: 10.1371/journal.ppat.1000447 19461880

11. Petnicki-Ocwieja T, Chung E, Acosta DI, Ramos LT, Shin OS, Ghosh S, et al. TRIF mediates Toll-like receptor 2-dependent inflammatory responses to Borrelia burgdorferi. Infect Immun. 2013;81:402–10. doi: 10.1128/IAI.00890-12 23166161

12. Hawley KL, Olson CM Jr., Carreras-Gonzalez A, Navasa N, Anguita J. Serum C3 Enhances Complement Receptor 3-Mediated Phagocytosis of Borrelia burgdorferi. Int J Biol Sci. 2015;11:1269–71. doi: 10.7150/ijbs.13395 26435692

13. Hawley KL, Martin-Ruiz I, Iglesias-Pedraz JM, Berwin B, Anguita J. CD14 targets complement receptor 3 to lipid rafts during phagocytosis of Borrelia burgdorferi. Int J Biol Sci. 2013;9:803–10. doi: 10.7150/ijbs.7136 23983613

14. Hawley KL, Olson CM Jr., Ig esias-Pedraz JM, Navasa N, Cervantes JL, Caimano MJ, et al. CD14 cooperates with complement receptor 3 to mediate MyD88-independent phagocytosis of Borrelia burgdorferi. Proc Natl Acad Sci U S A. 2012;109:1228–32. doi: 10.1073/pnas.1112078109 22232682

15. Carreras-Gonzalez A, Navasa N, Martin-Ruiz I, Lavin JL, Azkargorta M, Atondo E, et al. A multi-omic analysis reveals the regulatory role of CD180 during the response of macrophages to Borrelia burgdorferi. Emerg Microbes Infect. 2018;7:19. doi: 10.1038/s41426-017-0018-5 29511161

16. Killpack TL, Ballesteros M, Bunnell SC, Bedugnis A, Kobzik L, Hu LT, et al. Phagocytic Receptors Activate Syk and Src Signaling during Borrelia burgdorferi Phagocytosis. Infect Immun. 2017;85.

17. Underhill DM, Goodridge HS. Information processing during phagocytosis. Nat Rev Immunol. 2012;12:492–502. doi: 10.1038/nri3244 22699831

18. Pluddemann A, Neyen C, Gordon S. Macrophage scavenger receptors and host-derived ligands. Methods. 2007;43:207–17. doi: 10.1016/j.ymeth.2007.06.004 17920517

19. Dambuza IM, Brown GD. C-type lectins in immunity: recent developments. Curr Opin Immunol. 2015;32:21–7. doi: 10.1016/j.coi.2014.12.002 25553393

20. Carroll MC. The role of complement and complement receptors in induction and regulation of immunity. Annu Rev Immunol. 1998;16:545–68. doi: 10.1146/annurev.immunol.16.1.545 9597141

21. Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol. 2008;8:34–47. doi: 10.1038/nri2206 18064051

22. Mittal R, Sukumaran SK, Selvaraj SK, Wooster DG, Babu MM, Schreiber AD, et al. Fcgamma receptor I alpha chain (CD64) expression in macrophages is critical for the onset of meningitis by Escherichia coli K1. PLoS Pathog. 2010;6:e1001203. doi: 10.1371/journal.ppat.1001203 21124939

23. Cervantes JL, Dunham-Ems SM, La Vake CJ, Petzke MM, Sahay B, Sellati TJ, et al. Phagosomal signaling by Borrelia burgdorferi in human monocytes involves Toll-like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN-{beta}. Proc Natl Acad Sci U S A. 2011;108:3683–8. doi: 10.1073/pnas.1013776108 21321205

24. Kerrigan AM, Brown GD. Syk-coupled C-type lectins in immunity. Trends Immunol. 2011;32:151–6. doi: 10.1016/ 21334257

25. Getahun A, Beavers NA, Larson SR, Shlomchik MJ, Cambier JC. Continuous inhibitory signaling by both SHP-1 and SHIP-1 pathways is required to maintain unresponsiveness of anergic B cells. J Exp Med. 2016;213:751–69. doi: 10.1084/jem.20150537 27114609

26. Netea MG, Brown GD, Kullberg BJ, Gow NA. An integrated model of the recognition of Candida albicans by the innate immune system. Nat Rev Microbiol. 2008;6:67–78. doi: 10.1038/nrmicro1815 18079743

27. Peyron P, Bordier C, N'Diaye EN, Maridonneau-Parini I. Nonopsonic phagocytosis of Mycobacterium kansasii by human neutrophils depends on cholesterol and is mediated by CR3 associated with glycosylphosphatidylinositol-anchored proteins. J Immunol. 2000;165:5186–91. doi: 10.4049/jimmunol.165.9.5186 11046051

28. Chen GY, Tang J, Zheng P, Liu Y. CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science. 2009;323:1722–5. doi: 10.1126/science.1168988 19264983

29. Belperron AA, Liu N, Booth CJ, Bockenstedt LK. Dual role for Fcgamma receptors in host defense and disease in Borrelia burgdorferi-infected mice. Front Cell Infect Microbiol. 2014;4:75. doi: 10.3389/fcimb.2014.00075 24967215

30. Osorio F, Reis e Sousa C. Myeloid C-type lectin receptors in pathogen recognition and host defense. Immunity. 2011;34:651–64. doi: 10.1016/j.immuni.2011.05.001 21616435

31. Navasa N, Fikrig E, Anguita J. Host defenses to spirochetes. In: Rich R, Fleisher T, Shearer W, Shoreder H, Frew A, Weyand C, editors. Clinical Immunology: Principles and Practice. 5th ed: Elsevier; 2018.

32. Liu N, Montgomery RR, Barthold SW, Bockenstedt LK. Myeloid differentiation antigen 88 deficiency impairs pathogen clearance but does not alter inflammation in Borrelia burgdorferi-infected mice. Infect Immun. 2004;72:3195–203. doi: 10.1128/IAI.72.6.3195-3203.2004 15155621

33. Ioan-Facsinay A, de Kimpe SJ, Hellwig SM, van Lent PL, Hofhuis FM, van Ojik HH, et al. FcgammaRI (CD64) contributes substantially to severity of arthritis, hypersensitivity responses, and protection from bacterial infection. Immunity. 2002;16:391–402. doi: 10.1016/s1074-7613(02)00294-7 11911824

34. Dunham-Ems SM, Caimano MJ, Pal U, Wolgemuth CW, Eggers CH, Balic A, et al. Live imaging reveals a biphasic mode of dissemination of Borrelia burgdorferi within ticks. J Clin Invest. 2009;119:3652–65. doi: 10.1172/JCI39401 19920352

35. Olson C, Bates T, Izadi H, Radolf J, Huber S, Boyson J, et al. Local Production of IFN-gamma by Invariant NKT Cells Modulates Acute Lyme Carditis. Journal of Immunology. 2009;182:3728–34.

36. Majeed M, Caveggion E, Lowell CA, Berton G. Role of Src kinases and Syk in Fcgamma receptor-mediated phagocytosis and phagosome-lysosome fusion. J Leukoc Biol. 2001;70:801–11. 11698501

37. Garcia-Cao I, Song MS, Hobbs RM, Laurent G, Giorgi C, de Boer VC, et al. Systemic elevation of PTEN induces a tumor-suppressive metabolic state. Cell. 2012;149:49–62. doi: 10.1016/j.cell.2012.02.030 22401813

38. Luhrmann A, Haas A. A method to purify bacteria-containing phagosomes from infected macrophages. Methods Cell Sci. 2000;22:329–41. doi: 10.1023/a:1017963401560 11549946

39. Vinet AF, Descoteaux A. Large scale phagosome preparation. Methods Mol Biol. 2009;531:329–46. doi: 10.1007/978-1-59745-396-7_20 19347326

40. Wisniewski JR, Zougman A, Nagaraj N, Mann M. Universal sample preparation method for proteome analysis. Nat Methods. 2009;6:359–62. doi: 10.1038/nmeth.1322 19377485

41. Perez-Riverol Y, Csordas A, Bai J, Bernal-Llinares M, Hewapathirana S, Kundu DJ, et al. The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Res. 2019;47:D442–D50. doi: 10.1093/nar/gky1106 30395289

Hygiena a epidemiologie Infekční lékařství Laboratoř

Článek vyšel v časopise

PLOS Pathogens

2019 Číslo 11
Nejčtenější tento týden
Nejčtenější v tomto čísle

Zvyšte si kvalifikaci online z pohodlí domova

Hypertenze a hypercholesterolémie – synergický efekt léčby
nový kurz
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Úloha kombinovaných preparátů v léčbě arteriální hypertenze
Autoři: prof. MUDr. Martin Haluzík, DrSc.

Autoři: MUDr. Ladislav Korábek, CSc., MBA

Terapie roztroušené sklerózy v kostce
Autoři: MUDr. Dominika Šťastná, Ph.D.

Všechny kurzy
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se