Amblyomma americanum ticks utilizes countervailing pro and anti-inflammatory proteins to evade host defense

English version

Autoři: Mariam Bakshi ^aff001; Tae Kwon Kim ^aff001; Lindsay Porter ^aff001; Waithaka Mwangi ^aff001; Albert Mulenga ^aff001
Působiště autorů: Department of Veterinary Pathobiology, College of Veterinary Medicine, TAMU, College Station, Texas, United States of America ^aff001; Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America ^aff002
Vyšlo v časopise: Amblyomma americanum ticks utilizes countervailing pro and anti-inflammatory proteins to evade host defense. PLoS Pathog 15(11): e32767. doi:10.1371/journal.ppat.1008128
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008128

Souhrn

Feeding and transmission of tick-borne disease (TBD) agents by ticks are facilitated by tick saliva proteins (TSP). Thus, defining functional roles of TSPs in tick evasion is expected to reveal potential targets in tick-antigen based vaccines to prevent TBD infections. This study describes two types of Amblyomma americanum TSPs: those that are similar to LPS activate macrophage (MΦ) to express pro-inflammation (PI) markers and another set that suppresses PI marker expression by activated MΦ. We show that similar to LPS, three recombinant (r) A. americanum insulin-like growth factor binding-related proteins (rAamIGFBP-rP1, rAamIGFBP-rP6S, and rAamIGFBP-rP6L), hereafter designated as PI-rTSPs, stimulated both PBMC -derived MΦ and mice RAW 267.4 MΦ to express PI co-stimulatory markers, CD40, CD80, and CD86 and cytokines, TNFα, IL-1, and IL-6. In contrast, two A. americanum tick saliva serine protease inhibitors (serpins), AAS27 and AAS41, hereafter designated as anti-inflammatory (AI) rTSPs, on their own did not affect MΦ function or suppress expression of PI markers, but enhanced expression of AI cytokines (IL-10 and TGFβ) in MΦ that were pre-activated by LPS or PI-rTSPs. Mice paw edema test demonstrated that in vitro validated PI- and AI-rTSPs are functional in vivo since injection of HEK293-expressed PI-rTSPs (individually or as a cocktail) induced edema comparable to carrageenan-induced edema and was characterized by upregulation of CD40, CD80, CD86, TNF-α, IL-1, IL-6, and chemokines: CXCL1, CCL2, CCL3, CCL5, and CCL11, whereas the AI-rTSPs (individually and cocktail) were suppressive. We propose that the tick may utilize countervailing PI and AI TSPs to regulate evasion of host immune defenses whereby TSPs such as rAamIGFBP-rPs activate host immune cells and proteins such as AAS27 and AAS41 suppress the activated immune cells.

Klíčová slova:

Cytokines – Chemokines – Immune cells – Inflammation – Saliva – Secretion – Ticks

Zdroje

1. Jongejan F, Uilenberg G. The global importance of ticks. Parasitology. 2004 Oct;129(S1):S3–14. doi: 10.1017/s0031182004005967 15938502

2. Dantas-Torres F, Chomel BB, Otranto D. Ticks and tick-borne diseases: a One Health perspective. Trends in parasitology. 2012 Oct 1;28(10):437–46. doi: 10.1016/j.pt.2012.07.003 22902521

3. Rosenberg R, Lindsey NP, Fischer M, Gregory CJ, Hinckley AF, Mead PS, Paz-Bailey G, Waterman SH, Drexler NA, Kersh GJ, Hooks H. Vital signs: trends in reported vector borne disease cases—United States and Territories, 2004–2016. Morbidity and Mortality Weekly Report. 2018 May 4;67(17):496. doi: 10.15585/mmwr.mm6717e1 29723166

4. George JE. Present and future technologies for tick control. Annals of the New York Academy of Sciences. 2000 Dec;916(1):583–8. doi: 10.1111/j.1749-6632.2000.tb05340.x 11193677

5. Andreotti R, Guerrero FD, Soares MA, Barros JC, Miller RJ, Léon AP. Acaricide resistance of Rhipicephalus (Boophilus) microplus in state of Mato Grosso do Sul, Brazil. Revista Brasileira de Parasitologia Veterinária. 2011 Jun;20(2):127–33. doi: 10.1590/s1984-29612011000200007 21722487

6. Graf JF, Gogolewski R, Leach-Bing N, Sabatini GA, Molento MB, Bordin EL, Arantes GJ. Tick control: an industry point of view. Parasitology. 2004 Oct;129(S1):S427–42. doi: 10.1017/s0031182004006079 15938522

7. Li AY, Davey RB, Miller RJ, George JE. Resistance to coumaphos and diazinon in Boophilus microplus (Acari: Ixodidae) and evidence for the involvement of an oxidative detoxification mechanism. Journal of Medical Entomology. 2003 Jul 1;40(4):482–90. doi: 10.1603/0022-2585-40.4.482 14680115

8. Guerrero FD, Li AY, Hernandez R. Molecular diagnosis of pyrethroid resistance in Mexican strains of Boophilus microplus (Acari: Ixodidae). Journal of Medical entomology. 2002 Sep 1;39(5):770–6. doi: 10.1603/0022-2585-39.5.770 12349861

9. Willadsen P, Bird P, Cobon GS, Hungerford J. Commercialization of a recombinant vaccine against Boophilus microplus. Parasitology. 1995;110 Suppl:S43–50. doi: 10.1017/s0031182000001487 7784128

10. Valle MR, Mèndez L, Valdez M, Redondo M, Espinosa CM, Vargas M, Cruz RL, Barrios HP, Seoane G, Ramirez ES, Boue O. Integrated control of Boophilus microplus ticks in Cuba based on vaccination with the anti-tick vaccine Gavac. Experimental & applied acarology. 2004 Nov 1;34(3–4):375–82. doi: 10.1007/s10493-004-1389-6 15651533

11. Brossard M. The use of vaccines and genetically resistant animals in tick control. Revue scientifique et technique-Office international des épizooties. 1998 Apr 1;17:188–93. doi: 10.20506/rst.17.1.1086 9638810

12. de la Fuente J, Almazán C, Canales M, de la Lastra JM, Kocan KM, Willadsen P. A ten-year review of commercial vaccine performance for control of tick infestations on cattle. Animal Health Research Reviews. 2007 Jun;8(1):23–8. doi: 10.1017/S1466252307001193 17692140

13. De la Fuente J, Kocan KM, Blouin EF. Tick vaccines and the transmission of tick-borne pathogens. Veterinary research communications. 2007 Aug 1;31(1):85–90. doi: 10.3389/fcimb.2013.00030 23847771

14. de la Fuente J, Moreno-Cid JA, Canales M, Villar M, de la Lastra JM, Kocan KM, Galindo RC, Almazán C, Blouin EF. Targeting arthropod subolesin/akirin for the development of a universal vaccine for control of vector infestations and pathogen transmission. Veterinary parasitology. 2011 Sep 8;181(1):17–22 doi: 10.1016/j.vetpar.2011.04.018 21561715

15. Marcelino I, De Almeida AM, Ventosa M, Pruneau L, Meyer DF, Martinez D, Lefrançois T, Vachiéry N, Coelho AV. Tick-borne diseases in cattle: applications of proteomics to develop new generation vaccines. Journal of proteomics. 2012 Jul 19;75(14):4232–50. doi: 10.1016/j.jprot.2012.03.026 22480908

16. Zhang XC, Zhang LX, Li WH, Wang SW, Sun YL, Wang YY, Guan ZZ, Liu XJ, Yang YS, Zhang SG, Yu HL. Ehrlichiosis and zoonotic anaplasmosis in suburban areas of Beijing, China. Vector-Borne and Zoonotic Diseases. 2012 Nov 1;12(11):932–7. doi: 10.1089/vbz.2012.0961 23025695

17. Radulović ŽM, Kim TK, Porter LM, Sze SH, Lewis L, Mulenga A. A 24–48 h fed Amblyomma americanum tick saliva immuno-proteome. BMC genomics. 2014 Dec;15(1):518. doi: 10.1186/1471-2164-15-518 24962723

18. Mulenga A, Sugimoto C, Onuma M. Issues in tick vaccine development: identification and characterization of potential candidate vaccine antigens. Microbes and Infection. 2000 Sep 1;2(11):1353–61. doi: 10.1016/s1286-4579(00)01289-2 11018452

19. Mulenga A, Sugino M, Nakajima M, Sugimoto C, Onuma M. Tick-Encoded serine proteinase inhibitors (serpins); potential target antigens for tick vaccine development. Journal of Veterinary Medical Science. 2001;63(10):1063–9. doi: 10.1292/jvms.63.1063 11714020

20. Kotál J, Langhansová H, Lieskovská J, Andersen JF, Francischetti IM, Chavakis T, Kopecký J, Pedra JH, Kotsyfakis M, Chmelař J. Modulation of host immunity by tick saliva. Journal of proteomics. 2015 Oct 14;128:58–68. doi: 10.1016/j.jprot.2015.07.005 26189360

21. Šimo L, Kazimirova M, Richardson J, Bonnet SI. The essential role of tick salivary glands and saliva in tick feeding and pathogen transmission. Frontiers in cellular and infection microbiology. 2017 Jun 22;7:281. doi: 10.3389/fcimb.2017.00281 28690983

22. Hermance ME, Santos RI, Kelly BC, Valbuena G, Thangamani S. Immune cell targets of infection at the tick-skin interface during Powassan virus transmission. PLoS One. 2016 May 20;11(5):e0155889. doi: 10.1371/journal.pone.0155889 27203436

23. Anderson JM, Moore IN, Nagata BM, Ribeiro J, Valenzuela JG, Sonenshine DE. Ticks, Ixodes scapularis, feed repeatedly on white-footed mice despite strong inflammatory response: an expanding paradigm for understanding tick–host interactions. Frontiers in immunology. 2017 Dec 18;8:1784. doi: 10.3389/fimmu.2017.01784 29326693

24. Langhansova H, Bopp T, Schmitt E, Kopecký J. Tick saliva increases production of three chemokines including monocyte chemoattractant protein‐1, a histamine‐releasing cytokine. Parasite immunology. 2015 Feb;37(2):92–6. doi: 10.1111/pim.12168 25545116

25. Lima e Silva MF, Szabo MP, Bechara GH. Microscopic Features of Tick‐Bite Lesions in Anteaters and Armadillos: Emas National Park and the Pantanal Region of Brazil. Annals of the New York Academy of Sciences. 2004 Oct;1026(1):235–41. doi: 10.1196/annals.1307.036 15604499

26. Arango Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol 2014 Oct 7;5:491. doi: 10.3389/fimmu.2014.00491 25339958

27. Zhou D, Huang C, Lin Z, Zhan S, Kong L, Fang C, Li J. Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways. Cellular signaling. 2014 Feb 1;26(2):192–7. doi: 10.1016/j.cellsig.2013.11.004 24219909

28. Brake DK, Wikel SK, Tidwell JP, de León AA. Rhipicephalus microplus salivary gland molecules induce differential CD86 expression in murine macrophages. Parasites & vectors. 2010 Dec;3(1):103. doi: 10.1186/1756-3305-3-103 21054882

29. Poole NM, Mamidanna G, Smith RA, Coons LB, Cole JA. Prostaglandin E 2 in tick saliva regulates macrophage cell migration and cytokine profile. Parasites & vectors. 2013 Dec;6(1):261. doi: 10.1186/1756-3305-6-261 24025197

30. Kramer CD, Poole NM, Coons LB, Cole JA. Tick saliva regulates migration, phagocytosis, and gene expression in the macrophage-like cell line, IC-21. Experimental parasitology. 2011 Mar 1;127(3):665–71. doi: 10.1016/j.exppara.2010.11.012 21145320

31. Rodrigues V, Fernandez B, Vercoutere A, Chamayou L, Andersen A, Vigy O, Demettre E, Seveno M, Aprelon R, Giraud-Girard K, Stachurski F. Immunomodulatory effects of Amblyomma variegatum saliva on bovine cells: characterization of cellular responses and identification of molecular determinants. Frontiers in cellular and infection microbiology. 2018 Jan 4;7:521. doi: 10.3389/fcimb.2017.00521 29354598

32. de Abreu MR, Pereira MC, Simioni PU, Nodari EF, Paiatto LN, Camargo-Mathias MI. Immunomodulatory and morphophysiological effects of Rhipicephalus sanguineus sl (Acari: Ixodidae) salivary gland extracts. Veterinary immunology and immunopathology. 2019 Jan 1;207:36–45. doi: 10.1016/j.vetimm.2018.11.017 30593349

33. Wasala NB, Jaworski DC. Dermacentor variabilis: characterization and modeling of macrophage migration inhibitory factor with phylogenetic comparisons to other ticks, insects and parasitic nematodes. Experimental parasitology. 2012 Mar 1;130(3):232–8. doi: 10.1016/j.exppara.2011.12.010 22306068

34. Wasala NB, Bowen CJ, Jaworski DC. Expression and regulation of macrophage migration inhibitory factor (MIF) in feeding American dog ticks, Dermacentor variabilis. Experimental and applied acarology. 2012 Jun 1;57(2):179–87. doi: 10.1007/s10493-012-9550-0 22476444

35. Jaworski DC, Jasinskas A, Metz CN, Bucala R, Barbour AG. Identification and characterization of a homologue of the pro‐inflammatory cytokine Macrophage Migration Inhibitory Factor in the tick, Amblyomma americanum. Insect molecular biology. 2001 Aug;10(4):323–31. doi: 10.1046/j.0962-1075.2001.00271.x 11520355

36. Jaworski DC, Bowen CJ, Wasala NB. Amblyomma americanum (L): tick macrophage migration inhibitory factor peptide immunization lengthens lone star tick feeding intervals in vivo. Experimental parasitology. 2009 Apr 1;121(4):384–7. doi: 10.1016/j.exppara.2008.12.003 19111543

37. Wang X, Shaw DK, Sakhon OS, Snyder GA, Sundberg EJ, Santambrogio L, Sutterwala FS, Dumler JS, Shirey KA, Perkins DJ, Richard K. The tick protein Sialostatin L2 binds to Annexin A2 and inhibits NLRC4-mediated inflammasome activation. Infection and immunity. 2016 Jun 1;84(6):1796–805. doi: 10.1128/IAI.01526-15 27045038

38. Mulenga A, Blandon M, Khumthong R. The molecular basis of the Amblyomma americanum tick attachment phase. Experimental and Applied Acarology. 2007 Apr 1;41(4):267–87. doi: 10.1007/s10493-007-9064-3 17406795

39. Radulović ŽM, Porter LM, Kim TK, Bakshi M, Mulenga A. Amblyomma americanum tick saliva insulin‐like growth factor binding protein‐related protein 1 binds insulin but not insulin‐like growth factors. Insect molecular biology. 2015 Oct;24(5):539–50. doi: 10.1111/imb.12180 26108887

40. Porter LM, Radulović ŽM, Mulenga A. A repertoire of protease inhibitor families in Amblyomma americanum and other tick species: inter-species comparative analyses. Parasites & vectors. 2017 Dec;10(1):152. doi: 10.1186/s13071-017-2080-1 28330502

41. Tirloni L, Kim TK, Pinto AF, Yates JR III, da Silva Vaz I Jr, Mulenga A. Tick-host range adaptation: changes in protein profiles in unfed adult Ixodes scapularis and Amblyomma americanum saliva stimulated to feed on different hosts. Frontiers in cellular and infection microbiology. 2017 Dec 19;7:517. doi: 10.3389/fcimb.2017.00517 29312895

42. Radulović ŽM, Kim TK, Porter LM, Sze SH, Lewis L, Mulenga A. A 24–48 h fed Amblyomma americanum tick saliva immuno-proteome. BMC genomics. 2014 Dec;15(1):518. 24962723

43. Mulenga A, Khumthong R. Silencing of three Amblyomma americanum (L.) insulin-like growth factor binding protein-related proteins prevents ticks from feeding to repletion. Journal of Experimental Biology. 2010 Apr 1;213(7):1153–61. doi: 10.1242/jeb.035204 20228352

44. Tirloni L, Kim TK, Berger M, Termignoni C, da Silva Vaz I Jr, Mulenga A. Amblyomma americanum serpin 27 (AAS27) is a tick salivary anti-inflammatory protein secreted into the host during feeding. PLoS neglected tropical diseases. 2019 Aug 26;13(8):e0007660. doi: 10.1371/journal.pntd.0007660 31449524

45. Cavaillon JM. Cytokines and macrophages. Biomedicine & pharmacotherapy. 1994 Jan 1;48(10):445–53. doi: 10.1016/0753-3322(94)90005-1 7858154

46. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013 Apr;496(7446):445. doi: 10.1038/nature12034 23619691

47. Lanier LL, O, Somoza C, Phillips JH, Linsley PS, Okumura K, Ito D, Azuma M. CD80 (B7) and CD86 (B70) provide similar costimulatory signals for T cell proliferation, cytokine production, and generation of CTL. The Journal of Immunology. 1995 Jan 1;154(1):97–105. 7527824

48. Fleischer J, Soeth E, Reiling N, Grage‐Griebenow E, FLAD HD, Ernst M. Differential expression and function of CD80 (B7‐1) and CD86 (B7‐2) on human peripheral blood monocytes. Immunology. 1996 Dec;89(4):592–8. doi: 10.1046/j.1365-2567.1996.d01-785.x 9014827

49. MacMicking J, Xie QW, Nathan C. Nitric oxide and macrophage function. Annual review of immunology. 1997 Apr;15(1):323–50. doi: 10.1146/annurev.immunol.15.1.323 9143691

50. Mills C. M1 and M2 macrophages: oracles of health and disease. Critical Reviews in Immunology. 2012;32(6). doi: 10.1615/critrevimmunol.v32.i6.10 23428224

51. Kotsyfakis M, Sa-Nunes A, Francischetti IM, Mather TN, Andersen JF, Ribeiro JM. Anti-inflammatory and immunosuppressive activity of sialostatin L, a salivary cystatin from the tick Ixodes scapularis. J Biol Chem 2006 Sep 8;281(36):26298–26307. doi: 10.1074/jbc.M513010200 16772304

52. Oliveira CJ, Cavassani KA, Moré DD, Garlet GP, Aliberti JC, Silva JS, Ferreira BR. Tick saliva inhibits the chemotactic function of MIP-1α and selectively impairs chemotaxis of immature dendritic cells by down-regulating cell-surface CCR5. International journal for parasitology. 2008 May 1;38(6):705–16. doi: 10.1016/j.ijpara.2007.10.006 18023445

53. Guo X, Booth CJ, Paley MA, Wang X, DePonte K, Fikrig E, et al. Inhibition of neutrophil function by two tick salivary proteins. Infect Immun 2009 Jun;77(6):2320–2329. doi: 10.1128/IAI.01507-08 19332533

54. Langhansova H, Bopp T, Schmitt E, Kopecký J. Tick saliva increases production of three chemokines including monocyte chemoattractant protein‐1, a histamine‐releasing cytokine. Parasite immunology. 2015 Feb;37(2):92–6. doi: 10.1111/pim.12168 25545116

55. Chmelar J, Calvo E, Pedra JH, Francischetti IM, Kotsyfakis M. Tick salivary secretion as a source of antihemostatics. Journal of proteomics. 2012 Jul 16;75(13):3842–54. doi: 10.1016/j.jprot.2012.04.026 22564820

56. Strle K, Drouin EE, Shen S, Khoury JE, McHugh G, Ruzic-Sabljic E, Strle F, Steere AC. Borrelia burgdorferi stimulates macrophages to secrete higher levels of cytokines and chemokines than Borrelia afzelii or Borrelia garinii. The Journal of infectious diseases. 2009 Dec 15;200(12):1936–43. doi: 10.1086/648091 19909078

57. Jones KL, Muellegger RR, Means TK, Lee M, Glickstein LJ, Damle N, Sikand VK, Luster AD, Steere AC. Higher mRNA levels of chemokines and cytokines associated with macrophage activation in erythema migrans skin lesions in patients from the United States than in patients from Austria with Lyme borreliosis. Clinical infectious diseases. 2008 Jan 1;46(1):85–92. doi: 10.1086/524022 18171218

58. Miura K, Matsuo J, Rahman MA, Kumagai Y, Li X, Rikihisa Y. Ehrlichia chaffeensis induces monocyte inflammatory responses through MyD88, ERK, and NF-κB but not through TRIF, interleukin-1 receptor 1 (IL-1R1)/IL-18R1, or Toll-like receptors. Infection and immunity. 2011 Dec 1;79(12):4947–56. doi: 10.1128/IAI.05640-11 21930764

59. Chen G, Severo MS, Sohail M, Sakhon OS, Wikel SK, Kotsyfakis M, Pedra JH. Ixodes scapularis saliva mitigates inflammatory cytokine secretion during Anaplasma phagocytophilum stimulation of immune cells. Parasites & vectors. 2012 Dec;5(1):229. doi: 10.1186/1756-3305-5-229 23050849

60. Hermance ME, Thangamani S. Proinflammatory cytokines and chemokines at the skin interface during Powassan virus transmission. The Journal of investigative dermatology. 2014 Aug;134(8):2280. doi: 10.1038/jid.2014.150 24658509

61. Nuttall PA. Tick saliva and its role in pathogen transmission. Wiener klinische Wochenschrift. 2019 May 6:1–2. doi: 10.1007/s00508-019-1500-y 31062185

62. Schoeler GB, Manweiler SA, Wikel SK. Ixodes scapularis: effects of repeated infestations with pathogen-free nymphs on macrophage and T lymphocyte cytokine responses of BALB/c and C3H/HeN mice. Experimental parasitology. 1999 Aug 1;92(4):239–48. doi: 10.1006/expr.1999.4426 10425152

63. Gwakisa P, Yoshihara K, To TL, Gotoh H, Amano F, Momotani E. Salivary gland extract of Rhipicephalus appendiculatus ticks inhibits in vitro transcription and secretion of cytokines and production of nitric oxide by LPS-stimulated JA-4 cells. Veterinary Parasitology. 2001 Jul 31;99(1):53–61. doi: 10.1016/s0304-4017(01)00445-9 11445155

64. Ferreira BR, Silva JS. Saliva of Rhipicephalus sanguineus tick impairs T cell proliferation and IFN-γ-induced macrophage microbicidal activity. Veterinary immunology and immunopathology. 1998 Jul 31;64(3):279–93. doi: 10.1016/s0165-2427(98)00135-4 9730222

65. Krause PJ, Grant-Kels JM, Tahan SR, Dardick KR, Alarcon-Chaidez F, Bouchard K, Visini C, Deriso C, Foppa IM, Wikel S. Dermatologic changes induced by repeated Ixodes scapularis bites and implications for prevention of tick-borne infection. Vector-Borne and Zoonotic Diseases. 2009 Dec 1;9(6):603–10. doi: 10.1089/vbz.2008.0091 19196014

66. Glatz M, Means T, Haas J, Steere AC, Müllegger RR. Characterization of the early local immune response to Ixodes ricinus tick bites in human skin. Experimental dermatology. 2017 Mar;26(3):263–9. doi: 10.1111/exd.13207 27623398

67. Heinze DM, Carmical JR, Aronson JF, Thangamani S. Early immunologic events at the tick-host interface. PloS one. 2012 Oct 15;7(10):e47301. doi: 10.1371/journal.pone.0047301 23077588

68. Butterfield TA, Best TM, Merrick MA. The dual roles of neutrophils and macrophages in inflammation: a critical balance between tissue damage and repair. Journal of athletic training. 2006 Oct;41(4):457. 17273473

69. Fujiwara N, Kobayashi K. Macrophages in inflammation. Current Drug Targets-Inflammation & Allergy. 2005 Jun 1;4(3):281–6. doi: 10.2174/1568010054022024 16101534

70. Freire MO, Van Dyke TE. Natural resolution of inflammation. Periodontology 2000. 2013 Oct;63(1):149–64. doi: 10.1111/prd.12034 23931059

71. Woldai S. The role of CD80 and CD86 in macrophage activation and its regulation following LPS stimulation (Doctoral dissertation, Université d'Ottawa/University of Ottawa).

72. Moser B, Willimann K. Chemokines: role in inflammation and immune surveillance. Annals of the rheumatic diseases. 2004 Nov 1;63(suppl 2):ii84–9. doi: 10.1136/ard.2004.028316 15479880

73. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity. 2000 Feb 1;12(2):121–7. doi: 10.1016/s1074-7613(00)80165-x 10714678

74. Mulenga A, Macaluso KR, Simser JA, Azad AF. The American dog tick, Dermacentor variabilis, encodes a functional histamine release factor homolog. Insect biochemistry and molecular biology. 2003 Sep 1;33(9):911–9. doi: 10.1016/s0965-1748(03)00097-3 12915182

75. Mulenga A, Azad AF. The molecular and biological analysis of ixodid ticks histamine release factors. Experimental & applied acarology. 2005 Dec 1;37(3–4):215–29. doi: 10.1007/s10493-005-3261-8 16323052

76. Lani R, Moghaddam E, Haghani A, Chang LY, AbuBakar S, Zandi K. Tick-borne viruses: a review from the perspective of therapeutic approaches. Ticks and tick-borne diseases. 2014 Sep 1;5(5):457–65. doi: 10.1016/j.ttbdis.2014.04.001 24907187

77. Westover JB, Rigas JD, Van Wettere AJ, Li R, Hickerson BT, Jung KH, Miao J, Reynolds ES, Conrad BL, Nielson S, Furuta Y. Heartland virus infection in hamsters deficient in type I interferon signaling: Protracted disease course ameliorated by favipiravir. Virology. 2017 Nov 1;511:175–83. doi: 10.1016/j.virol.2017.08.004 28865344

78. Portolano N, Watson PJ, Fairall L, Millard CJ, Milano CP, Song Y, et al. Recombinant protein expression for structural biology in HEK 293F suspension cells: a novel and accessible approach. J Vis Exp 2014 Oct 16;(92):e51897. (92):e51897. doi: 10.3791/51897 25349981

79. Longo PA, Kavran JM, Kim MS, Leahy DJ. Transient mammalian cell transfection with polyethylenimine (PEI). InMethods in enzymology 2013 Jan 1 (Vol. 529, pp. 227–240). Academic Press. doi: 10.1016/B978-0-12-418687-3.00018-5 24011049

80. Winter CA, Risley EA, Nuss GW. Carrageenan-induced edema in hind paw of the rat as an assay for anti-inflammatory drugs. Proceedings of the society for experimental biology and medicine. 1962 Dec;111(3):544–7. doi: 10.3181/00379727-111-27849 14001233

81. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. methods. 2001 Dec 1;25(4):402–8. doi: 10.1006/meth.2001.1262 11846609

82. Dann SM, Spehlmann ME, Hammond DC, Iimura M, Hase K, Choi LJ, Hanson E, Eckmann L. IL-6-dependent mucosal protection prevents establishment of a microbial niche for attaching/effacing lesion-forming enteric bacterial pathogens. The Journal of Immunology. 2008 May 15;180(10):6816–26. doi: 10.4049/jimmunol.180.10.6816 18453602

83. Mazur PK, Herner A, Mello SS, Wirth M, Hausmann S, Sánchez-Rivera FJ, Lofgren SM, Kuschma T, Hahn SA, Vangala D, Trajkovic-Arsic M. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nature medicine. 2015 Oct;21(10):1163. doi: 10.1038/nm.3952 26390243

84. Guma M, Ronacher L, Liu‐Bryan R, Takai S, Karin M, Corr M. Caspase 1–independent activation of interleukin‐1β in neutrophil‐predominant inflammation. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 2009 Dec;60(12):3642–50. doi: 10.1002/art.24959 19950258

85. Vicente‐Suarez I, Takahashi Y, Cheng F, Horna P, Wang HW, Wang HG, Sotomayor EM. Identification of a novel negative role of flagellin in regulating IL‐10 production. European journal of immunology. 2007 Nov;37(11):3164–75. doi: 10.1002/eji.200737306 17948265

86. Morgado P, Sudarshana DM, Gov L, Harker KS, Lam T, Casali P, et al. Type II Toxoplasma gondii induction of CD40 on infected macrophages enhances interleukin-12 responses. Infect Immun 2014 Oct;82(10):4047–4055. doi: 10.1128/IAI.01615-14 25024369

87. Li JG, Du YM, Yan ZD, Yan J, Zhuansun YX, Chen R, Zhang W, Feng SL, Ran PX. CD80 and CD86 knockdown in dendritic cells regulates Th1/Th2 cytokine production in asthmatic mice. Experimental and therapeutic medicine. 2016 Mar 1;11(3):878–84. doi: 10.3892/etm.2016.2989 26998006

88. Saluzzo S, Gorki AD, Rana BM, Martins R, Scanlon S, Starkl P, Lakovits K, Hladik A, Korosec A, Sharif O, Warszawska JM. First-breath-induced type 2 pathways shape the lung immune environment. Cell reports. 2017 Feb 21;18(8):1893–905. doi: 10.1016/j.celrep.2017.01.071 28228256

89. Bando Y, Hagiwara Y, Suzuki Y, Yoshida K, Aburakawa Y, Kimura T, Murakami C, Ono M, Tanaka T, Jiang YP, Mitrovi B. Kallikrein 6 secreted by oligodendrocytes regulates the progression of experimental autoimmune encephalomyelitis. Glia. 2018 Feb;66(2):359–78. doi: 10.1002/glia.23249 29086442

90. Chang CT, Lin H, Ho TY, Li CC, Lo HY, Wu SL, Huang YF, Liang JA, Hsiang CY. Comprehensive assessment of host responses to ionizing radiation by nuclear factor-κB bioluminescence imaging-guided transcriptomic analysis. PloS one. 2011 Aug 24;6(8):e23682. doi: 10.1371/journal.pone.0023682 21887294

91. Davis MJ, Tsang TM, Qiu Y, Dayrit JK, Freij JB, Huffnagle GB, Olszewski MA. Macrophage M1/M2 polarization dynamically adapts to changes in cytokine microenvironments in Cryptococcus neoformans infection. MBio. 2013 Jul 1;4(3):e00264–13. doi: 10.1128/mBio.00264-13 23781069