The genetically determined production of the alarmin eosinophil-derived neurotoxin is reduced in visceral leishmaniasis
Kristin Blom
Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
Search for more papers by this authorAmir I. Elshafie
Department of Clinical Pathology and Microbiology, Alribat University Hospital, Khartoum, Sudan
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
Search for more papers by this authorUlla-Britt Jönsson
Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
Search for more papers by this authorJohan Rönnelid
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
Search for more papers by this authorLena Douhan Håkansson
Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
Search for more papers by this authorCorresponding Author
Per Venge
Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
Per Venge, Department of Medical Sciences, Clinical Chemistry, Uppsala University Hospital, Uppsala SE-751 85, Sweden. e-mail: [email protected]Search for more papers by this authorKristin Blom
Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
Search for more papers by this authorAmir I. Elshafie
Department of Clinical Pathology and Microbiology, Alribat University Hospital, Khartoum, Sudan
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
Search for more papers by this authorUlla-Britt Jönsson
Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
Search for more papers by this authorJohan Rönnelid
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
Search for more papers by this authorLena Douhan Håkansson
Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
Search for more papers by this authorCorresponding Author
Per Venge
Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
Per Venge, Department of Medical Sciences, Clinical Chemistry, Uppsala University Hospital, Uppsala SE-751 85, Sweden. e-mail: [email protected]Search for more papers by this authorAbstract
Visceral leishmaniasis (VL) is the most severe form of leishmaniasis. Recent findings indicate that dendritic cells have a key role in the defense against the Leishmania parasite and that the activity of this cell may be modified by the eosinophil secretory protein eosinophil-derived neurotoxin (EDN). We hypothesized that the interactions between dendritic cells and EDN might be of importance in the disease development. Cellular content of EDN was analyzed by ELISA. The single-nucleotide polymorphisms at positions 405, 416, and 1122 in the EDN gene were analyzed by real-time PCR with TaqMan® reagents. The study cohorts comprised 239 Sudanese subjects (65 healthy controls and 174 with VL) and 300 healthy Swedish controls. The eosinophil content of EDN was lower in VL as compared with controls (p < 0.0001). The EDN405 (G>C) genotype distribution was similar among Swedish and Sudanese controls, whereas VL subjects had a higher prevalence of the EDN405-GG genotype (p < 0.0001). The content of EDN in the eosinophils was closely linked to the EDN405 polymorphism (p = 0.0002). Our findings suggest that the predisposition to acquire VL is related to the genetic polymorphism of the EDN gene and the reduced production by the eosinophil of this gene product.
Supporting Information
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| apm12780-sup-0001-TableS1.docxWord document, 11.7 KB | Table S1. Primers and probes. |
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References
- 1Leishmaniasis Desjeux P. Public health aspects and control. Clin Dermatol 1996; 14: 417–23.
- 2Pearson RD, Sousa AQ. Clinical spectrum of Leishmaniasis. Clin Infect Dis 1996; 22: 1–13.
- 3Chappuis F, Sundar S, Hailu A, Ghalib H, Rijal S, Peeling RW, et al. Visceral leishmaniasis: what are the needs for diagnosis, treatment and control? Nat Rev Microbiol 2007; 5: 873–82.
- 4Silva ES, Gontijo CM, Pacheco RS, Fiuza VO, Brazil RP. Visceral leishmaniasis in the Metropolitan Region of Belo Horizonte, State of Minas Gerais, Brazil. Mem Inst Oswaldo Cruz 2001; 96: 285–91.
- 5Zijlstra EE, Musa AM, Khalil EA, el-Hassan IM, El-Hassan AM. Post-kala-azar dermal leishmaniasis. Lancet Infect Dis 2003; 3: 87–98.
- 6Zijlstra EE, Khalil EA, Kager PA, El-Hassan AM. Post-kala-azar dermal leishmaniasis in the Sudan: clinical presentation and differential diagnosis. Br J Dermatol 2000; 143: 136–43.
- 7Zijlstra EE, El-Hassan AM. Leishmaniasis in Sudan. Post kala-azar dermal leishmaniasis. Trans R Soc Trop Med Hyg 2001; 95(Suppl 1): S59–76.
- 8Zijlstra EE, El-Hassan AM. Leishmaniasis in Sudan. Visceral leishmaniasis. Trans R Soc Trop Med Hyg 2001; 95(Suppl 1): S27–58.
- 9Liu D, Uzonna JE. The early interaction of Leishmania with macrophages and dendritic cells and its influence on the host immune response. Front Cell Infect Microbiol 2012; 2: 83.
- 10McLaren DJ, Peterson CGB, Venge P. Schistosoma mansoni: further studies of the interaction between schistosomula and granulocyte-derived cationic proteins in vitro. Parasitology 1984; 88: 491–503.
- 11ElShafie AI, Hlin E, Håkansson LD, Elghazali G, Safi SH, Rönnelid J, et al. Activity and turnover of eosinophil and neutrophil granulocytes are altered in visceral leishmaniasis. Int J Parasitol 2011; 41: 463–9.
- 12Rodriguez NE, Wilson ME. Eosinophils and mast cells in leishmaniasis. Immunol Res 2014; 59: 129–41.
10.1007/s12026-014-8536-x Google Scholar
- 13Venge P, Bergstrand H, Håkansson L. Neutrophils and eosinophils. In: WN Kelley, ED Harris, S Ruddy, CB Sledge, editors. Textbook of Rheumatology, 5th ed. Philadelphia, PA: W.B. Saunders Company, 1996: 146–60.
- 14Peterson CGB, Venge P. Purification and characterization of a new cationic protein – eosinophil protein-x(EPX) – from granules of human eosinophils. Immunology 1983; 50: 19–26.
- 15Olsson I, Venge P. Cationic proteins of human granulocytes. II. Separation of the cationic proteins of the granules of leukemic myeloid cells. Blood 1974; 44: 235–46.
- 16Gullberg U, Widegren B, Arnason U, Egesten A, Olsson I. The cytotoxic eosinophil cationic protein (ECP) has ribonuclease activity. Biochem Biophys Res Commun 1986; 139: 1239–42.
- 17Venge P, Byström J, Carlson M, Håkansson L, Karawacjzyk M, Peterson C, et al. Eosinophil cationic protein (ECP): molecular and biological properties and the use of ECP as a marker of eosinophil activation in disease. Clin Exp Allergy 1999; 29: 1172–86.
- 18Byström J, Amin K, Bishop-Bailey D. Analysing the eosinophil cationic protein–a clue to the function of the eosinophil granulocyte. Respir Res 2011; 12: 10.
- 19Gleich GJ, Adolphson CR. The eosinophil leukocyte: structure and function. Adv Immunol 1986; 39: 177–253.
- 20McLaren DJ, McKean JR, Peterson CGB, Kay AB, Venge P. Cytotoxic effects of granulocyte proteins on schistosome parasites. In: P Venge, A Lindbom, editors. Inflammation Basic Mechanisms, Tissue Injuring Principles and Clinical Models, 1st ed. Stockholm: Almqvist & Wiksell International, 1985: 341–5.
- 21Yang D, Chen Q, Su SB, Zhang P, Kurosaka K, Caspi RR, et al. Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2-MyD88 signal pathway in dendritic cells and enhances Th2 immune responses. J Exp Med 2008; 205: 79–90.
- 22Hamann KJ, Ten RM, Loegering DA, Jenkins RB, Heise MT, Schad CR, et al. Structure and chromosome localization of the human eosinophil- derived neurotoxin and eosinophil cationic protein genes: evidence for intronless coding sequences in the ribonuclease gene superfamily. Genomics 1990; 7: 535–46.
- 23Blom K, Rubin J, Halfvarson J, Torkvist L, Rönnblom A, Sangfelt P, et al. Eosinophil associated genes in the inflammatory bowel disease 4 region: correlation to inflammatory bowel disease revealed. World J Gastroenterol 2012; 18: 6409–19.
- 24ElShafie AI, Åhlin E, Mathsson L, Elghazali G, Rönnelid J. Circulating immune complexes (IC) and IC-induced levels of GM-CSF are increased in sudanese patients with acute visceral Leishmania donovani infection undergoing sodium stibogluconate treatment: implications for disease pathogenesis. J Immunol 2007; 178: 5383–9.
- 25Jönsson UB, Byström J, Stålenheim G, Venge P. A (G->C) transversion in the 3′ UTR of the human ECP (eosinophil cationic protein) gene correlates to the cellular content of ECP. J Leukoc Biol 2006; 79: 846–51.
- 26Livak KJ. Allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Genet Anal 1999; 14: 143–9.
- 27Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–5.
- 28Mejia JS, Toot-Zimmer AL, Schultheiss PC, Beaty BJ, Titus RG. BluePort: a platform to study the eosinophilic response of mice to the bite of a vector of Leishmania parasites, Lutzomyia longipalpis sand flies. PLoS ONE 2010; 5: e13546.
10.1371/journal.pone.0013546 Google Scholar
- 29Liu YJ, Kanzler H, Soumelis V, Gilliet M. Dendritic cell lineage, plasticity and cross-regulation. Nat Immunol 2001; 2: 585–9.
- 30Antoine JC, Prina E, Courret N, Lang T. Leishmania spp.: on the interactions they establish with antigen-presenting cells of their mammalian hosts. Adv Parasitol 2004; 58: 1–68.
- 31Alexander J, Bryson K. T helper (h)1/Th2 and Leishmania: paradox rather than paradigm. Immunol Lett 2005; 99: 17–23.
- 32Yang D, Rosenberg HF, Chen Q, Dyer KD, Kurosaka K, Oppenheim JJ. Eosinophil-derived neurotoxin (EDN), an antimicrobial protein with chemotactic activities for dendritic cells. Blood 2003; 102: 3396–403.
- 33Yang D, Chen Q, Rosenberg HF, Rybak SM, Newton DL, Wang ZY, et al. Human ribonuclease A superfamily members, eosinophil-derived neurotoxin and pancreatic ribonuclease, induce dendritic cell maturation and activation. J Immunol 2004; 173: 6134–42.
- 34Revest M, Donaghy L, Cabillic F, Guiguen C, Gangneux JP. Comparison of the immunomodulatory effects of L. donovani and L. major excreted-secreted antigens, particulate and soluble extracts and viable parasites on human dendritic cells. Vaccine 2008; 26: 6119–23.
- 35Maroof A, Kaye PM. Temporal regulation of interleukin-12p70 (IL-12p70) and IL-12-related cytokines in splenic dendritic cell subsets during Leishmania donovani infection. Infect Immun 2008; 76: 239–49.
- 36Bersudsky M, Apte RN, El-On J. Interleukin 1alpha activity of peritoneal and bone marrow macrophages infected with Leishmania major and Leishmania donovani in vitro. Exp Parasitol 2000; 94: 150–7.
- 37Dermine JF, Scianimanico S, Prive C, Descoteaux A, Desjardins M. Leishmania promastigotes require lipophosphoglycan to actively modulate the fusion properties of phagosomes at an early step of phagocytosis. Cell Microbiol 2000; 2: 115–26.
- 38Prive C, Descoteaux A. Leishmania donovani promastigotes evade the activation of mitogen-activated protein kinases p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase-1/2 during infection of naive macrophages. Eur J Immunol 2000; 30: 2235–44.
- 39Becker I, Salaiza N, Aguirre M, Delgado J, Carrillo-Carrasco N, Kobeh LG, et al. Leishmania lipophosphoglycan (LPG) activates NK cells through toll-like receptor-2. Mol Biochem Parasitol 2003; 130: 65–74.
- 40De TC, Brait M, Leo O, Aebischer T, Torrentera FA, Carlier Y, et al. Myd88-dependent in vivo maturation of splenic dendritic cells induced by Leishmania donovani and other Leishmania species. Infect Immun 2004; 72: 824–32.
- 41Flandin JF, Chano F, Descoteaux A. RNA interference reveals a role for TLR2 and TLR3 in the recognition of Leishmania donovani promastigotes by interferon-gamma-primed macrophages. Eur J Immunol 2006; 36: 411–20.
