title: Chronicity of dermal leishmaniasis caused by Leishmania panamensis is associated with parasite-mediated induction of chemokine gene expression.
abstract: Chronic tegumentary leishmaniasis is characterized by a scarcity of parasites in lesions and a heightened inflammatory response. Deregulated and hyperactive inflammation contributes to tissue damage and parasite persistence. The mechanisms by which immune cells are recruited to the lesion and their relationship to clinical outcomes remain elusive. We examined the expression levels of chemokines and their receptors in relation to clinical outcome in dermal leishmaniasis caused by Leishmania (Viannia) panamensis. Primary macrophages from healthy donors were infected with L. panamensis strains isolated from self-healing patients (n = 4) and those presenting chronic disease (n = 5). A consistent pattern of upregulation of neutrophil (cxcl1, cxcl2, cxcl5, and cxcl8/il-8) and monocyte (ccl2, ccl7, ccl8, cxcl3, and cxcl10) chemotactic chemokines and ccr1 and ccr5 receptor genes, evaluated by reverse transcription-quantitative PCR (qRT-PCR), was observed upon infection with strains from patients with chronic dermal leishmaniasis; induction of CXCL5 and CCL8 was corroborated at the protein level. No apparent upregulation was elicited in macrophages infected with strains from self-healing patients. Expression levels of ccl8, cxcl2, cxcl3, and cxcl5 in lesion biopsy specimens from patients with chronic cutaneous leishmaniasis (CL) were compared to those in biopsy specimens from Montenegro skin tests of individuals with asymptomatic infection. Increased expression levels of cxcl5 (P < 0.05), ccl8, and cxcl3 were corroborated in chronic CL lesions. Our study revealed a dichotomy in macrophage chemokine gene expression elicited by L. panamensis strains from patients with self-healing disease and those presenting chronic disease, consistent with parasite-mediated hyperactivation of the inflammatory response driving chronicity. The predominant upregulation of neutrophil and monocyte chemoattractants indicates novel mechanisms of sustained inflammatory activation and may provide new therapeutic targets against chronic dermal leishmaniasis.
authors.affiliation: Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia.
authors.forename: Adriana
authors.initials: A
authors.lastname: Navas
authors.affiliation: Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia.
authors.forename: Deninson Alejandro
authors.initials: DA
authors.lastname: Vargas
authors.affiliation: Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Freudzon
authors.affiliation: Yale School of Public Health, New Haven, Connecticut, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: McMahon-Pratt
authors.affiliation: Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia.
authors.forename: Nancy Gore
authors.initials: NG
authors.lastname: Saravia
authors.affiliation: Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia mgomez@cideim.org.co.
authors.forename: María Adelaida
authors.initials: MA
authors.lastname: Gómez
mesh_terms: D000328:Adult; D000368:Aged; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D002908:Chronic Disease; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007891:Leishmania / Q000145:classification* / Q000235:genetics; D016773:Leishmaniasis, Cutaneous / Q000378:metabolism* / Q000469:parasitology*; D007962:Leukocytes / Q000378:metabolism / Q000469:parasitology; D008264:Macrophages / Q000378:metabolism / Q000469:parasitology; D008297:Male; D008875:Middle Aged; D010802:Phylogeny; D055815:Young Adult
chemical_list: D018925:Chemokines
references.citation: J Immunol. 1985 Dec;135(6):4144-8
references.pmid: 4067312
references.citation: J Infect Dis. 1993 Sep;168(3):709-14
references.pmid: 8354913
references.citation: Trends Parasitol. 2009 Nov;25(11):505-10
references.pmid: 19762280
references.citation: Eur J Immunol. 2008 Apr;38(4):1071-81
references.pmid: 18383035
references.citation: Mol Immunol. 2014 Feb;57(2):74-85
references.pmid: 24084096
references.citation: Infect Immun. 2005 Feb;73(2):1191-5
references.pmid: 15664963
references.citation: J Infect Dis. 1989 Apr;159(4):725-35
references.pmid: 2647862
references.citation: Front Biosci (Landmark Ed). 2009 Jan 01;14:540-51
references.pmid: 19273084
references.citation: J Clin Invest. 2008 Feb;118(2):801-11
references.pmid: 18188454
references.citation: Infect Immun. 2002 Aug;70(8):4177-84
references.pmid: 12117926
references.citation: PLoS One. 2012;7(3):e33413
references.pmid: 22457760
references.citation: Exp Parasitol. 1996 Jan;82(1):21-6
references.pmid: 8617327
references.citation: PLoS One. 2012;7(11):e48727
references.pmid: 23144947
references.citation: Clin Infect Dis. 2000 Jul;31(1):199-201
references.pmid: 10913426
references.citation: J Immunol. 2007 Sep 15;179(6):3988-94
references.pmid: 17785837
references.citation: Infect Immun. 2003 Mar;71(3):1587-9
references.pmid: 12595483
references.citation: Infect Immun. 2004 Aug;72(8):4918-23
references.pmid: 15271961
references.citation: Eur J Immunol. 2000 Nov;30(11):3111-20
references.pmid: 11093125
references.citation: Mem Inst Oswaldo Cruz. 1988 Nov;83 Suppl 1:256-9
references.pmid: 3267029
references.citation: Science. 2008 Aug 15;321(5891):970-4
references.pmid: 18703742
references.citation: Parasite Immunol. 2007 Apr;29(4):211-7
references.pmid: 17371458
references.citation: J Clin Microbiol. 2009 Sep;47(9):2818-25
references.pmid: 19587302
references.citation: J Infect Dis. 1996 Mar;173(3):699-709
references.pmid: 8627035
references.citation: J Immunol. 2010 Aug 15;185(4):2360-71
references.pmid: 20624948
references.citation: J Infect Dis. 2002 Mar 1;185(5):673-81
references.pmid: 11865425
references.citation: Trends Parasitol. 2006 Jan;22(1):32-40
references.pmid: 16310413
references.citation: J Immunol. 1994 Feb 1;152(3):1265-76
references.pmid: 8301130
references.citation: Med Microbiol Immunol. 2001 Nov;190(1-2):73-6
references.pmid: 11770115
references.citation: J Infect Dis. 2006 May 15;193(10):1375-83
references.pmid: 16619185
references.citation: Clin Infect Dis. 2002 Jun 1;34(11):E54-8
references.pmid: 12015707
references.citation: Am J Trop Med Hyg. 1995 Sep;53(3):273-7
references.pmid: 7573712
references.citation: J Infect Dis. 2010 Aug 15;202(3):406-15
references.pmid: 20583921
references.citation: Exp Parasitol. 2010 Nov;126(3):389-96
references.pmid: 20206625
references.citation: Braz J Med Biol Res. 1998 Jan;31(1):143-8
references.pmid: 9686192
references.citation: J Immunol. 2009 Dec 15;183(12):8088-98
references.pmid: 19923470
references.citation: BMC Med Genet. 2010 Jan 20;11:10
references.pmid: 20089160
references.citation: J Parasitol. 1996 Jun;82(3):454-7
references.pmid: 8636852
references.citation: J Immunol. 2004 Dec 1;173(11):6521-5
references.pmid: 15557140
references.citation: Am J Dermatopathol. 1997 Dec;19(6):585-90
references.pmid: 9415615
references.citation: Infect Immun. 1994 Mar;62(3):837-42
references.pmid: 8112853
references.citation: Trends Parasitol. 2002 Aug;18(8):332-4
references.pmid: 12377273
references.citation: Clin Exp Immunol. 2006 Oct;146(1):124-32
references.pmid: 16968407
references.citation: BMC Genomics. 2008 May 21;9:238
references.pmid: 18495030
references.citation: Lancet. 2005 Oct 29-Nov 4;366(9496):1561-77
references.pmid: 16257344
references.citation: Crit Rev Microbiol. 2005;31(3):145-54
references.pmid: 16170905
references.citation: Biomedica. 2006 Oct;26 Suppl 1:38-48
references.pmid: 17361840
references.citation: Parasite Immunol. 2009 Aug;31(8):432-9
references.pmid: 19646207