title: Local Delivery of the Toll-Like Receptor 9 Ligand CpG Downregulates Host Immune and Inflammatory Responses, Ameliorating Established Leishmania (Viannia) panamensis Chronic Infection.
abstract: Infection byLeishmania(Viannia)panamensis, the predominant etiologic agent for cutaneous leishmaniasis in Colombia, is characterized by a chronic mixed inflammatory response. Current treatment options are plagued by toxicity, lengthy treatment regimens, and growing evidence of drug resistance. Immunotherapy, modulating the immune system to mount a protective response, may provide an alternate therapeutic approach. We investigated the ability of the Toll-like receptor 9 (TLR9) ligand CpG to modulate established disease in theL(V)panamensismouse model. Treatment of established infection with a high dose (50 μg) of CpG ameliorated disease and lowered parasite burden. Interestingly, immediately after treatment there was a significant increase in transforming growth factor β (TGF-β) and concomitantly an increase in T regulatory cell (Treg) function. Although a general reduction in cell-mediated immune cytokine and chemokine (gamma interferon [IFN-γ], interleukin 10 [IL-10], IL-13, IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-4, and MIP-1α) responses of the treated mice was observed, certain chemokines (RANTES, monocyte chemoattractant protein 1[MCP-1], and IP-10) were increased. Further, in peripheral blood mononuclear cells (PBMCs) from patients with cutaneous leishmaniasis, CpG treatment similarly exhibited a dose-response effect on the production of IFN-γ, IL-17, IL-10, and IL-13, with reductions observed at higher doses. To further understand the underlying mechanisms and cell populations driving the CpG mediated response, we examined theex vivodose effects mediated by the TLR9+cell populations (dendritic cells, macrophages, and B cells) found to accumulate labeled CpGin vivoNotably, B cells altered the production of IL-17, IL-13, and IFN-γ, supporting a role for B cells functioning as antigen-presenting cells (APCs) and/or regulatory cells during infection. Interestingly, B cells have been previously demonstrated as a primary type of APC in patients infected withL(V)panamensisand thus may be useful targets of immunotherapy. Collectively, our results show that CpG-induced immune regulation leads to a dampening of the host immune response and healing in the mouse model, and it may provide an alternate approach to treatment of cutaneous leishmaniasis caused byL(V)panamensis.
authors.affiliation: Yale University School of Public Health, New Haven, Connecticut, USA allisonk.ehrlich@gmail.com.
authors.forename: Allison K
authors.initials: AK
authors.lastname: Ehrlich
authors.affiliation: Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia.
authors.forename: Olga L
authors.initials: OL
authors.lastname: Fernández
authors.affiliation: Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia.|Facultad de Medicina, Facultad de Ciencias de la Salud, Universidad de las Américas, Quito, Ecuador.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rodriguez-Pinto
authors.affiliation: Yale University School of Public Health, New Haven, Connecticut, USA.
authors.forename: Tiago M
authors.initials: TM
authors.lastname: Castilho
authors.affiliation: Department of Animal Health, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Corral Caridad
authors.affiliation: Yale University School of Public Health, New Haven, Connecticut, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Goldsmith-Pestana
authors.affiliation: Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia.
authors.forename: Nancy Gore
authors.initials: NG
authors.lastname: Saravia
authors.affiliation: Yale University School of Public Health, New Haven, Connecticut, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: McMahon-Pratt
mesh_terms: D000328:Adult; D000818:Animals; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D056747:Immunomodulation; D018334:Leishmania guyanensis / Q000276:immunology*; D007897:Leishmaniasis, Mucocutaneous / Q000276:immunology* / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology; D008024:Ligands; D008297:Male; D051379:Mice; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000378:metabolism*; D059208:Parasite Load; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D055815:Young Adult
chemical_list: D016207:Cytokines; D008024:Ligands; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9
keywords: CpG; Leishmania; Treg; immunomodulation; inflammation