Local Delivery of the Toll-Like Receptor 9 Ligand CpG Downregulates Host Immune and Inflammatory Responses, Ameliorating Established Leishmania (Viannia) panamensis Chronic Infection

• Published in: Infection and immunity Vol. 85; no. 3
• Main Authors: Ehrlich, Allison K, Fernández, Olga L, Rodriguez-Pinto, Daniel, Castilho, Tiago M, Corral Caridad, Maria J, Goldsmith-Pestana, Karen, Saravia, Nancy Gore, McMahon-Pratt, Diane
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01-03-2017
• Subjects: Adult; Animals; Chronic Disease; Cytokines - metabolism; Female; Fungal and Parasitic Infections; Humans; Immunomodulation; Leishmania guyanensis - immunology; Leishmaniasis, Mucocutaneous - immunology; Leishmaniasis, Mucocutaneous - metabolism; Leishmaniasis, Mucocutaneous - parasitology; Leishmaniasis, Mucocutaneous - pathology; Ligands; Male; Mice; Middle Aged; Oligodeoxyribonucleotides - metabolism; Parasite Load; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Toll-Like Receptor 9 - metabolism; Young Adult; immunomodulation; CpG; inflammation; Leishmania; Treg
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00981-16

Infection by
(
)
, 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 the
(
)
mouse 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 the
dose effects mediated by the TLR9
cell populations (dendritic cells, macrophages, and B cells) found to accumulate labeled CpG
Notably, 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 with
(
)
and 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 by
(
)
.