title: Topical resiquimod protects against visceral infection with Leishmania infantum chagasi in mice.
abstract: New prevention and treatment strategies are needed for visceral leishmaniasis, particularly ones that can be deployed simply and inexpensively in areas where leishmaniasis is endemic. Synthetic molecules that activate Toll-like receptor 7 and 8 (TLR7/8) pathways have previously been demonstrated to enhance protection against cutaneous leishmaniasis. We initially sought to determine whether the TLR7/8-activating molecule resiquimod might serve as an effective vaccine adjuvant targeting visceral leishmaniasis caused by infection with Leishmania infantum chagasi. Resiquimod was topically applied to the skin of mice either prior to or after systemic infection with L. infantum chagasi, and parasite burdens were assessed. Surprisingly, topical resiquimod application alone, in the absence of vaccination, conferred robust resistance to mice against future intravenous challenge with virulent L. infantum chagasi. This protection against L. infantum chagasi infection persisted as long as 8 weeks after the final topical resiquimod treatment. In addition, in mice with existing infections, therapeutic treatment with topical resiquimod led to significantly lower visceral parasite loads. Resiquimod increased trafficking of leukocytes, including B cells, CD4(+) and CD8(+) T cells, dendritic cells, macrophages, and granulocytes, in livers and spleens, which are the key target organs of visceralizing infection. We conclude that topical resiquimod leads to systemic immune modulation and confers durable protection against visceralizing L. infantum chagasi infection, in both prophylactic and therapeutic settings. These studies support continued studies of TLR-modulating agents to determine mechanisms of protection and also provide a rationale for translational development of a critically needed, novel class of topical, preventative, and therapeutic agents for these lethal infections.
authors.affiliation: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Craft
authors.affiliation: Division of Dermatology, Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Birnbaum
authors.affiliation: Division of Dermatology, Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Quanquin
authors.affiliation: Division of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Marie Crisel B
authors.initials: MC
authors.lastname: Erfe
authors.affiliation: Division of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Cara
authors.initials: C
authors.lastname: Quant
authors.affiliation: Division of Dermatology, Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Haskell
authors.affiliation: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA Division of Molecular Medicine, Harbor-UCLA Medical Center, Torrance, California, USA David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA kbruhn@usc.edu.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Bruhn
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018890:Chemoprevention / Q000379:methods; D004195:Disease Models, Animal; D005260:Female; D006098:Granulocytes / Q000276:immunology; D007093:Imidazoles / Q000008:administration & dosage*; D007898:Leishmaniasis, Visceral / Q000517:prevention & control*; D008099:Liver / Q000276:immunology; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000276:immunology
chemical_list: D000981:Antiprotozoal Agents; D007093:Imidazoles; C402365:resiquimod