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.