Abstract
BackgroundThe development of cost-effective prophylactic strategies to prevent leishmaniasis has become a high-priority. The present study has used the phage display technology to identify new immunogens, which were evaluated as vaccines in the murine model of visceral leishmaniasis (VL). Epitope-based immunogens, represented by phage-fused peptides that mimic Leishmania infantum antigens, were selected according to their affinity to antibodies from asymptomatic and symptomatic VL dogs' sera.Methodology/Main FindingsTwenty phage clones were selected after three selection cycles, and were evaluated by means of in vitro assays of the immune stimulation of spleen cells derived from naive and chronically infected with L. infantum BALB/c mice. Clones that were able to induce specific Th1 immune response, represented by high levels of IFN-γ and low levels of IL-4 were selected, and based on their selectivity and specificity, two clones, namely B10 and C01, were further employed in the vaccination protocols. BALB/c mice vaccinated with clones plus saponin showed both a high and specific production of IFN-γ, IL-12, and GM-CSF after in vitro stimulation with individual clones or L. infantum extracts. Additionally, these animals, when compared to control groups (saline, saponin, wild-type phage plus saponin, or non-relevant phage clone plus saponin), showed significant reductions in the parasite burden in the liver, spleen, bone marrow, and paws' draining lymph nodes. Protection was associated with an IL-12-dependent production of IFN-γ, mainly by CD8+ T cells, against parasite proteins. These animals also presented decreased parasite-mediated IL-4 and IL-10 responses, and increased levels of parasite-specific IgG2a antibodies.Conclusions/SignificanceThis study describes two phage clones that mimic L. infantum antigens, which were directly used as immunogens in vaccines and presented Th1-type immune responses, and that significantly reduced the parasite burden. This is the first study that describes phage-displayed peptides as successful immunogens in vaccine formulations against VL.
Highlights
Leishmaniasis is a disease with a wide spectrum of clinical manifestations caused by different species of protozoa belonging to the Leishmania genus [1]
A positive selection process was performed, by recovering the phage clones that were recognized by antibodies present in the sera samples of dogs with asymptomatic and symptomatic visceral leishmaniasis (VL)
Phage display was applied to the identification of antigens based on phage clones that could be evaluated in murine models, such as vaccines against VL
Summary
Leishmaniasis is a disease with a wide spectrum of clinical manifestations caused by different species of protozoa belonging to the Leishmania genus [1]. Canine visceral leishmaniasis (CVL) due to Leishmania infantum is a major global zoonosis that is potentially fatal to dogs [4] This disease can be found in Southern Europe, Africa, Asia, and Central and South America; and is endemic in approximately 70 countries worldwide [5]. CVL is expanding its geographic distribution throughout the Western hemisphere, where it occurs from northern Argentina to the United States [6], even reaching as far as provinces of southern Canada [7] This disease is an important concern in nonendemic countries, where imported sick or infected dogs constitute a veterinary and public health problem [6,7]. Epitope-based immunogens, represented by phage-fused peptides that mimic Leishmania infantum antigens, were selected according to their affinity to antibodies from asymptomatic and symptomatic VL dogs’ sera
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