Abstract
Domestic dogs are the main reservoir of Leishmania infantum, a causative agent of visceral leishmaniasis (VL). The number of human disease cases is associated with the rate of canine infection. Currently available drugs are not efficient at treating canine leishmaniasis (CanL) and months after the treatment most dogs show disease relapse, therefore the development of new drugs or new therapeutic strategies should be sought. In CanL, dogs lack the ability to mount a specific cellular immune response suitable for combating the parasite and manipulation of cytokine signaling pathway has the potential to form part of effective immunotherapeutic methods. In this study, recombinant canine cytokines (rcaIL-12, rcaIL-2, rcaIL-15 and rcaIL-7) and soluble receptor IL-10R1 (rcasIL-10R1), with antagonistic activity, were evaluated for the first time in combination (rcaIL-12/rcaIL-2, rcaIL-12/rcaIL-15, rcaIL-12/rcasIL-10R1, rcaIL-15/rcaIL-7) or alone (rcasIL-10R1) to evaluate their immunomodulatory capacity in peripheral blood mononuclear cells (PBMCs) from dogs with leishmaniasis. All the combinations of recombinant proteins tested were shown to improve lymphoproliferative response. Further, the combinations rcaIL-12/rcaIL-2 and rcaIL-12/rcaIL-15 promoted a decrease in programmed cell death protein 1 (PD-1) expression in lymphocytes. These same combinations of cytokines and rcaIL-12/rcasIL-10R1 induced IFN-γ and TNF-α production in PBMCs. Furthermore, the combination IL-12/IL-15 led to an increased in T-bet expression in lymphocytes. These findings are encouraging and indicate the use of rcaIL-12 and rcaIL-15 in future in vivo studies aimed at achieving polarization of cellular immune responses in dogs with leishmaniasis, which may contribute to the development of an effective treatment against CanL.
Highlights
The zoonotic form of visceral leishmaniasis (VL) is caused by the obligate intracellular protozoan Leishmania infantum
Dogs are the main reservoir of Leishmania infantum, a protozoan parasite that causes lethal systemic disease in human beings (Visceral Leishmaniasis, VL) and dogs (Canine Leishmaniasis, canine leishmaniasis (CanL))
The findings reported here are encouraging and indicate the use of a combination of two recombinant cytokines in future immunotherapeutic trials for CanL
Summary
The zoonotic form of visceral leishmaniasis (VL) is caused by the obligate intracellular protozoan Leishmania infantum VL is the most severe form of leishmaniasis and is fatal in 95% of untreated cases [3]. VL is distributed worldwide, occurring mainly in tropical and subtropical regions with approximately 300.000 new infections each year and an estimated 20.000 to 50.000 deaths [4]. Domestic dogs are considered the main reservoir of the parasite in urban areas [5]. There is a correlation between the prevalence of seropositive dogs and number of human cases of VL [6,7,8], suggesting that controlling infection and/or disease in dogs (CanL) could contribute to effectively curbing human disease [8]
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