Abstract
BackgroundA wide spectrum of clinical manifestations and immune responses exist in canine L. infantum infection. Ibizan hounds are more “resistant” to disease than other dog breeds. Recognition of pathogen-associated molecule patterns by toll like receptors (TLRs) rapidly triggers a variety of anti-microbial immune responses through the induction of pro-inflammatory cytokines such as TNF-α and IL-6 which may play an important role in controlling Leishmania infection. The main objective of this study was to investigate and compare the effect of a TLR2 agonist (TLR2a) alone or in combination with L. infantum antigen (LSA) on ex vivo whole blood cytokine production from healthy seronegative IFN-γ non-producer dogs from an area of low in canine leishmaniosis endemicity (n = 11); sick seropositive dogs with low production of IFN-γ (n = 17) and healthy seronegative or low positive Ibizan hounds with a predominant IFN-γ production (n = 21) from a highly endemic area. Whole blood was stimulated with medium alone (Ø), LSA, concanavalin A, TLR2 (Pam3CSK4) receptor agonist (Ø + TLR2a) and TLR2a and LSA (LSA + TLR2a) for 48 h. Supernatants were harvested for measurement of canine TNF-α and IL-6 cytokines by ELISA.ResultsA significant increase of TNF-α was found in the supernatants of stimulated blood from all groups (Ø + TLR2a and LSA + TLR2a) when compared with medium alone. A similar pattern was observed for IL-6. Interestingly, a significant increase of TNF-α production was only observed when stimulation with LSA + TLR2a was compared with TLR2a alone in Ibizan hounds. A significant increase of TNF-α production was observed with stimulation of LSA + TLR2a when compared with LSA in all groups. Significantly higher concentrations of TNF-α and IL-6 were detected in Ibizan hounds, especially for the Ø + TLR2a and LSA + TLR2a treatments compared with other groups.ConclusionsThis study demonstrated that TLR2a alone enhances the production of the inflammatory cytokines TNF-α and IL-6 in sick, “resistant” and healthy non-infected dogs. In addition, a combination of LSA+TLR2a promoted a synergistic pro-inflammatory effect with TNF-α in Ibizan hounds but not in seropositive sick dogs and seronegative healthy dogs. These findings might suggest the importance of Pam3CSK4 as a possible immunomodulator for CanL.
Highlights
A wide spectrum of clinical manifestations and immune responses exist in canine L. infantum infection
This study demonstrated that TLR2 agonist (TLR2a) alone enhances the production of the inflammatory cytokines Tumor necrosis factor-alpha (TNF-α) and IL-6 in sick, “resistant” and healthy non-infected dogs
The diagnosis of Canine leishmaniosis (CanL) was made based on the results of the physical examination, a complete blood count using System Siemens Advia 120 (Siemens Healthcare GmbH, Germany), a biochemical profile including creatinine, urea, total proteins, ALT and total cholesterol measured by the Olympus Analyzer AU 400 (Olympus, Center Valley, USA), protein serum electrophoresis by Hydrasys® (Sebia Electrophoresis, Lisses, France), urinalysis with urinary protein/creatinine ratio (UPC) and quantitative serology for the detection of L. infantum-specific antibodies by means of a serial dilution in house Enzyme-linked immunosorbent assay (ELISA) [25]
Summary
A wide spectrum of clinical manifestations and immune responses exist in canine L. infantum infection. Canine leishmaniosis (CanL) due to L. infantum is a lifethreatening sand fly-borne zoonotic disease with a wide distribution in Central and South America, Asia, Africa and the Mediterranean basin regions [1]. Ibizan hounds appear to be more “resistant” than other more susceptible dog breeds and rarely develop clinical signs related with L. infantum infection [5,6,7]. This breed provides an interesting model to study the origin of this kind of apparently immunological resistance. Dog breeds that are predisposed to developing a disseminated infection and progressing towards clinical CanL are considered susceptible (e.g., Boxer, Cocker Spaniel, Rottweiler and German Shepherd) [7]
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