Interleukin 6 and interferon gamma haplotypes are related to cytokine serum levels in dogs in an endemic Leishmania infantum region

Abstract

Background The Ibizan Hound is a canine breed native to the Mediterranean region, where leishmaniasis is an endemic zoonosis. Several studies indicate a low prevalence of this disease in Ibizan Hound dogs, whereas other canine breeds present a high prevalence. However, the underlying molecular mechanisms still remain unknown. The aim of this work is to analyse the relationship between serum levels of cytokines and the genomic profiles in two canine breeds, Ibizan Hound (resistant canine breed model) and Boxer (susceptible canine breed model). Methods In this study, we analyse the haplotypes of genes encoding cytokines related to immune response of Leishmania infantum infection in twenty-four Boxers and twenty-eight Ibizan Hounds apparently healthy using CanineHD DNA Analysis BeadChip including 165,480 mapped positions. The haplo.glm extension of haplo.score was used to perform a General Linear Model (GLM) regression to estimate the magnitude of individual haplotype effects within each cytokine. Results Mean levels of interferon gamma (IFN-γ), interleukin 2 (IL-2) and IL-18 in Boxer dogs were 0.19 ± 0.05 ng/ml, 46.70 ± 4.54 ng/ml, and 36.37 ± 30.59 pg/ml, whereas Ibizan Hound dogs present 0.49 ± 0.05 ng/ml, 64.55 ± 4.54 ng/ml, and 492.10 ± 31.18 pg/ml, respectively. The GLM regression shows fifteen haplotypes with statistically significant effect on the cytokine serum levels (P < 0.05). The more relevant are IL6-CGAAG and IFNG-GCA haplotypes, which increase and decrease the IL-2, IL-8 and IFN-γ serum levels, respectively. Conclusions Haplotypes in the IFNG and IL6 genes have been correlated to serum levels of IFN-γ, IL-2 and IL-18, and a moderate effect has been found on IL8 haplotype correlated to IL-8 and IL-18 serum levels. The results indicate that the resistance to L. infantum infection could be a consequence of certain haplotypes with a high frequency in the Ibizan Hound dog breed, while susceptibility to the disease would be related to other specific haplotypes, with high frequency in Boxer. Future studies are needed to elucidate whether these differences and haplotypes are related to different phenotypes in immune response and expression gene regulation to L. infantum infections in dogs and their possible application in new treatments and vaccines. Graphical Abstract

Effect of Breed on Hematological and Biochemical Parameters of Apparently Healthy Dogs Infected with Zoonotic Pathogens Endemic to the Mediterranean Basin

“…The cell membrane receptor of IFN-γ in macrophages stimulates the JAK-STA-1 pathway [ 69 ], and the activation of macrophages via IFN-γ regulates positively MHC II, increases ROS and NOS production, and induces autophagy for intracellular pathogens’ elimination [ 70 ]. In fact, high serum levels of IFN-γ and haplotypes in genes encoding this cytokine have been related to resistance to L. infantum infection in Ibizan hound dogs [ 71 , 72 ]. No studies have been conducted in Cirneco dell’Etna dogs related to cytokines serum levels, immune response, and resistance to intracellular infection.…”

An integrated analysis of the structural changes and gene expression of spleen in human visceral leishmaniasis with and without HIV coinfection

“…It showed high expression of genes from IL6 signaling pathway ( JAK1 , JAK2 and PRDM1 ), and a high density of IL6-producing cells in the RP and the WP, differing from organized spleen, suggesting that this pathway can also be involved in spleen disorganization. IL6 is involved in the induction of inflammatory processes and is found at high levels in plasma of humans and dogs infected with Leishmania infantum [ 29 – 31 ]. The IL6 levels have been proposed as a biomarker of prognosis and death in VL [ 13 , 32 ].…”

An integrated analysis of the structural changes and gene expression of spleen in human visceral leishmaniasis with and without HIV coinfection

“…It showed high expression of genes from IL6 signaling pathway (JAK1, JAK2 and PRDM1), and a high density of IL6-producing cells in the RP, differing from organized spleen, suggesting that this pathway can also be involved in spleen disorganization. IL6 is involved in the induction of inflammatory processes and is found at high levels in plasma of humans and dogs infected with Leishmania infantum (29)(30)(31). The IL6 levels have been proposed as a biomarker of prognosis and death in VL (13,32).…”