|Utsunomiya, Y - Collaborator|
|Ribeiro, E - Collaborator|
|Quintal, A - Collaborator|
|Sangalli, J - Collaborator|
|Gazola, V - Collaborator|
|Paula, H - Collaborator|
|Trinconi, C - Collaborator|
|Lima, V - Collaborator|
|Perri, S - Collaborator|
|Taylor, J - University Of Missouri|
|Schnabel, R - University Of Missouri|
|Sonstegard, T - Former ARS Employee|
|Garcia, J - Collaborator|
|Nunes, C - Collaborator|
Submitted to: PLoS One
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/7/2015
Publication Date: 9/8/2015
Citation: Utsunomiya, Y.T., Ribeiro, E.S., Quintal, A.P., Sangalli, J.R., Gazola, V.R., Paula, H.B., Trinconi, C.M., Lima, V.M., Perri, S.H., Taylor, J.F., Schnabel, R.D., Sonstegard, T.S., Garcia, J.F., Nunes, C.M. 2015. Genome-wide scan for visceral leishmaniasis in mixed-breed dogs identifies candidate genes involved in T helper cells and macrophage signaling. PLoS One. 10(9):e0136749.
Interpretive Summary: Visceral leishmaniasis (VL), also known as black fever, is a neglected parasitic tropical disease that inflicts approximately 500,000 people yearly. Dogs have been reported to be susceptible to VR and as such serve as the main urban reservoir and also a means to understand the host-parasite genetic interaction. Genetic markers were used to scan the genomes of 20 infected and 28 healthy dogs from a highly endemic area in Brazil to identify genes associated with susceptibility to VL. We identified two candidate regions on dog chromosomes 1 and 2 located near genes implicated in T helper cell immune function.. The results of this study suggest the protective response against VL in dogs is mechanistically similar to that in humans. More detailed studies of these regions may lead to the idenitifcation of specific variants applicable to human health.
Technical Abstract: We conducted a genome-wide scan for visceral leishmaniasis in mixed-breed dogs from a highly endemic area in Brazil using 149,648 single nucleotide polymorphism (SNP) markers genotyped in 20 cases and 28 controls. Using a mixed model approach, we found two candidate loci on canine autosomes 1 and 2. The positional association on chromosome 2 mapped to a predicted DNAse sensitive site in CD14+ monocytes that serve as a cis-regulatory element for the expression of interleukin alpha receptors 2 (IL2RA) and 15 (IL15RA). Both interleukins were previously found to lead to protective T helper 1 cell (Th1) response against Leishmania spp. in humans and mice. The associated marker on chromosome 1 was located between two predicted transcription factor binding sites regulating the expression of the transducin-like enhancer of split 1 gene (TLE1), an important player in Notch signaling. This pathway is critical for macrophage activity and CD4+ T cell differentiation into Th1 and T helper 2. Together, these findings suggest that the human and mouse model for protective response against Leishmania spp., which involves Th1 and macrophage modulation by interleukins 2, 15, gamma interferon and Notch signaling, may also hold for the canine model.