Identification of genetic markers associated to clinical, antibody and cellmediated reponses to natural Leishmania (Leishmania) infantum infection in dogs

Author(s)

Luís Fábio da Silva Batista

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina Veterinária e Zootecnia (FMVZ/SBD)
• Defense date: 2016-03-22

Examining board members

Marcia Dalastra Laurenti; Paulo César Maiorka; Claudia Momo; Luiz Felipe Domingues Passero; Nancy Starobinas

• Advisor: Marcia Dalastra Laurenti

Abstract

Leishmania (Leishmania) infantum infection in dogs leads to a range of immunopathological responses, which depend on a parasite - host interaction and are defined by environmental factors and genetic of host. Neverthless, immunogenetic of the canine leishmaniasis (CanL) remains unexplored. We performed diagnosis and clinical evaluation, lymphoproliferation assay (LPA), leishmanin skin test (LST), quantification of cytokine, anti-L. (L. ) infantum IgA, IgE, IgG, IgM, anti- sandfly saliva IgG levels and genome wide association scan of 110.165 SNPs (GWAS) in order to indentify loci associated to clinical, antibody, cell-mediated responses and status of infection in 189 dogs, employng a expedited efficient mix model of association (EMMAX). Control of stratification effects due to sample structure was evideced by the low inflation factors. Status of infection was associated to SNPs in linkage desequilibrium (LD) with PRGR_CANFA, RAB38, NOX4, PRKCI and in the neighborhood of SMAD7, IL1RA, IL12A_CANFA genes related to phagocyte maturation, killing of pathogens and proinflamatory response; clinical outcome was associated to CATA_CANFA, LIAS, IL17A, IL17F loci involved in prevention of oxidative burst mediated injury and proinflamatory response; LST+ was associated to Th1 response although it has not prevented symptoms, whereas LST- was associated to Treg response and enhanced parasite load. Overall, LST response was associated to MEP1B, PTPRM, TLN1, TGFBR1, ITGA9, EPCAM e CALM1 loci committed to phagocyte maturation, leukocyte adhesion and migration, stability in immunological synapse, lymphocyte diferenciation and proliferation. Lymphocyte proliferation was rely on parasit burden and associated to FOCAD, PIAS2 loci in the neighborhood of SMAD2 e IL6R genes, wich are implicated in tumor supression and Treg/Th17 decision; Increased levels of anti-L. (L. ) infantum IgA, IgE, IgG were observed in severity of CanL. In contrast, anti- sandfly saliva IgG was enhenced in asymptomatic dogs. IgM response was associated to NXN e SH3BP5 loci related to fate, growing and activation of B cells; anti-L. (L. ) infantum IgG levels was associated to region containing IL17RB, SH2B3 and replication of NOX4, RAB38, CTSC suscptibility loci involved in proinflamatory response, microbicidal activity, lymphopoiesis and cytokinesis; IgA levels were associated to SNPs on LIN28A and MAFB, wich are implicated glomerular nephropathy, whereas anti-sandfly saliva IgG levels were associated to ERBB2IP, CD180, RAB7A_CANFA, FOXP1, RUNX1, SOD1, Q3HTU8_CANFA, IFNAR1, IFNAR2 e IFNGR2 loci, wich are related to supression of inflamation, antibody response through the TLR4 pathway and survival of intracellular pathogens. These findins provide insights for responses to L. (L. ) infantum infection and point to potential targets for functional investigations, therapeutic and prophylactic strategies (AU)

• FAPESP's process: 12/05847-9 - Clinical, immunological evaluation and their correlation with genetic markers in canine visceral leishmaniasis
• Grantee: Luís Fábio da Silva Batista
• Support Opportunities: Scholarships in Brazil - Doctorate