Degree Type

Dissertation

Date of Award

2013

Degree Name

Doctor of Philosophy

Department

Veterinary Pathology

Major

Immunobiology

First Advisor

Christine A. Petersen

Abstract

Visceral leishmaniasis (VL) caused by certain species of the genus Leishmania results in a significant disease burden worldwide. This is most pronounced in some of the world's poorest communities. In South America and the Mediterranean basin, dogs are the major domestic reservoir for Leishmania infantum, one cause of human VL. In addition, dogs infected with L. infantum have an immune response and pathophysiology similar to human cases, making them a representative naturally-occurring animal model of VL. Chronic infection with Leishmania infantum can result in asymptomatic infection for a long period of time or symptomatic, potentially life-threatening visceralizing disease. Immunopathology that contributes to the precipitation of clinical disease during natural infection is incompletely understood. The goal of the research presented in this thesis was to evaluate immunopathology potentially contributing to the onset of symptomatic VL and to evaluate a potential candidate for canine vaccination against Leishmania infantum. Using a prospective cohort of dogs naturally infected with L. infantum, we identified the presence of both CD4+ and CD8+ T cell exhaustion during symptomatic VL, mediated through coinhibitory receptor Programmed Death 1 (PD-1). Blockage of the interaction of PD-1 and one of it's ligands, B7 homolog 1 (B7.H1), partially recovered proliferation and IFNγ production in both CD4+ and CD8+ T cells. Furthermore, the blockage of PD-1/B7.H1 improved superoxide production in canine monocyte-derived phagocytes, and resulted in improved parasite clearance from peripheral blood after 7 days of culture. This data significantly contributes to knowledge of immunopathology during VL. In dogs with Leishmania-associated glomerulopathy, we evaluated glomerular lesions, describing the occurrence of type I membranoproliferative glomerulonephritis, with expansion of the mesangium and podocyte retraction with mesangial cell interposition. These lesions were associated with glomerular deposits containing L. infantum antigen, IgG, and to a lesser extent, complement protein C3. Symptomatic disease was associated with increased glomerular Nod-like receptor protein 3 (NLRP3) and increased positivity for autophagy marker Microtubule-associated protein light chain 3 (LC3). This research expands the characterization of Leishmania-associated glomerulonephropathy, and the presence of inflammasome activation and autophagy during immune complex glomerulonephritis. The final chapter of this thesis evaluates a vaccine candidate for prevention of canine leishmaniasis. This research demonstrates the immunogenicity of this vaccine candidate after administration. As a whole, the work in this thesis is a significant advancement of the understanding of the pathophysiology and immunopathology of canine infection with Leishmania infantum with potential correlates to human VL, and a report of the immunogenicity of a potential canine leishmaniasis vaccine.

Copyright Owner

Kevin Jan Esch

Language

en

File Format

application/pdf

File Size

161 pages

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