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Host-parasite relationship in canine visceral leishmaniasis (L.infantum /L. chagasi): Development and validation of the dog model

Objective

* To define the kinetics and characteristics of infection, immune response and clinical evolution of Leishmania infantum infection in the dog, the main reservoir of visceral leishmaniasis.

* To describe the natural history of canine leishmaniasis in inbred dogs, with emphasis on the prepatent period

* To develop reagents that may have prognostic value.

* To develop a model useful for future immunoprophylactic and therapeutic studies and to establish a reproducible infection protocol that results in consistent parasitological, immunological and clinical patterns.

* To compare and validate the experimental model with natural infection in endemic areas (New and Old World). Validate the experimental model by comparing clinical, immunological and parasitological data of asymptomatic dogs (defined by parasite burden, and biochemical analysis) from endemic areas in Colombia and Spain.
Expected Outcome

* A better understanding of the infection on the basis of correlating the immunobiology, clinical and epidemiological features.
* Practical recommendations will result from this project in terms of risk for humans and control measures through a better understanding of the natural history of canine leishmaniasis.
* Moreover, the response to defined antigens will establish the immunological basis for further projects related to vaccine development or for drug/immunological synergy.
* Finally, several reagents are expected to be obtained for both diagnosis and cytokine detection, that will be of value for the scientific community.
The natural history of canine leishmaniasis in inbred dogs will be investigated with emphasis on the prepatent period by:

* Clinical analysis including analytical biochemistry and blood cell count.
* Measurement of systemic and cutaneous cell-mediated responses by studying immunocytochemical characterization of the first and second signals of lymphocyte activation. Cytokines will be measured and the specific response to defined antigens will be studied and T-cell subsets established.
* Investigation of the immunostimulatory and effector roles of dendritic cells in a canine model of visceral leishmaniasis.
* Measurement of antibody isotype responses in particular IgM, IgG and IgE
* Parasite burden and parasite distribution will be established by direct microscopy, by culture in NNN and by PCR.
* Infectivity for sandflies (epidemiological risk) will be assessed at different time points by Xenodiagnosis with Phlebotomus perniciosus or Lutzomyia longipalpis and asymptomatic and symptomatic dogs from endemic areas (Spain and Colombia).

Reagents that may have prognostic value including PCR primers for IL-4, IL-10, IL-12, and TGF-( will be developed together with a quantitative PCR of genomic DNA for determining parasite burden.

Additional work will attempt to develop a model useful for future immunoprophylactic and therapeutic studies with the aim of establishing a reproducible infection protocol that results in consistent parasitological, immunological and clinical patterns. The experimental model will be validated with natural infection in endemic areas (New and Old World) by comparing clinical, immunological and parasitological data of asymptomatic dogs (defined by parasite burden, and biochemical analysis) from endemic areas in Colombia and Spain.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Instituto de Salud 'Carlos III'
Address
Km.2,carretera De Majadahonda A Pozuelo
28220 Madrid
Spain

Participants (4)

CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS
Spain
Address
144,Velazquez 144
28006 Madrid
Centro Internacional de Entrenamientoe Investigaciones Medicas
Colombia
Address
3-03,Avenida L Norte
0344406 Cali - Valle
Universidad Central de Venezuela
Venezuela
Address
4042,Patdo.
1010 A Caracas
University of Cambridge
United Kingdom
Address
Tennis Court Road
CB2 1QP Cambridge