Experimental challenge models for canine leishmaniasis in hamsters and dogs, optimization and application in vaccine research

Abstract

In dogs, leishmaniasis caused by the protozoan parasite Leishmania infantum is a serious and potentially fatal disease. This parasite can also cause zoonotic visceral leishmaniasis in children and immunocompromised adults. A vaccine for dogs would not only be of great value in veterinary medicine but could potentially also reduce the incidence of zoonotic disease since dogs are the main reservoir for this parasite. In order to be able to test the efficacy of candidate vaccines, we have established challenge models for L.infantum in hamsters and dogs in our laboratory. Intravenous injection of a relatively high dose of in vitro cultured promastigotes (the stage transmitted by the sandfly vector) was found to reliably infect dogs and produce clinical symptoms in most of them. A detailed and prolonged follow-up of challenged dogs was found to be necessary for reliable results. Hamsters were found to be extremely susceptible to the infection and are therefore more suited as a model for L.infantum than mice. Increasing the challenge dose was found to decrease the prepatent period. A relatively high dose of parasites was therefore chosen as the standard since this enables the use of small groups of animals and decreases the follow-up period. Cysteine peptidases (CP’s) are known virulence factors in many parasites, including Leishmania. Previous research has indicated the protective potential both of CP knockout strains and of recombinant CP’s when used to vaccinate mice against L.mexicana. Two different L.infantum vaccine candidates were tested. A live attenuated strain of L.infantum, generated by targeted gene disruption of cysteine peptidase genes, was tested in hamsters. Although the strains were found to have attenuated virulence, protection could not be detected. Furthermore a formulation containing recombinant CP proteins and recombinant canine Interleukin-12 was tested in dogs; protection was again not found. More research is needed to find an effective vaccine for canine leishmaniasis. It is very important to test (new) candidate vaccines in dogs since it appears that results in the mouse model can not be directly translated to the dog. Results of dog vaccination studies are important, irrespective of the result, because this can increase knowledge of canine leishmaniasis and subsequently direct future research.