Use of athymic nude mice in a mouse model of Dirofilaria immitis and its utilization in drug screening

Background The heartworm Dirofilaria immitis mouse model has been a recent topic of research and discussion as a tool that is more logistically feasible and economical to study the efficacy of new drugs as opposed to using dogs and/or cats. Often, for the initial screening of novel antifilarial compounds, larval development assay (LDA) is used in vitro. However, a reliable D. immitis mouse model would be beneficial as in vitro benchtop assays cannot fully mimic the in vivo system. Methods Several strains of mice were evaluated for their susceptibility to the infective larval stage of D. immitis while attempting to use a low cost, low maintenance mouse. Experimental infections were performed by injecting third-stage infective larvae subcutaneously and performing necropsies at several time points post-infection (PI). Results By 7–10 days PI, 89–96% of the worms recovered from the subcutaneous tissue were determined to have molted to the fourth stage. Among the mouse strains tested for susceptibility to D. immitis larval infection, the athymic nude mouse strain, J:NU, proved to be the best candidate for developing the heartworm-mouse model. When infected with 50–100 infective third-stage larvae, the recovery rate of fourth stage larvae was consistently 20–30% at 7–10 days PI. This model was then evaluated using the macrocyclic lactones (ML) ivermectin and moxidectin, and emodepside, a cyclic depsipeptide, as a treatment against the third-stage and fourth-stage infective larvae of a ML-susceptible and resistant heartworm isolate. Results show that the MLs had good efficacy and emodepside was nearly 100% effective against the ML susceptible D. immitis isolate. In addition, mice were also necropsied 77 to 96 days post infection of third-stage infective larvae with recovery rates of up to 46% of adult worms found in the heart and lungs as well as other areas of the body. Conclusions Although target animals (dogs and cats) should be used to confirm the efficacy of new drugs to combat D. immitis , this heartworm mouse model will give a more economical and efficient approach to screen novel compounds.