Authors

J Dagley¹; S Hegde¹; AE Marriott¹; A Steven¹; C Fricks³; U DiCosty³; A Mansour³; EJ Campbell²; CM Wilson²; SA Ward¹; A Moorhead²; S McCall³; JW McCall²; MJ Taylor¹; JD Turner¹;  ¹ Liverpool School of Tropical Medicine, UK;  ² University of Georgia, United States;  ³ TRS Laboratories, UK

Discussion

Dirofilaria immitis is a filarial nematode causing potentially lethal veterinary heartworm disease in cats and dogs. Dirofilaria spp can also cause zoonotic infections and pathologies in humans. Currently, control of heartworm disease relies on chemoprophylaxis with the macrocyclic lactones (ML), however, ML-resistant isolates are increasing and resulting in preventative treatment failure. Heartworm drug research relies on long-term experimental cat and dog studies, with the potential to cause severe welfare issues. Thus, there is a need for alternative refined heartworm models for rapid pre-clinical research to reduce cat and dog experimentation. We discovered lymphopenic mouse strains with ablation of the interleukin-2/7 common gamma chain (NSG/NXG) are susceptible to larval infections of D. immitis. Larvae at 2-5 weeks post-infection were retrieved from subcutaneous and muscle tissues and were morphologically representative of the L4 stage in dogs. Mice did not display any clinical signs of infection. Using single subcutaneous injections of moxidectin, we identified 60-88% reductions in parasites 14-28 days post-infection. Oral oxfendazole dosing on day 1 and 28 also yielded 90% reductions in parasite yields on day 35. Using seven-day oral doxycycline, we demonstrated a 70-90% Wolbachia depletion within D. immitis L4 in our mouse model. Furthermore, we validated two additional mouse strains as being susceptible to D. immitis infection, C.B-17 SCID and Rag2/Il2rg, improving the commercial availability of mice as heartworm models and working towards the reduction and replacement of cats and dogs in heartworm preventative drug research.