Heartworm Disease – Intervention and Industry Perspective<sup>1</sup>

Noack, Sandra; Harrington, John; Carithers, Douglas S.; Kaminsky, Ronald; Selzer, Paul M.

doi:10.1002/9783527823413.ch9

Cited by 1 publication

(1 citation statement)

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“…Advantages of immunodeficient mouse models for filariasis drug screening include increased throughput, ease of maintenance, potential for international commercial supply, standardization with murine pharmacology models, reduced costs, and, potentially, a reduction in the use of "specially protected, " highly sentient animal species (cats, dogs, and non-human primates). Considering these advantages, academic investigators and animal healthcare companies have latterly begun to research rodent infection models of D. immitis, including the application of immunodeficient mice as potential drug screens (Noack et al, 2021;Hess et al, 2023). Here, we demonstrate that multiple lymphopenic immunodeficient mouse strains with ablation of the interleukin-2/7 common gamma chain (γc) are susceptible to the initial tissue larval development phase of D. immitis.…”

Section: Ahs (mentioning

confidence: 94%

Dirofilariasis mouse models for heartworm preclinical research

et al. 2023

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IntroductionDirofilariasis, including heartworm disease, is a major emergent veterinary parasitic infection and a human zoonosis. Currently, experimental infections of cats and dogs are used in veterinary heartworm preclinical drug research.MethodsAs a refined alternative in vivo heartworm preventative drug screen, we assessed lymphopenic mouse strains with ablation of the interleukin-2/7 common gamma chain (γc) as susceptible to the larval development phase of Dirofilaria immitis.ResultsNon-obese diabetic (NOD) severe combined immunodeficiency (SCID)γc−/− (NSG and NXG) and recombination-activating gene (RAG)2−/−γc−/− mouse strains yielded viable D. immitis larvae at 2–4 weeks post-infection, including the use of different batches of D. immitis infectious larvae, different D. immitis isolates, and at different laboratories. Mice did not display any clinical signs associated with infection for up to 4 weeks. Developing larvae were found in subcutaneous and muscle fascia tissues, which is the natural site of this stage of heartworm in dogs. Compared with in vitro-propagated larvae at day 14, in vivo-derived larvae had completed the L4 molt, were significantly larger, and contained expanded Wolbachia endobacteria titres. We established an ex vivo L4 paralytic screening system whereby assays with moxidectin or levamisole highlighted discrepancies in relative drug sensitivities in comparison with in vitro-reared L4 D. immitis. We demonstrated effective depletion of Wolbachia by 70%−90% in D. immitis L4 following 2- to 7-day oral in vivo exposures of NSG- or NXG-infected mice with doxycycline or the rapid-acting investigational drug, AWZ1066S. We validated NSG and NXG D. immitis mouse models as a filaricide screen by in vivo treatments with single injections of moxidectin, which mediated a 60%−88% reduction in L4 larvae at 14–28 days.DiscussionFuture adoption of these mouse models will benefit end-user laboratories conducting research and development of novel heartworm preventatives via increased access, rapid turnaround, and reduced costs and may simultaneously decrease the need for experimental cat or dog use.

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Section: Ahs (mentioning

confidence: 94%