Dirofilariasis mouse models for heartworm preclinical research



Marriott, AE, Dagley, JL, Hegde, S, Steven, A, Fricks, C, DiCosty, U, Mansour, A, Campbell, EJ, Wilson, CM, Gusovsky, F
et al (show 8 more authors) (2023) Dirofilariasis mouse models for heartworm preclinical research. FRONTIERS IN MICROBIOLOGY, 14. 1208301-.

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Abstract

<h4>Introduction</h4>Dirofilariasis, 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.<h4>Methods</h4>As a refined alternative <i>in vivo</i> 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 <i>Dirofilaria immitis</i>.<h4>Results</h4>Non-obese diabetic (NOD) severe combined immunodeficiency (SCID)γc<sup>-/-</sup> (NSG and NXG) and recombination-activating gene (RAG)2<sup>-/-</sup>γc<sup>-/-</sup> mouse strains yielded viable <i>D. immitis</i> larvae at 2-4 weeks post-infection, including the use of different batches of <i>D. immitis</i> infectious larvae, different <i>D. immitis</i> 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 <i>in vitro-</i>propagated larvae at day 14, <i>in vivo-</i>derived larvae had completed the L4 molt, were significantly larger, and contained expanded <i>Wolbachia</i> endobacteria titres. We established an <i>ex vivo</i> L4 paralytic screening system whereby assays with moxidectin or levamisole highlighted discrepancies in relative drug sensitivities in comparison with <i>in vitro-</i>reared L4 <i>D. immitis</i>. We demonstrated effective depletion of <i>Wolbachia</i> by 70%-90% in <i>D. immitis</i> L4 following 2- to 7-day oral <i>in vivo</i> exposures of NSG- or NXG-infected mice with doxycycline or the rapid-acting investigational drug, AWZ1066S. We validated NSG and NXG <i>D. immitis</i> mouse models as a filaricide screen by <i>in vivo</i> treatments with single injections of moxidectin, which mediated a 60%-88% reduction in L4 larvae at 14-28 days.<h4>Discussion</h4>Future 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.

Item Type: Article
Uncontrolled Keywords: dirofilariasis, heartworm, Wolbachia, pharmacology, parasitology, symbiosis, one health, drug development
Divisions: Faculty of Science and Engineering > School of Physical Sciences
Depositing User: Symplectic Admin
Date Deposited: 09 Aug 2023 14:06
Last Modified: 09 Aug 2023 14:06
DOI: 10.3389/fmicb.2023.1208301
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3172091