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-.
|
PDF
Dirofilariasis mouse models for heartworm preclinical research.pdf - Open Access published version Download (5MB) | Preview |
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 |
Dimensions
Dimensions
