Human filariasis—contributions of the Litomosoides sigmodontis and Acanthocheilonema viteae animal model

Abstract

Filariae are vector-borne parasitic nematodes that are endemic worldwide, in tropical and subtropical regions. Important human filariae spp. include Onchocerca volvulus, Wuchereria bancrofti and Brugia spp., and Loa loa and Mansonella spp. causing onchocerciasis (river blindness), lymphatic filariasis (lymphedema and hydrocele), loiasis (eye worm), and mansonelliasis, respectively. It is estimated that over 1 billion individuals live in endemic regions where filarial diseases are a public health concern contributing to significant disability adjusted life years (DALYs). Thus, efforts to control and eliminate filarial diseases were already launched by the WHO in the 1970s, especially against lymphatic filariasis and onchocerciasis, and are mainly based on mass drug administration (MDA) of microfilaricidal drugs (ivermectin, diethylcarbamazine, albendazole) to filarial endemic areas accompanied with vector control strategies with the goal to reduce the transmission. With the United Nations Sustainable Development Goals (SDGs), it was decided to eliminate transmission of onchocerciasis and stop lymphatic filariasis as a public health problem by 2030. It was also requested that novel drugs and treatment strategies be developed. Mouse models provide an important platform for anti-filarial drug research in a preclinical setting. This review presents an overview about the Litomosoides sigmodontis and Acanthocheilonema viteae filarial mouse models and their role in immunological research as well as preclinical studies about novel anti-filarial drugs and treatment strategies.

Genetic diversity of vector-borne pathogens in spotted and brown hyenas from Namibia and Tanzania relates to ecological conditions rather than host taxonomy

“…In the genus Acanthocheilonema this variation in vectors is particularly high. While the rodent parasite Acanthocheilonema viteae uses the soft tick Ornithodorus tartakovskyi [ 106 ], A. dracunculoides infecting domestic dogs is transmitted by the brown dog tick Rhipicephalus sanguineus [ 107 , 108 ] and the louse fly H. longipennis [ 38 ]. The other Acanthocheilonema species commonly found in domestic dogs, A. reconditum , uses various fleas (including Ctenocephalides spp.…”

Onchocerciasis drug development: from preclinical models to humans

“…From this screen, Tylosin A (TylA), a commercial veterinary macrolide antibiotic, was identified as novel lead. TylA is a macrolide antibiotic that is active mostly against Gram-positive bacteria and mycoplasmas by binding to the 50S ribosomal subunit, inhibiting protein synthesis (Risch et al 2021). TylA has displayed potent anti-Wolbachia activity with an in vitro EC 50 of 28 nM, but TylA is characterized by poor oral bioavailability resulting from low permeability (< 0.1•10 −6 cm/s) in a canine kidney cell monolayer system (MDR-MDCK).…”

Evaluation of the in vitro susceptibility of various filarial nematodes to emodepside

“…In contrast, within the same laboratory but differences in culture media, the L3 stage of L. sigmodontis was less sensitive than microfilariae as none of the tested emodepside concentrations were able to inhibit L3 L. sigmodontis completely. L. sigmodontis is used as a rodent model for human filarial infections ( Hübner et al, 2009 ; Risch et al, 2021 ), and previous in vivo studies of emodepside in a rodent model have already indicated that emodepside is not effective at killing larval and pre-adult stages of L. sigmodontis or B. malayi ( Zahner et al, 2001a ). Only microfilariae of B. malayi were tested in this study, and therefore the in vitro susceptibility of the L3 stage of B. malayi remains unknown.…”

“…To evaluate the filaricidal activity spectrum of emodepside as part of the preclinical package, this study investigates emodepside in vitro susceptibility of a range of filariae, including Acanthocheilonema viteae, B. malayi , B. pahangi , Dirofilaria immitis, Litomosoides sigmodontis , O. gutturosa , and O. lienalis. These species are commonly used as model organisms for human filariasis ( Townson et al, 2005 ; Morris et al, 2013 ; Risch et al, 2021 ) . Different stages including microfilariae, third-stage (L3) and fourth-stage (L4) larvae, as well as adult male and female worms, were exposed to varying concentrations of emodepside in order to measure drug effects on helminth motility, using established and adapted protocols ( Tagboto and Townson, 1996 ; Townson et al, 2007 ; Storey et al, 2014 ; Maclean et al, 2017 ).…”