Abstract
The quinazolines CBR417 and CBR490 were previously shown to be potent anti-wolbachials that deplete Wolbachia endosymbionts of filarial nematodes and present promising pre-clinical candidates for human filarial diseases such as onchocerciasis. In the present study we tested both candidates in two models of chronic filarial infection, namely the Litomosoides sigmodontis and Brugia pahangi jird model and assessed their long-term effect on Wolbachia depletion, microfilariae counts and filarial embryogenesis 16−18 weeks after treatment initiation (wpt). Once per day (QD) oral treatment with CBR417 (50 mg/kg) for 4 days or twice per day (BID) with CBR490 (25 mg/kg) for 7 days during patent L. sigmodontis infection reduced the Wolbachia load by >99% and completely cleared peripheral microfilaremia from 10–14 wpt. Similarly, 7 days of QD treatments (40 mg/kg) with CBR417 or CBR490 cleared >99% of Wolbachia from B. pahangi and reduced peritoneal microfilariae counts by 93% in the case of CBR417 treatment. Transmission electron microscopy analysis indicated intensive damage to the B. pahangi ovaries following CBR417 treatment and in accordance filarial embryogenesis was inhibited in both models after CBR417 or CBR490 treatment. Suboptimal treatment regimens of CBR417 or CBR490 did not lead to a maintained reduction of the microfilariae and Wolbachia load. In conclusion, CBR417 or CBR490 are pre-clinical candidates for filarial diseases, which achieve long-term clearance of Wolbachia endosymbionts of filarial nematodes, inhibit filarial embryogenesis and clear microfilaremia with treatments as short as 7 days.
Highlights
The neglected tropical disease known as onchocerciasis or river blindness is caused by the filarial nematode Onchocerca volvulus
Based on the previously described efficacy against Wolbachia using short treatment durations with the quinazolines CBR417 and CBR490 in the L. sigmodontis mouse model (Bakowski et al, 2019), we performed a more detailed analysis of their efficacy in the L. sigmodontis jird model that included parasitological analysis and compared it to doxycycline treatment given for 14 days
4- and 7-day QD regimens of 50 mg/kg CBR417 (Fig. 1A and B), as well as BID treatments with 75 and 25 mg/kg CBR490 for 7 days (Fig. 1A and B) significantly reduced the Wolbachia load in the female worms by more than 99% in comparison to untreated controls. These CBR417 and CBR490 treatment regimens were superior to a BID treatment of 40 mg/ kg doxycycline given for 14 days, which resulted in no Wolbachia reduction at 16 and 18 wpt in comparison to untreated controls (Fig. 1A and B)
Summary
The neglected tropical disease known as onchocerciasis or river blindness is caused by the filarial nematode Onchocerca volvulus. The disease is characterized by adult worms residing in subcutaneous nodules and the release of microfilariae (mf) into the skin by the female worms (Hoerauf et al, 2011). Disease pathology occurs as a result of mf death in dermal and ocular tissues leading to release of somatic inflammatory molecules including release of the filarial bacterial endosymbiont, Wolbachia. Since the 1970s several control programs, initially based on vector control, were conducted to prevent the transmission of onchocerciasis but later included mass drug administration (MDA) with ivermectin (IVM) (Hoerauf et al, 2011). The recently stated sustainable development goal by the United Nations is to eliminate the transmission of infection and disease, and
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