Advances in preclinical platforms of Loa loa for filarial neglected tropical disease drug and diagnostics research

Abstract

The tropical disease, loiasis, caused by the filarial parasite, Loa, has gained prominence in global public health as a cause of excess mortality and a barrier to the elimination of the related prioritized neglected tropical diseases (NTDs), lymphatic filariasis and onchocerciasis, within Central Africa. There are no effective drug cures or vaccines available to treat loiasis safely. Here we review recent advances in loiasis preclinical platform technologies, including novel in vitro culturing systems, animal models and innovations in experimental infections of the L. loa vector, Chrysops, that have facilitated access to all L. loa filarial life-cycle stages. We detail applications of these new model systems in anti-filarial drug screening, diagnostic development, immunology, and pathophysiology research. Finally, we provide an overview of how loiasis preclinical platforms may be further utilized in translational medicine applications to support the development of much needed new interventions against filarial NTDs.

Keywords: Loa; filariasis; loiasis; lymphatic filariasis; neglected tropical disease; onchocerciasis.

Figure 1. Performance of loiasis microfilaraemic mouse models.

A) microfilaraemias ≥10000 mf/ml can be achieved in both BALB/c (immunocompetent) and CB.17 SCID mice by increasing unit of inoculation B) L. loa mf ethically sourced from human volunteers establishes similar microfilaraemias to those derived from NHP C) consistent >90% depletions in L. loa microfilaraemias are mediated following single oral treatment with ivermectin 2 days (left) or 7 days (right) post-treatment in CB.17 SCID mice in multiple independent experiments. Data plotted is mean ±SEM. Lines are global averages of vehicle treated mice (red) and 95% confidence intervals (dashed). Significant differences are indicated ***P<0.001 and **P<0.01. Data is previously unpublished (A,B) and combination of published (42) and previously unpublished (C).

Figure 2. Summary of loiasis preclinical platforms and applications in translational research.

Left: generation of all life cycle stages is achievable by blood sampling human patients, purification of L. loa mf, experimental injections in Chrysops, isolation of infectious stage larvae and chronic infections of either compound lymphopenic mice or splenectomised baboons. Derived L. loa mf, L3 or adults can be utilised in long-term in vitro cultures for drug or diagnostic biomarker discovery. It is proposed that mf from chronic mouse infections can be used to passage into Chrysops to establish a full laboratory life cycle (dashed loop). Right: in vivo infection models can be utilised to determine selective macrofilaricidal efficacy, validate candidate biomarkers and to research the aetiology of ivermectin adverse events including targetable pathways for adjunct therapeutics

Figure 3. Application of a chronic loiasis mouse model in candidate macrofilaricide drug evaluation.

A) strategy for developing microfilaraemic mice with defined implanted number of male and female L. loa. B) schematic of drug screen to comprehensively evaluate macrofilaricidal activity of candidate drugs. C) PK modelling of effective macrofilaricidal drug exposures to predict human efficacious dose