Abstract
Elimination of the helminth disease, river blindness, remains challenging due to ivermectin treatment-associated adverse reactions in loiasis co-infected patients. Here, we address a deficit in preclinical research tools for filarial translational research by developing Loa loa mouse infection models. We demonstrate that adult Loa loa worms in subcutaneous tissues, circulating microfilariae (mf) and presence of filarial biomarkers in sera occur following experimental infections of lymphopenic mice deficient in interleukin (IL)-2/7 gamma-chain signaling. A microfilaraemic infection model is also achievable, utilizing immune-competent or -deficient mice infused with purified Loa mf. Ivermectin but not benzimidazole treatments induce rapid decline (>90%) in parasitaemias in microfilaraemic mice. We identify up-regulation of inflammatory markers associated with allergic type-2 immune responses and eosinophilia post-ivermectin treatment. Thus, we provide validation of murine research models to identify loiasis biomarkers, to counter-screen candidate river blindness cures and to interrogate the inflammatory etiology of loiasis ivermectin-associated adverse reactions.
Highlights
Elimination of the helminth disease, river blindness, remains challenging due to ivermectin treatment-associated adverse reactions in loiasis co-infected patients
Infectious stage L. loa larvae develop into mature adults that migrate within subcutaneous tissues and the sub-conjunctiva
When examining sera from mice infected with L. loa L3, we found that antigenaemia detection with Filarial Test Strip (FTS) was reproducibly apparent, dependent on Loa adult infection status, but independent of the age of adult worm infection or microfilaraemic status
Summary
Elimination of the helminth disease, river blindness, remains challenging due to ivermectin treatment-associated adverse reactions in loiasis co-infected patients. Loiasis is an urgent global health problem, as severe and potentially fatal neurological serious adverse events (SAE) may occur in hypermicrofilaraemic patients (≥30,000 mf/ml blood) following annual mass drug administration (MDA) of ivermectin (IVM, Mectizan®) for the treatment of the related filarial disease, onchocerciasis ( known as river blindness)[8]. This hypermicrofilaraemic threshold, loiasis individuals remain at significant risk of developing non-neurological, febrile, temporarily debilitating AE following IVM treatment[8,9]. We have recently established immunodeficient mouse models of related filarial infections (Brugia and Onchocerca) and implemented them as preclinical macrofilaricidal drug screens[21,22,23,24,25]
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