Abstract
The neglected tropical disease onchocerciasis, or river blindness, is caused by infection with the filarial nematode Onchocerca volvulus. Current estimates indicate that 17 million people are infected worldwide, the majority of them living in Africa. Today there are no non-invasive tests available that can detect ongoing infection, and that can be used for effective monitoring of elimination programs. In addition, to enable pharmacodynamic studies with novel macrofilaricide drug candidates, surrogate endpoints and efficacy biomarkers are needed but are non-existent. We describe the use of a multimodal untargeted mass spectrometry-based approach (metabolomics and lipidomics) to identify onchocerciasis-associated metabolites in urine and plasma, and of specific lipid features in plasma of infected individuals (O. volvulus infected cases: 68 individuals with palpable nodules; lymphatic filariasis cases: 8 individuals; non-endemic controls: 20 individuals). This work resulted in the identification of elevated concentrations of the plasma metabolites inosine and hypoxanthine as biomarkers for filarial infection, and of the urine metabolite cis-cinnamoylglycine (CCG) as biomarker for O. volvulus. During the targeted validation study, metabolite-specific cutoffs were determined (inosine: 34.2 ng/ml; hypoxanthine: 1380 ng/ml; CCG: 29.7 ng/ml) and sensitivity and specificity profiles were established. Subsequent evaluation of these biomarkers in a non-endemic population from a different geographical region invalidated the urine metabolite CCG as biomarker for O. volvulus. The plasma metabolites inosine and hypoxanthine were confirmed as biomarkers for filarial infection. With the availability of targeted LC-MS procedures, the full potential of these 2 biomarkers in macrofilaricide clinical trials, MDA efficacy surveys, and epidemiological transmission studies can be investigated.
Highlights
Onchocerciasis, or river blindness, is an infectious disease caused by the filarial parasitic nematode Onchocerca volvulus with an estimated prevalence of current infection of 17 million people worldwide and 120 million people at risk
The work presented here describes the use of multiple mass spectrometry-based screening methods to search for biomarkers indicative of infection with Onchocerca volvulus
This resulted in the identification of elevated concentrations of the plasma metabolites inosine and hypoxanthine as biomarkers for filarial infection, and of the urine metabolite cis-cinnamoylglycine as biomarker for O. volvulus
Summary
Onchocerciasis, or river blindness, is an infectious disease caused by the filarial parasitic nematode Onchocerca volvulus with an estimated prevalence of current infection of 17 million people worldwide and 120 million people at risk. To be able to monitor and evaluate these MDA programs, epidemiological mapping is performed to identify all high-risk areas where ivermectin treatment is needed. These mappings are mainly based on examination of individuals for the presence of palpable onchocercomas, presence of microfilariae (mf) in skin biopsies, and the rapid diagnostic test (RDT) for the detection of IgG4 antibodies to the parasitic antigen Ov16 [6,7,8,9,10,11,12,13,14]. There is a need for surrogate markers of infection and preferably of the presence of live and active adult worms [15]
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