Metabolomics-Based Discovery of Diagnostic Biomarkers for Onchocerciasis

Denery, Judith R.; Nunes, Ashlee A. K.; Hixon, Mark S.; Dickerson, Tobin J.; Janda, Kim D.

doi:10.1371/journal.pntd.0000834

Cited by 70 publications

(52 citation statements)

References 42 publications

(44 reference statements)

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“…This finding can be rationalized based on the presence of genetically different O. volvulus species (18). This result is also in line with previous observations for blood biomarkers specific for African O. volvulus infections, including a report detailing nonoverlapping polypeptide composition as well as IgG 4 response differences seen between Central American and West African samples (11,19). Due to the close phylogenetic relationship between O. volvulus and other filarial species, we examined samples of patients with lymphatic filariasis infections.…”

Section: −8supporting

confidence: 85%

“…The initial screening for the identification of potent biomarker mass signals was analyzed using the statistical analysis program XCMS online (11). Different sample sets of onchocerciasis-positive and African-negative control samples were analyzed using the standard parameters for an ESI-TOF system.…”

Section: Methodsmentioning

confidence: 99%

“…A potential alternative would be the identification of specific metabolites in blood or urine samples because, in theory, this could provide both infection status and a quantitative measure of infection based on metabolite concentration (9,10). Using liquid chromatography (LC)-MS to analyze O. volvulus-infected serum samples, we demonstrated the promise of metabolomics as an onchocerciasis diagnostic (11). However, technical constraints, such as a need for multiple mass biomarkers and an inability of compound biomarker assignment, led us to investigate whether urine analysis might serve as a better platform for O. volvulus biomarker diagnostics.…”

mentioning

confidence: 99%

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Onchocerca volvulus -neurotransmitter tyramine is a biomarker for river blindness

Globisch

Moreno

Hixon

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Onchocerciasis, also known as “river blindness”, is a neglected tropical disease infecting millions of people mainly in Africa and the Middle East but also in South America and Central America. Disease infectivity initiates from the filarial parasitic nematode Onchocerca volvulus , which is transmitted by the blackfly vector Simulium sp. carrying infectious third-stage larvae. Ivermectin has controlled transmission of microfilariae, with an African Program elimination target date of 2025. However, there is currently no point-of-care diagnostic that can distinguish the burden of infection—including active and/or past infection—and enable the elimination program to be effectively monitored. Here, we describe how liquid chromatography-MS–based urine metabolome analysis can be exploited for the identification of a unique biomarker, N -acetyltyramine- O ,β-glucuronide (NATOG), a neurotransmitter-derived secretion metabolite from O. volvulus . The regulation of this tyramine neurotransmitter was found to be linked to patient disease infection, including the controversial antibiotic doxycycline treatment that has been shown to both sterilize and kill adult female worms. Further clues to its regulation have been elucidated through biosynthetic pathway determination within the nematode and its human host. Our results demonstrate that NATOG tracks O. volvulus metabolism in both worms and humans, and thus can be considered a host-specific biomarker for onchocerciasis progression. Liquid chromatography-MS–based urine metabolome analysis discovery of NATOG not only has broad implications for a noninvasive host-specific onchocerciasis diagnostic but provides a basis for the metabolome mining of other neglected tropical diseases for the discovery of distinct biomarkers and monitoring of disease progression.

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Section: −8supporting

confidence: 85%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Onchocerca volvulus -neurotransmitter tyramine is a biomarker for river blindness

Globisch

Moreno

Hixon

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…In one example for invasive ovarian carcinomas and ovarian borderline tumors, a differential analysis of 291 detected metabolites in sixty-six invasive ovarian carcinomas and nine borderline tumors of the ovary revealed 51 metabolites that were significantly different between borderline tumors and carcinoma with a FDR controlled at 7.8% (Denkert et al, 2006). For Onchocera volvulus, analysis of an African sample set of 73 serum and plasm samples based on LC-MS revealed a set of 14 biomarkers that showed excellent discrimination between Onchocera volvuluspositive and negative individuals (Denery et al, 2010). Controlling FDR at 54% using Storey's q-value approach (Storey, 2002) resulted in 194 features selected from a total of 2350 mass features.…”

Section: Computational Methods For Interpreting Metabolomicsmentioning

confidence: 99%

Computational Methods to Interpret and Integrate Metabolomic Data

Li¹,

Wang²,

Zhang³

2012

Metabolomics

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“…Several new antifilarial drugs are under development including antibiotics that target Wolbachia endosymbionts as an alternative anthelminthic strategy 79. In parallel, development of several new diagnostic platforms to improve helminth diagnoses are underway including a metabolomics approach for filarial infections,80 as well as blood- and urine-based schistosomiasis diagnostics 81 82. Though none of these products are currently ready for implementation, we hope that they will one day be valuable tools in NTD control.…”

Section: A Partial Solution: Mda and Preventive Chemotherapymentioning

confidence: 99%

Global trends in neglected tropical disease control and elimination: impact on child health

Barry

Simon

Mistry

et al. 2013

Archives of Disease in Childhood

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The neglected tropical diseases (NTDs) are a group of 17 lesser known chronic infections which predominantly affect poor and disenfranchised communities. There are a number of NTDs that cause significant global morbidity in children, including the three major soil transmitted helminth (STH) infections (ascariasis, trichuriasis and hookworm infection), schistosomiasis and trachoma. These NTDs, together with lymphatic filariasis and onchocerciasis, are currently being targeted for global control and elimination through mass drug administration (MDA) campaigns. They represent the most common NTDs and share significant geographical overlap. Additionally, many individuals are polyparasitised with more than a single NTD. Integrated NTD control and elimination MDA programmes offer safe and efficacious treatments for all seven NTDs. However, the current global level of MDA coverage for the leading childhood NTDs, that is, STH infections, schistosomiasis and trachoma, remains well under 50%. Limiting factors for global coverage include insufficient global financial support, drug donation capacity of pharmaceutical companies and targeting school age children to the exclusion of other age groups in need of treatment, such as preschool age children. There is also a need for development of novel prevention and treatment modalities, such as next-generation small molecule drugs and vaccines. Efforts are underway to harness the momentum of a 2012 London Declaration on NTDs and a 2013 World Health Assembly (WHA) resolution as a means to control or in some cases eliminate by 2020 these NTDs that affect children worldwide.

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Metabolomics-Based Discovery of Diagnostic Biomarkers for Onchocerciasis

Cited by 70 publications

References 42 publications

Onchocerca volvulus -neurotransmitter tyramine is a biomarker for river blindness

Onchocerca volvulus -neurotransmitter tyramine is a biomarker for river blindness

Computational Methods to Interpret and Integrate Metabolomic Data

Global trends in neglected tropical disease control and elimination: impact on child health

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