Onchocerca volvulus-neurotransmitter tyramine is a biomarker for river blindness

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 11; pp. 4218 - 4223
• Main Authors: Globisch, Daniel, Moreno, Amira Y., Hixon, Mark S., Nunes, Ashlee A. K., Denery, Judith R., Specht, Sabine, Hoerauf, Achim, Janda, Kim D.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 12.03.2013; National Acad Sciences
• Series: From the Cover
• Subjects: Animals; Anti-Bacterial Agents - therapeutic use; Biochemical pathways; Biological markers; Biomarkers; Biomarkers - urine; Chromatography; Doxycycline - therapeutic use; Female; Humans; Infections; Intestinal volvulus; Male; Metabolic diseases; Metabolism; Metabolome; Neglected diseases; Nematodes; Neurotransmitter Agents - urine; Neurotransmitters; Onchocerca volvulus - metabolism; Onchocerciasis; Onchocerciasis, Ocular - diagnosis; Onchocerciasis, Ocular - drug therapy; Onchocerciasis, Ocular - urine; Parasites; Physical Sciences; Tropical diseases; Tropical medicine; Tyramine - urine; Urine; Middle East; South America; Central America; Africa
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1221969110

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.