Poveda Marta Campillo, Löser Stephan, Gillan Victoria, Richards Josh, Ciancia Claire, Blackburn Gavin, Kerr Erin, Barrett Michael, Hildersley Katie A, Jay Philippe, Devaney Eileen, McNeilly Tom N, Britton Collette, Maizels Rick M
School of Infection and Immunity, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK.
GlaxoSmithKline GmbH, Prinzregentenplatz 9, 81675, Munich, Germany.
Metabolomics. 2025 Apr 21;21(3):55. doi: 10.1007/s11306-025-02248-w.
Intestinal helminth parasites trigger the host immune response through epithelial sensory tuft cells, but helminth-derived molecules that may activate tuft cells are poorly characterized.
The study aimed to identify small molecules released in vitro by two nematode parasites, that infect rodents (Nippostrongylus brasiliensis) and ruminants (Haemonchus contortus), and to test candidate ligands in an in vivo model of tuft cell differentiation.
Small molecules were analyzed by hydrophilic interaction liquid chromatography (HILIC) of material released by adult parasites incubated in serum-free media, followed by mass spectrometry; selected molecules were administered to mice and tuft cell expansion enumerated after 5 days.
A range of different conditions (culture media, timing, oxygenation) were tested, and comparisons made between the conditions, and between the two nematode species at selected points. Common products across the conditions and species included carboxylic acids (malate, succinate), medium chain fatty acids (such as decanoic and undecanoic acids), purines (guanine, xanthine and their derivatives), and phosphocholine compounds. We selected 19 of the prominent molecules for in vivo testing by oral administration, including succinate, a known activator of tuft cell differentiation. Malate elicited a low but significant level of tuft cell expansion, while undecanoic acids with or without a bromine substitution were also able to induce significant differentiation comparable to succinate. Other molecules including phosphorylcholine had no effect.
Multiple molecular species including decanoic and undecanoic acids released by helminths may contribute to activation of tuft cells in vivo.
肠道蠕虫寄生虫通过上皮感觉簇细胞触发宿主免疫反应，但可能激活簇细胞的蠕虫衍生分子的特征尚不明确。
本研究旨在鉴定两种感染啮齿动物（巴西日圆线虫）和反刍动物（捻转血矛线虫）的线虫寄生虫在体外释放的小分子，并在簇细胞分化的体内模型中测试候选配体。
通过对在无血清培养基中培养的成年寄生虫释放的物质进行亲水相互作用液相色谱（HILIC）分析，然后进行质谱分析来分析小分子；将选定的分子给予小鼠，并在5天后计数簇细胞的扩增情况。
测试了一系列不同条件（培养基、时间、氧合），并在选定时间点对不同条件之间以及两种线虫物种之间进行了比较。不同条件和物种的共同产物包括羧酸（苹果酸、琥珀酸）、中链脂肪酸（如癸酸和十一酸）、嘌呤（鸟嘌呤、黄嘌呤及其衍生物）和磷酸胆碱化合物。我们选择了19种突出的分子进行口服给药的体内测试，包括琥珀酸，一种已知的簇细胞分化激活剂。苹果酸引起了低水平但显著的簇细胞扩增，而有或没有溴取代的十一酸也能够诱导与琥珀酸相当的显著分化。包括磷酸胆碱在内的其他分子没有效果。
蠕虫释放的多种分子种类，包括癸酸和十一酸，可能有助于体内簇细胞的激活。
