{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:35:43Z","timestamp":1760060143056,"version":"build-2065373602"},"reference-count":83,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T00:00:00Z","timestamp":1754611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Ministry of Science and Innovation of Spain (MCIN)","doi-asserted-by":"publisher","award":["PID2021-122490NB-I00","PI20CIII-00037","TEC-2024\/BIO-66","PIPF-2023\/SAL-GL-31091"],"award-info":[{"award-number":["PID2021-122490NB-I00","PI20CIII-00037","TEC-2024\/BIO-66","PIPF-2023\/SAL-GL-31091"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"European Regional Development Fund ERDF \u201cA way of making Europe\u201d","doi-asserted-by":"publisher","award":["PID2021-122490NB-I00","PI20CIII-00037","TEC-2024\/BIO-66","PIPF-2023\/SAL-GL-31091"],"award-info":[{"award-number":["PID2021-122490NB-I00","PI20CIII-00037","TEC-2024\/BIO-66","PIPF-2023\/SAL-GL-31091"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Consejer\u00eda de Educaci\u00f3n, Ciencia y Universidades (Comunidad de Madrid) Madrid, Spain","award":["PID2021-122490NB-I00","PI20CIII-00037","TEC-2024\/BIO-66","PIPF-2023\/SAL-GL-31091"],"award-info":[{"award-number":["PID2021-122490NB-I00","PI20CIII-00037","TEC-2024\/BIO-66","PIPF-2023\/SAL-GL-31091"]}]},{"name":"Community of Madrid","award":["PID2021-122490NB-I00","PI20CIII-00037","TEC-2024\/BIO-66","PIPF-2023\/SAL-GL-31091"],"award-info":[{"award-number":["PID2021-122490NB-I00","PI20CIII-00037","TEC-2024\/BIO-66","PIPF-2023\/SAL-GL-31091"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Babesia divergens is a tick-borne apicomplexan parasite that causes human babesiosis, a malaria-like disease. B. divergens metabolism remains poorly characterized. Here, we employed a multiplatform mass spectrometry-based metabolomics approach (using CE-TOF\/MS, GC-QTOF\/MS, LC-QTOF\/MS, and LC-QqQ\/MS) to profile intra- and extracellular metabolic changes in B. divergens-infected and uninfected red blood cells (RBCs) and their supernatants. Our results indicate alterations in the metabolome caused by B. divergens infection and proliferation within RBCs. These findings are consistent with the major metabolic dependencies of B. divergens, including extracellular glucose, glutamine, and arginine, accompanied by the accumulation of glycolytic and TCA cycle intermediates. We identified altered nucleotide metabolism, pentose phosphate pathway activity, and redox imbalance. Depletion of lysoglycerophospholipids, glucose, arginine, and glutamine, and accumulation of free heme and sphingolipids suggested pathogenic effects. Growth experiments indicate that glucose and glutamine, but not hypoxanthine, are required for parasite growth. We additionally discovered a phosphorylated HEPES derivative (PEPES) produced upon B. divergens infection of RBCs in vitro. Collectively, these findings and their global interpretation provide insights into B. divergens metabolism and metabolic dependencies and host\u2013parasite metabolic interactions and outline potential directions for future studies on human babesiosis diagnosis, prognosis assessment, and treatment.<\/jats:p>","DOI":"10.3390\/ijms26167677","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T13:20:09Z","timestamp":1754659209000},"page":"7677","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Application of Multiplatform Mass Spectrometry to the Study of Babesia divergens Metabolism and the Pathogenesis of Human Babesiosis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4114-0766","authenticated-orcid":false,"given":"Miguel","family":"Fern\u00e1ndez-Garc\u00eda","sequence":"first","affiliation":[{"name":"Centro de Metabol\u00f3mica y Bioan\u00e1lisis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanizaci\u00f3n Montepr\u00edncipe, 28660 Boadilla del Monte, Spain"},{"name":"Departamento de Ciencias M\u00e9dicas B\u00e1sicas, Facultad de Medicina, Universidad San Pablo-CEU, CEU Universities, Urbanizaci\u00f3n Montepr\u00edncipe, 28660 Boadilla del Monte, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9107-2450","authenticated-orcid":false,"given":"Luis Miguel","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Parasitology Reference and Research Laboratory, Centro Nacional de Microbiolog\u00eda, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Sevilla","sequence":"additional","affiliation":[{"name":"Parasitology Reference and Research Laboratory, Centro Nacional de Microbiolog\u00eda, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4525-1086","authenticated-orcid":false,"given":"Aitor","family":"Gil","sequence":"additional","affiliation":[{"name":"Parasitology Reference and Research Laboratory, Centro Nacional de Microbiolog\u00eda, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrique","family":"Santos-Oliveira","sequence":"additional","affiliation":[{"name":"Centro de Metabol\u00f3mica y Bioan\u00e1lisis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanizaci\u00f3n Montepr\u00edncipe, 28660 Boadilla del Monte, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Belen","family":"Revuelta","sequence":"additional","affiliation":[{"name":"Parasitology Reference and Research Laboratory, Centro Nacional de Microbiolog\u00eda, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4722-491X","authenticated-orcid":false,"given":"Coral","family":"Barbas","sequence":"additional","affiliation":[{"name":"Centro de Metabol\u00f3mica y Bioan\u00e1lisis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanizaci\u00f3n Montepr\u00edncipe, 28660 Boadilla del Monte, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0873-4485","authenticated-orcid":false,"given":"M\u00aa Fernanda","family":"Rey-Stolle","sequence":"additional","affiliation":[{"name":"Centro de Metabol\u00f3mica y Bioan\u00e1lisis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanizaci\u00f3n Montepr\u00edncipe, 28660 Boadilla del Monte, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3852-960X","authenticated-orcid":false,"given":"Estrella","family":"Montero","sequence":"additional","affiliation":[{"name":"Parasitology Reference and Research Laboratory, Centro Nacional de Microbiolog\u00eda, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1521-8489","authenticated-orcid":false,"given":"Antonia","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"Centro de Metabol\u00f3mica y Bioan\u00e1lisis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanizaci\u00f3n Montepr\u00edncipe, 28660 Boadilla del Monte, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"doi-asserted-by":"crossref","unstructured":"Kumar, A., O\u2019Bryan, J., and Krause, P.J. 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