{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T07:21:01Z","timestamp":1778656861751,"version":"3.51.4"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T00:00:00Z","timestamp":1637539200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Serial passaging of the human fungal pathogen <jats:italic>Candida albicans<\/jats:italic> in the gastrointestinal tract of antibiotics-treated mice selects for virulence-attenuated strains. These gut-evolved strains protect the host from infection by a wide range of pathogens <jats:italic>via<\/jats:italic> trained immunity. Here, we further investigated the molecular and cellular mechanisms underlying this innate immune memory. Both Dectin-1 (the main receptor for \u03b2-glucan; a well-described immune training molecule in the fungal cell wall) and Nod2 (a receptor described to mediate BCG-induced trained immunity), were redundant for the protection induced by gut-evolved <jats:italic>C. albicans<\/jats:italic> against a virulent <jats:italic>C. albicans<\/jats:italic> strain, suggesting that gut-evolved <jats:italic>C. albicans<\/jats:italic> strains induce trained immunity <jats:italic>via<\/jats:italic> other pathways. Cytometry by time of flight (CyTOF) analysis of mouse splenocytes revealed that immunization with gut-evolved <jats:italic>C. albicans<\/jats:italic> resulted in an expansion of neutrophils and a reduction in natural killer (NK) cells, but no significant numeric changes in monocytes, macrophages or dendritic cell populations. Systemic depletion of phagocytes or neutrophils, but not of macrophages or NK cells, reduced protection mediated by gut-evolved <jats:italic>C. albicans<\/jats:italic>. Splenocytes and bone marrow cells of mice immunized with gut-evolved <jats:italic>C. albicans<\/jats:italic> demonstrated metabolic changes. In particular, splenic neutrophils displayed significantly elevated glycolytic and respiratory activity in comparison to those from mock-immunized mice. Although further investigation is required for fully deciphering the trained immunity mechanism induced by gut-evolved <jats:italic>C. albicans<\/jats:italic> strains, this data is consistent with the existence of several mechanisms of trained immunity, triggered by different training stimuli and involving different immune molecules and cell types.<\/jats:p>","DOI":"10.3389\/fcimb.2021.743735","type":"journal-article","created":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T06:31:21Z","timestamp":1637562681000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Gut-Evolved Candida albicans Induces Metabolic Changes in Neutrophils"],"prefix":"10.3389","volume":"11","author":[{"given":"Jose Antonio","family":"Reales-Calderon","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gloria H. W.","family":"Tso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alrina S. M.","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pei Xiang","family":"Hor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"B\u00f6hme","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen W. W.","family":"Teng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evan W.","family":"Newell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amit","family":"Singhal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norman","family":"Pavelka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2562","DOI":"10.1016\/j.celrep.2016.11.011","article-title":"Immunometabolic Pathways in BCG-Induced Trained Immunity","volume":"17","author":"Arts","year":"2016","journal-title":"Cell Rep."},{"key":"B2","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1016\/j.cmet.2016.10.008","article-title":"Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity","volume":"24","author":"Arts","year":"2016","journal-title":"Cell Metab."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1038\/ni.3006","article-title":"High-Dimensional Analysis of the Murine Myeloid Cell System","volume":"15","author":"Becher","year":"2014","journal-title":"Nat. Immunol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1084\/jem.20020470","article-title":"Dectin-1 Is a Major Beta-Glucan Receptor on Macrophages","volume":"196","author":"Brown","year":"2002","journal-title":"J. Exp. Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1250684","DOI":"10.1126\/science.1250684","article-title":"mTOR- and HIF-1alpha-Mediated Aerobic Glycolysis as Metabolic Basis for Trained Immunity","volume":"345","author":"Cheng","year":"2014","journal-title":"Science"},{"key":"B6","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1146\/annurev.phyto.42.040803.140421","article-title":"Systemic Acquired Resistance","volume":"42","author":"Durrant","year":"2004","journal-title":"Annu. Rev. Phytopathol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1002\/cyto.a.22271","article-title":"Normalization of Mass Cytometry Data With Bead Standards","volume":"83","author":"Finck","year":"2013","journal-title":"Cytomet. A."},{"key":"B8","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1111\/j.1365-2958.2005.04557.x","article-title":"Granulocytes Govern the Transcriptional Response, Morphology and Proliferation of Candida Albicans in Human Blood","volume":"56","author":"Fradin","year":"2005","journal-title":"Mol. Microbiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1016\/j.immuni.2016.08.015","article-title":"Unsupervised High-Dimensional Analysis Aligns Dendritic Cells Across Tissues and Species","volume":"45","author":"Guilliams","year":"2016","journal-title":"Immunity"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.1016\/j.cmi.2019.05.024","article-title":"Heterologous Effects of Vaccination and Trained Immunity","volume":"25","author":"Gyssens","year":"2019","journal-title":"Clin. Microbiol. Infect."},{"key":"B11","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/s41374-018-0137-1","article-title":"Characterization of Immune Cell Subtypes in Three Commonly Used Mouse Strains Reveals Gender and Strain-Specific Variations","volume":"99","author":"Hensel","year":"2019","journal-title":"Lab. Invest."},{"key":"B12","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1016\/j.it.2019.04.013","article-title":"The Neutrophil Life Cycle","volume":"40","author":"Hidalgo","year":"2019","journal-title":"Trends Immunol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1016\/j.cell.2017.12.031","article-title":"BCG Educates Hematopoietic Stem Cells to Generate Protective Innate Immunity Against Tuberculosis","volume":"172","author":"Kaufmann","year":"2018","journal-title":"Cell"},{"key":"B14","doi-asserted-by":"publisher","first-page":"17537","DOI":"10.1073\/pnas.1202870109","article-title":"Bacille Calmette-Guerin Induces NOD2-Dependent Nonspecific Protection From Reinfection via Epigenetic Reprogramming of Monocytes","volume":"109","author":"Kleinnijenhuis","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B15","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.clim.2014.10.005","article-title":"BCG-Induced Trained Immunity in NK Cells: Role for non-Specific Protection to Infection","volume":"155","author":"Kleinnijenhuis","year":"2014","journal-title":"Clin. Immunol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1038\/s41590-018-0176-1","article-title":"Epigenetic Control of Innate and Adaptive Immune Memory","volume":"19","author":"Lau","year":"2018","journal-title":"Nat. Immunol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"108387","DOI":"10.1016\/j.celrep.2020.108387","article-title":"BCG Vaccination Induces Long-Term Functional Reprogramming of Human Neutrophils","volume":"33","author":"Moorlag","year":"2020","journal-title":"Cell Rep."},{"key":"B18","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1038\/s41573-019-0025-4","article-title":"Therapeutic Targeting of Trained Immunity","volume":"18","author":"Mulder","year":"2019","journal-title":"Nat. Rev. Drug Discovery"},{"key":"B19","doi-asserted-by":"publisher","first-page":"aaf1098","DOI":"10.1126\/science.aaf1098","article-title":"Trained Immunity: A Program of Innate Immune Memory in Health and Disease","volume":"352","author":"Netea","year":"2016","journal-title":"Science"},{"key":"B20","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/j.chom.2011.04.006","article-title":"Trained Immunity: A Memory for Innate Host Defense","volume":"9","author":"Netea","year":"2011","journal-title":"Cell Host Microbe"},{"key":"B21","doi-asserted-by":"publisher","first-page":"3712","DOI":"10.4049\/jimmunol.172.6.3712","article-title":"Toll-Like Receptor 2 Suppresses Immunity Against Candida Albicans Through Induction of IL-10 and Regulatory T Cells","volume":"172","author":"Netea","year":"2004","journal-title":"J. Immunol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1354","DOI":"10.1016\/j.cell.2016.09.034","article-title":"Beta-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance","volume":"167","author":"Novakovic","year":"2016","journal-title":"Cell"},{"key":"B23","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.chom.2012.06.006","article-title":"Candida Albicans Infection Affords Protection Against Reinfection via Functional Reprogramming of Monocytes","volume":"12","author":"Quintin","year":"2012","journal-title":"Cell Host Microbe"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1251086","DOI":"10.1126\/science.1251086","article-title":"Epigenetic Programming of Monocyte-to-Macrophage Differentiation and Trained Innate Immunity","volume":"345","author":"Saeed","year":"2014","journal-title":"Science"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e1007811","DOI":"10.1371\/journal.ppat.1007811","article-title":"Innate Immune Memory Through TLR2 and NOD2 Contributes to the Control of Leptospira Interrogans Infection","volume":"15","author":"Santecchia","year":"2019","journal-title":"PloS Pathog."},{"key":"B26","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1038\/nature07665","article-title":"Adaptive Immune Features of Natural Killer Cells","volume":"457","author":"Sun","year":"2009","journal-title":"Nature"},{"key":"B27","doi-asserted-by":"publisher","first-page":"4410","DOI":"10.4049\/jimmunol.172.7.4410","article-title":"Subpopulations of Mouse Blood Monocytes Differ in Maturation Stage and Inflammatory Response","volume":"172","author":"Sunderkotter","year":"2004","journal-title":"J. Immunol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/ni1408","article-title":"Dectin-1 Is Required for Beta-Glucan Recognition and Control of Fungal Infection","volume":"8","author":"Taylor","year":"2007","journal-title":"Nat. Immunol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"129","DOI":"10.3109\/13693780902964339","article-title":"Absence of TLR2 Influences Survival of Neutrophils After Infection With Candida Albicans","volume":"48","author":"Tessarolli","year":"2010","journal-title":"Med. Mycol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1126\/science.aat0537","article-title":"Experimental Evolution of a Fungal Pathogen Into a Gut Symbiont","volume":"362","author":"Tso","year":"2018","journal-title":"Science"},{"key":"B31","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1172\/JCI29919","article-title":"Critical Roles for CCR2 and MCP-3 in Monocyte Mobilization From Bone Marrow and Recruitment to Inflammatory Sites","volume":"117","author":"Tsou","year":"2007","journal-title":"J. Clin. Invest."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2021.743735\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T06:31:25Z","timestamp":1637562685000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2021.743735\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,22]]},"references-count":31,"alternative-id":["10.3389\/fcimb.2021.743735"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2021.743735","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,22]]},"article-number":"743735"}}