@article{ad9e72c6f4ca4c028a97389d540acbaf,
title = "Rewilding of laboratory mice enhances granulopoiesis and immunity through intestinal fungal colonization",
abstract = "The paucity of blood granulocyte populations such as neutrophils in laboratory mice is a notable difference between this model organism and humans, but the cause of this species-specific difference is unclear. We previously demonstrated that laboratory mice released into a seminatural environment, referred to as rewilding, display an increase in blood granulocytes that is associated with expansion of fungi in the gut microbiota. Here, we find that tonic signals from fungal colonization induce sustained granulopoiesis through a mechanism distinct from emergency granulopoiesis, leading to a prolonged expansion of circulating neutrophils that promotes immunity. Fungal colonization after either rewilding or oral inoculation of laboratory mice with Candida albicans induced persistent expansion of myeloid progenitors in the bone marrow. This increase in granulopoiesis conferred greater long-term protection from bloodstream infection by gram-positive bacteria than by the trained immune response evoked by transient exposure to the fungal cell wall component β-glucan. Consequently, introducing fungi into laboratory mice may restore aspects of leukocyte development and provide a better model for humans and free-living mammals that are constantly exposed to environmental fungi.",
author = "Chen, {Ying Han} and Frank Yeung and Lacey, {Keenan A.} and Kimberly Zaldana and Lin, {Jian Da} and Bee, {Gavyn Chern Wei} and Caroline McCauley and Barre, {Ramya S.} and Liang, {Shen Huan} and Hansen, {Christina B.} and Downie, {Alexander E.} and Kyle Tio and Weiser, {Jeffrey N.} and Torres, {Victor J.} and Bennett, {Richard J.} and P{\textquoteright}ng Loke and Graham, {Andrea L.} and Ken Cadwell",
note = "Funding Information: Acknowledgments:W ethanktheNYUGrossmanSchoolofMedicineFlowCytometryandCell Sorting,Microscopy,GenomicT echnology ,andHistologyCores(supportedbyNIHgrants P31CA016087,S10OD01058,andS10OD018338)andM.Alva,J.Carrasquillo,andD.Basnightof theGnotobioticsfacilityfortheirtechnicalsupportanduseofinstruments.Funding:This research was supported by NIH grants DK093668 (K.C.), AI121244 (K.C. and V .J.T .), HL123340 (K.C.),AI130945(K.C.),AI140754(K.C.),DK124336(K.C.),andDK122698(F .Y .), AI140754(K.C.and V .J.T .), andIntramuralResearchProgramoftheNIAID,NIH(P .L.). Additionalsupportwas provided by the Fa culty Scholar grant from the Howard Hughes Medical Institute (K.C.), Crohn{\textquoteright}s &ColitisFoundation(K.C.andJ.A.),KennethRaininFoundation(K.C.),Judith&Stew art Colton Center of Autoimmunity (K.C. and J.A.), research station and research rebate awards from PU EEB(A.L.G.),NationalScienceFoundation(A.L.G.).K.C.andV .J.T .areaBurroughsW ellcome Fund Investiga tors inthePa thogenesis ofInfectiousDiseases.Thisworkwasalsosupportedbythe BernardLevinePostdoctoralResearchFellowshipinImmunology(Y .-H.C.) andtheCharles H.RevsonSeniorFellowshipsinBiomedicalScience(Y .-H.C.) andaCysticFibrosisFoundation postdoctoralfellowshipawardLA CEY19F O(K.A.L.).Authorcontributions:Designof experiments,dataanalysis,datadiscussion,andinterpretation:Y .-H.C., F .Y ., P .L., A.L.G.,andK.C.; primaryresponsibilityforexecutionofexperiments:Y .-H.C., F .Y ., K.A.L.,K.Z.,J.-D.L.,andG.C.W .B.; generation of C. albicans efg1∆/∆ and flo8∆/∆ strains: S.-H.L. and R.J.B. Y .-H.C. and K.C. wrote themanuscriptwiththehelpofallotherauthors.Competinginterests:K.C.hasreceived research support from Pfizer, Takeda, Pa cific Biosciences, Genentech, and Abbvie. K.C. has consultedfororreceivedanhonorariafromPuretechHealth,Genentech,andAbbvie.K.C.isan inventoronU.S.patent10,722,600andprovisionalpatent62/935,035and63/157,225.V .J.T .has consulted for Janssen Research & Development LLC, and hav e received honoraria from GenentechandMedimmune.Heisalsoaninventoronpatentsandpatentapplicationsfiledby NewYorkUniversity,whicharecurrentlyundercommerciallicensetoJanssenBiotechInc. JanssenBiotechInc.pro vides researchfundingandotherpaymentsassociatedwithalicensing agreement.Dataandmaterialsavailability:ThescRNAsequencingdataforthisstudyhave beendepositedinGEO(GSE231824).RequestsforfungalstrainsshouldbeaddressedtoK.C. (forwildfungi)orR.J.B.(forC.albicans)andshouldbecoveredbyamaterialtransferagreement. Requests for Rorc−/− mice should be addressed to the donating investigator. All other geneticallyengineeredmiceusedinthisstudyarecommerciallyavailable.Alldataneededto evaluatetheconclusionsinthepaperarepresentinthepaperortheSupplementaryMaterials. Funding Information: This research was supported by NIH grants DK093668 (K.C.), AI121244 (K.C. and V.J.T.), HL123340 (K.C.), AI130945 (K.C.), AI140754 (K.C.), DK124336 (K.C.), and DK122698 (F.Y.), AI140754 (K.C. and V.J.T.), and Intramural Research Program of the NIAID, NIH (P.L.). Additional support was provided by the Faculty Scholar grant from the Howard Hughes Medical Institute (K.C.), Crohn{\textquoteright}s & Colitis Foundation (K.C. and J.A.), Kenneth Rainin Foundation (K.C.), Judith & Stewart Colton Center of Autoimmunity (K.C. and J.A.), research station and research rebate awards from PU EEB (A.L.G.), National Science Foundation (A.L.G.). K.C. and V.J.T. are a Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases. This work was also supported by the Bernard Levine Postdoctoral Research Fellowship in Immunology (Y.-H.C.) and the Charles H. Revson Senior Fellowships in Biomedical Science (Y.-H.C.) and a Cystic Fibrosis Foundation postdoctoral fellowship award LACEY19FO (K.A.L.). Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved.",
year = "2023",
month = jun,
doi = "10.1126/sciimmunol.add6910",
language = "English (US)",
volume = "8",
journal = "Science immunology",
issn = "2470-9468",
publisher = "American Association for the Advancement of Science",
number = "84",
}