{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:51:48Z","timestamp":1790077908978,"version":"4.0.1"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2015,2,1]],"date-time":"2015-02-01T00:00:00Z","timestamp":1422748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Blastomyces dermatitidis, a dimorphic fungus and the causative agent of blastomycosis, is widely considered an extracellular pathogen, with little evidence for a facultative intracellular lifestyle. We infected mice with spores, that is, the infectious particle, via the pulmonary route and studied intracellular residence, transition to pathogenic yeast, and replication inside lung cells. Nearly 80% of spores were inside cells at 24 h postinfection with 104 spores. Most spores were located inside of alveolar macrophages, with smaller numbers in neutrophils and dendritic cells. Real-time imaging showed rapid uptake of spores into alveolar macrophages, conversion to yeast, and intracellular multiplication during in vitro coculture. The finding of multiple yeast in a macrophage was chiefly due to intracellular replication rather than multiple phagocytic events or fusion of macrophages. Depletion of alveolar macrophages curtailed infection in mice infected with spores and led to a 26-fold reduction in lung CFU by 6 d postinfection versus nondepleted mice. Phase transition of the spores to yeast was delayed in these depleted mice over a time frame that correlated with reduced lung CFU. Spores cultured in vitro converted to yeast faster in the presence of macrophages than in medium alone. Thus, although advanced B. dermatitidis infection may exhibit extracellular residence in tissue, early lung infection with infectious spores reveals its unappreciated facultative intracellular lifestyle.<\/jats:p>","DOI":"10.4049\/jimmunol.1303089","type":"journal-article","created":{"date-parts":[[2015,1,15]],"date-time":"2015-01-15T06:36:46Z","timestamp":1421303806000},"page":"1796-1805","source":"Crossref","is-referenced-by-count":39,"title":["The Unappreciated Intracellular Lifestyle of <i>Blastomyces dermatitidis<\/i>"],"prefix":"10.1093","volume":"194","author":[{"given":"Alana K","family":"Sterkel","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin\u2013Madison , Madison, WI 53792"},{"name":"Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin\u2013Madison , Madison, WI 53792"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Mettelman","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin\u2013Madison , Madison, WI 53792"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"W\u00fcthrich","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin\u2013Madison , Madison, WI 53792"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce S","family":"Klein","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, University of Wisconsin\u2013Madison , Madison, WI 53792"},{"name":"Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin\u2013Madison , Madison, WI 53792"},{"name":"Department of Internal Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin\u2013Madison , Madison, WI 53792"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,2,15]]},"reference":[{"key":"2025030705055197900_r1","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1053\/adpa.2002.34575","article-title":"Blastomycosis: the great pretender can also be an opportunist. Initial clinical diagnosis and underlying diseases in 123 patients","volume":"6","author":"Lemos","year":"2002","journal-title":"Ann. Diagn. Pathol."},{"key":"2025030705055197900_r2","doi-asserted-by":"crossref","first-page":"50","DOI":"10.7326\/0003-4819-88-1-50","article-title":"Endogenous activation in blastomycosis","volume":"88","author":"Laskey","year":"1978","journal-title":"Ann. Intern. Med."},{"key":"2025030705055197900_r3","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1086\/500405","article-title":"Hospitalizations for endemic mycoses: a population-based national study","volume":"42","author":"Chu","year":"2006","journal-title":"Clin. Infect. Dis."},{"key":"2025030705055197900_r4","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1086\/322606","article-title":"Trends in mortality due to invasive mycotic diseases in the United States, 1980\u20131997","volume":"33","author":"McNeil","year":"2001","journal-title":"Clin. Infect. Dis."},{"key":"2025030705055197900_r5","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1093\/clinids\/13.5.1005","article-title":"Blastomycosis in Africa: clinical features, diagnosis, and treatment","volume":"13","author":"Baily","year":"1991","journal-title":"Rev. Infect. Dis."},{"key":"2025030705055197900_r6","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.4269\/ajtmh.1978.27.1203","article-title":"Occurrence of Blastomyces dermatitidis in Israel. First autochthonous Middle Eastern case","volume":"27","author":"Kuttin","year":"1978","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"2025030705055197900_r7","first-page":"728","article-title":"Blastomycosis: a new endemic focus in Canada","volume":"129","author":"Kane","year":"1983","journal-title":"Can. Med. Assoc. J."},{"key":"2025030705055197900_r8","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/BF02051495","article-title":"Blastomycosis-epidemiology and biology of its etiologic agent Ajellomyces dermatitidis","volume":"41","author":"McDonough","year":"1970","journal-title":"Mycopathol. Mycol. Appl."},{"key":"2025030705055197900_r9","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1093\/ajcp\/21.11.999","article-title":"Blastomycosis","volume":"21","author":"Schwarz","year":"1951","journal-title":"Am. J. Clin. Pathol."},{"key":"2025030705055197900_r10","doi-asserted-by":"crossref","first-page":"e1003027","DOI":"10.1371\/journal.ppat.1003027","article-title":"Morphogenesis in fungal pathogenicity: shape, size, and surface","volume":"8","author":"Wang","year":"2012","journal-title":"PLoS Pathog."},{"key":"2025030705055197900_r11","first-page":"737","article-title":"Intracellular and extracellular defenses of human phagocytes against Blastomyces dermatitidis conidia and yeasts","volume":"105","author":"Drutz","year":"1985","journal-title":"J. Lab. Clin. Med."},{"key":"2025030705055197900_r12","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1126\/science.1124105","article-title":"Global control of dimorphism and virulence in fungi","volume":"312","author":"Nemecek","year":"2006","journal-title":"Science"},{"key":"2025030705055197900_r13","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1164\/ajrccm.149.2.8306053","article-title":"Development of pulmonary infection in mice inoculated with Blastomyces dermatitidis conidia","volume":"149","author":"Williams","year":"1994","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025030705055197900_r14","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/978-3-642-66703-9_5","article-title":"Blastomycosis. A review of 152 cases","volume":"65","author":"Schwarz","year":"1977","journal-title":"Curr. Top. Pathol."},{"key":"2025030705055197900_r15","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1093\/ajcp\/54.3.384","article-title":"North American blastomycosis: a study of ten cases","volume":"54","author":"Van\u0115k","year":"1970","journal-title":"Am. J. Clin. Pathol."},{"key":"2025030705055197900_r16","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1093\/infdis\/151.1.57","article-title":"Intracellular growth and phagocytosis of Blastomyces dermatitidis by monocyte-derived macrophages from previously infected and normal subjects","volume":"151","author":"Bradsher","year":"1985","journal-title":"J. Infect. Dis."},{"key":"2025030705055197900_r17","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1128\/EC.00401-06","article-title":"Development and application of a green fluorescent protein sentinel system for identification of RNA interference in Blastomyces dermatitidis illuminates the role of septin in morphogenesis and sporulation","volume":"6","author":"Krajaejun","year":"2007","journal-title":"Eukaryot. Cell"},{"key":"2025030705055197900_r18","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1046\/j.1365-2958.2001.02300.x","article-title":"Selective expression of the virulence factor BAD1 upon morphogenesis to the pathogenic yeast form of Blastomyces dermatitidis: evidence for transcriptional regulation by a conserved mechanism","volume":"39","author":"Rooney","year":"2001","journal-title":"Mol. Microbiol."},{"key":"2025030705055197900_r19","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1165\/rcmb.2012-0366MA","article-title":"Identification of myeloid cell subsets in murine lungs using flow cytometry","volume":"49","author":"Zaynagetdinov","year":"2013","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025030705055197900_r20","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1165\/rcmb.2013-0086MA","article-title":"Flow cytometric analysis of macrophages and dendritic cell subsets in the mouse lung","volume":"49","author":"Misharin","year":"2013","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025030705055197900_r21","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1182\/blood-2012-07-445197","article-title":"Emergence, origin, and function of neutrophil-dendritic cell hybrids in experimentally induced inflammatory lesions in mice","volume":"121","author":"Geng","year":"2013","journal-title":"Blood"},{"key":"2025030705055197900_r22","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1086\/315473","article-title":"Investigation of anti-WI-1 adhesin antibody-mediated protection in experimental pulmonary blastomycosis","volume":"181","author":"W\u00fcthrich","year":"2000","journal-title":"J. Infect. Dis."},{"key":"2025030705055197900_r23","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.tcb.2009.07.005","article-title":"Molecular mediators of macrophage fusion","volume":"19","author":"Helming","year":"2009","journal-title":"Trends Cell Biol."},{"key":"2025030705055197900_r24","doi-asserted-by":"crossref","first-page":"6428","DOI":"10.4049\/jimmunol.175.10.6428","article-title":"CD11chigh dendritic cell ablation impairs lymphopenia-driven proliferation of naive and memory CD8+ T cells","volume":"175","author":"Zaft","year":"2005","journal-title":"J. Immunol."},{"key":"2025030705055197900_r25","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1084\/jem.187.7.1019","article-title":"Neutrophil granulocyte-committed cells can be driven to acquire dendritic cell characteristics","volume":"187","author":"Oehler","year":"1998","journal-title":"J. Exp. Med."},{"key":"2025030705055197900_r26","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1002\/eji.200636788","article-title":"Macrophage fusion induced by IL-4 alternative activation is a multistage process involving multiple target molecules","volume":"37","author":"Helming","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"2025030705055197900_r27","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1128\/iai.36.1.297-303.1982","article-title":"Opposite effects of human monocytes, macrophages, and polymorphonuclear neutrophils on replication of Blastomyces dermatitidis in vitro","volume":"36","author":"Brummer","year":"1982","journal-title":"Infect. Immun."},{"key":"2025030705055197900_r28","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/nmeth.1905","article-title":"Functionally relevant neutrophilia in CD11c diphtheria toxin receptor transgenic mice","volume":"9","author":"Tittel","year":"2012","journal-title":"Nat. Methods"},{"key":"2025030705055197900_r29","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1080\/02681218880000461","article-title":"Experimental blastomycosis pneumonia in mice by infection with conidia","volume":"26","author":"Sugar","year":"1988","journal-title":"J. Med. Vet. Mycol."},{"key":"2025030705055197900_r30","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.1128\/IAI.01249-10","article-title":"Blastomyces dermatitidis yeast cells inhibit nitric oxide production by alveolar macrophage inducible nitric oxide synthase","volume":"79","author":"Rocco","year":"2011","journal-title":"Infect. Immun."},{"key":"2025030705055197900_r31","doi-asserted-by":"crossref","first-page":"2665","DOI":"10.4049\/jimmunol.166.4.2665","article-title":"The WI-1 adhesin blocks phagocyte TNF-\u03b1 production, imparting pathogenicity on Blastomyces dermatitidis","volume":"166","author":"Finkel-Jimenez","year":"2001","journal-title":"J. Immunol."},{"key":"2025030705055197900_r32","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1093\/infdis\/163.2.371","article-title":"Macrophage- and oxidant-mediated inhibition of the ability of live Blastomyces dermatitidis conidia to transform to the pathogenic yeast phase: implications for the pathogenesis of dimorphic fungal infections","volume":"163","author":"Sugar","year":"1991","journal-title":"J. Infect. Dis."},{"key":"2025030705055197900_r33","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/BF00436902","article-title":"Live Blastomyces dermatitidis yeast-induced responses of immune and nonimmune human mononuclear cells","volume":"87","author":"Bradsher","year":"1984","journal-title":"Mycopathologia"},{"key":"2025030705055197900_r34","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/S0378-1097(03)00384-7","article-title":"The budding index of Saccharomyces cerevisiae deletion strains identifies genes important for cell cycle progression","volume":"223","author":"Zettel","year":"2003","journal-title":"FEMS Microbiol. Lett."},{"key":"2025030705055197900_r35","first-page":"388","article-title":"Characterization of the biological activity of Cryptococcus infections in surgical pathology. The Budding Index and Carminophilic Index","volume":"18","author":"Schwartz","year":"1988","journal-title":"Ann. Clin. Lab. Sci."},{"key":"2025030705055197900_r36","doi-asserted-by":"crossref","first-page":"4225","DOI":"10.1128\/IAI.68.7.4225-4237.2000","article-title":"Cryptococcus neoformans is a facultative intracellular pathogen in murine pulmonary infection","volume":"68","author":"Feldmesser","year":"2000","journal-title":"Infect. Immun."},{"key":"2025030705055197900_r37","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/978-1-60761-421-0_28","article-title":"Defining in vivo dendritic cell functions using CD11c-DTR transgenic mice","volume":"595","author":"Bar-On","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"2025030705055197900_r38","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1111\/cmi.12067","article-title":"Cryptococcus interactions with macrophages: evasion and manipulation of the phagosome by a fungal pathogen","volume":"15","author":"Johnston","year":"2013","journal-title":"Cell. Microbiol."},{"key":"2025030705055197900_r39","doi-asserted-by":"crossref","first-page":"2596","DOI":"10.1172\/JCI116498","article-title":"Enhancement of macrophage candidacidal activity by interferon-gamma. Increased phagocytosis, killing, and calcium signal mediated by a decreased number of mannose receptors","volume":"91","author":"Mar\u00f3di","year":"1993","journal-title":"J. Clin. Invest."},{"key":"2025030705055197900_r40","doi-asserted-by":"crossref","first-page":"3244","DOI":"10.4049\/jimmunol.175.5.3244","article-title":"An innate immune system cell is a major determinant of species-related susceptibility differences to fungal pneumonia","volume":"175","author":"Shao","year":"2005","journal-title":"J. Immunol."},{"key":"2025030705055197900_r41","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.fgb.2013.04.005","article-title":"Binding of the wheat germ lectin to Cryptococcus neoformans chitooligomers affects multiple mechanisms required for fungal pathogenesis","volume":"60","author":"Fonseca","year":"2013","journal-title":"Fungal Genet. Biol."},{"key":"2025030705055197900_r42","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1016\/S1286-4579(00)01317-4","article-title":"Leukocyte-facilitated entry of intracellular pathogens into the central nervous system","volume":"2","author":"Drevets","year":"2000","journal-title":"Microbes Infect."},{"key":"2025030705055197900_r43","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1086\/341564","article-title":"Pathogenesis of cerebral Cryptococcus neoformans infection after fungemia","volume":"186","author":"Chr\u00e9tien","year":"2002","journal-title":"J. Infect. Dis."},{"key":"2025030705055197900_r44","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1128\/IAI.01065-08","article-title":"Evidence of a role for monocytes in dissemination and brain invasion by Cryptococcus neoformans","volume":"77","author":"Charlier","year":"2009","journal-title":"Infect. Immun."},{"key":"2025030705055197900_r45","doi-asserted-by":"crossref","first-page":"4985","DOI":"10.1128\/IAI.72.9.4985-4995.2004","article-title":"Cryptococcal yeast cells invade the central nervous system via transcellular penetration of the blood-brain barrier","volume":"72","author":"Chang","year":"2004","journal-title":"Infect. Immun."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/194\/4\/1796\/62236280\/1303089.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/194\/4\/1796\/62236280\/1303089.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T06:28:33Z","timestamp":1741328913000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/194\/4\/1796\/7961016"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,2]]},"references-count":45,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2015,2,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1303089","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,2]]},"published":{"date-parts":[[2015,2]]}}}