title: Candida albicans ISW2 Regulates Chlamydospore Suspensor Cell Formation and Virulence In Vivo in a Mouse Model of Disseminated Candidiasis.
abstract: Formation of chlamydospores by Candida albicans was an established medical diagnostic test to confirm candidiasis before the molecular era. However, the functional role and pathological relevance of this in vitro morphological transition to pathogenesis in vivo remain unclear. We compared the physical properties of in vitro-induced chlamydospores with those of large C. albicans cells purified by density gradient centrifugation from Candida-infected mouse kidneys. The morphological and physical properties of these cells in kidneys of mice infected intravenously with wild type C. albicans confirmed that chlamydospores can form in infected kidneys. A previously reported chlamydospore-null Δisw2/Δisw2 mutant was used to investigate its role in virulence and chlamydospore induction. Virulence of the Δisw2/Δisw2 mutant strain was reduced 3.4-fold compared to wild type C. albicans or the ISW2 reconstituted strain. Altered host inflammatory reactions to the null mutant further indicate that ISW2 is a virulence factor in C. albicans. ISW2 deletion abolished chlamydospore formation within infected mouse kidneys, whereas the reconstituted strain restored chlamydospore formation in kidneys. Under chlamydospore inducing conditions in vitro, deletion of ISW2 significantly delayed chlamydospore formation, and those late induced chlamydospores lacked associated suspensor cells while attaching laterally to hyphae via novel spore-hypha septa. Our findings establish the induction of chlamydospores by C. albicans during mouse kidney colonization. Our results indicate that ISW2 is not strictly required for chlamydospores formation but is necessary for suspensor cell formation. The importance of ISW2 in chlamydospore morphogenesis and virulence may lead to additional insights into morphological differentiation and pathogenesis of C. albicans in the host microenvironment.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Dhammika H M L P
authors.initials: DH
authors.lastname: Navarathna
authors.affiliation: School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America.
authors.forename: Ruvini U
authors.initials: RU
authors.lastname: Pathirana
authors.affiliation: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Michail S
authors.initials: MS
authors.lastname: Lionakis
authors.affiliation: School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Nickerson
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: David D
authors.identifier: http://orcid.org/0000-0002-2481-2981
authors.initials: DD
authors.lastname: Roberts
mesh_terms: D000251:Adenosine Triphosphatases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002176:Candida albicans / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity*; D002177:Candidiasis / Q000382:microbiology / Q000473:pathology*; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D005838:Genotype; D007668:Kidney / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008858:Microscopy, Phase-Contrast; D013172:Spores, Fungal / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014774:Virulence
chemical_list: D018925:Chemokines; D016207:Cytokines; D005656:Fungal Proteins; C086468:ISWI protein; D014157:Transcription Factors; D000251:Adenosine Triphosphatases