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.

Endothelial nitric oxide synthase limits host immunity to control disseminated Candida albicans infections in mice

“…Nos3 -/- mice had significantly lower kidney neutrophil infiltration compared with infected WT kidneys. Kidney is the major target organ in disseminated candidiasis and is responsible for mouse mortality as shown previously [24,35,36,43,47,54,55]. The decreased recruitment of innate immune cells was associated with a decreased fungal burden at the sub-acute phase in the infected Nos3 -/- kidneys.…”

Whole RNA-Sequencing and Transcriptome Assembly of Candida albicans and Candida africana under Chlamydospore-Inducing Conditions

“…The biological function of chlamydospores is unknown and the reasons why only C. albicans , and its closely related species C. dubliniensis , have retained this phenotype throughout evolution remains a mystery ( Palige et al 2013 ; Navarathna et al 2016 ).…”

“…It was proposed that chlamydospores could allow the survival of the fungus in harsh environmental conditions or, given that C. albicans and C. dubliniensis are restricted to humans, could facilitate persistence or survival of these species within the mammalian host ( Staib and Morschhäuser 2007 ). However, rarely have chlamydospores been observed in infected tissues ( Heineman et al 1961 ; Ho and O'Day 1981 ; Chabasse et al 1988 ; Cole et al 1991 ) although a recent study documenting their formation in the kidneys of experimentally infected mice suggested a role in pathogenesis ( Navarathna et al 2016 ).…”

A Homeobox Transcription Factor UvHOX2 Regulates Chlamydospore Formation, Conidiogenesis, and Pathogenicity in Ustilaginoidea virens

“…In the human pathogenic yeast Candida albicans , several genes were found to be involved in chlamydospore formation, including homeobox transcription factor (TF) gene grf10 (Ghosh et al, 2015), phosphate mannose synthase encoding genes (Juchimiuk et al, 2015), mitogen-activated protein kinase gene hog1 (Eisman et al, 2006), gene encoding dolichol phosphate mannose synthase (Juchimiuk et al, 2015), chromatin remodeling complex gene isw2 (Nobile et al, 2003; Navarathna et al, 2016), MDS3, RIM101, RIM13, SCH9 , and SUV3 (Nobile et al, 2003). Meanwhile, very few genes in filamentous fungi were found relative to chlamydospore formation, the limited examples include VELVET gene vel1 in biocontrol fungus Trichoderma virens (Mukherjee and Kenerley, 2010); and a group of genes in Clonostachys rosea identified from a study using RNA-seq (Sun et al, 2018).…”