Overlooked Candida glabrata petites are echinocandin tolerant, induce host inflammatory responses, and display poor in vivo fitness

ABSTRACT Small colony variants are relatively common among some bacterial species and are associated with poor prognosis and recalcitrant infections. Similarly, Candida glabrata—a major intracellular fungal pathogen—produces small and slow-growing respiratory-deficient colonies, termed “petite.” Despite reports of clinical petite C. glabrata strains, our understanding of petite behavior in the host remains obscure. Moreover, controversies exist regarding in-host petite fitness and its clinical relevance. Herein, we employed whole-genome sequencing (WGS), dual-RNAseq, and extensive ex vivo and in vivo studies to fill this knowledge gap. WGS identified multiple petite-specific mutations in nuclear and mitochondrially encoded genes. Consistent with dual-RNAseq data, petite C. glabrata cells did not replicate inside host macrophages and were outcompeted by their non-petite parents in macrophages and in gut colonization and systemic infection mouse models. The intracellular petites showed hallmarks of drug tolerance and were relatively insensitive to the fungicidal activity of echinocandin drugs. Petite-infected macrophages exhibited a pro-inflammatory and type I IFN-skewed transcriptional program. Interrogation of international C. glabrata blood isolates (n = 1000) showed that petite prevalence varies by country, albeit at an overall low prevalence (0%–3.5%). Collectively, our study sheds new light on the genetic basis, drug susceptibility, clinical prevalence, and host-pathogen responses of a clinically overlooked phenotype in a major fungal pathogen. Importance Candida glabrata is a major fungal pathogen, which is able to lose mitochondria and form small and slow-growing colonies, called “petite.” This attenuated growth rate has created controversies and questioned the clinical importance of petiteness. Herein, we have employed multiple omics technologies and in vivo mouse models to critically assess the clinical importance of petite phenotype. Our WGS identifies multiple genes potentially underpinning petite phenotype. Interestingly, petite C. glabrata cells engulfed by macrophages are dormant and, therefore, are not killed by the frontline antifungal drugs. Interestingly, macrophages infected with petite cells mount distinct transcriptomic responses. Consistent with our ex vivo observations, mitochondrial-proficient parental strains outcompete petites during systemic and gut colonization. Retrospective examination of C. glabrata isolates identified petite prevalence a rare entity, which can significantly vary from country to country. Collectively, our study overcomes the existing controversies and provides novel insights regarding the clinical relevance of petite C. glabrata isolates. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Amir Arastehfar [verfasserIn] Farnaz Daneshnia [verfasserIn] Hrant Hovhannisyan [verfasserIn] Diego Fuentes [verfasserIn] Nathaly Cabrera [verfasserIn] Christopher Quinteros [verfasserIn] Macit Ilkit [verfasserIn] Nevzat Ünal [verfasserIn] Suleyha Hilmioğlu-Polat [verfasserIn] Kauser Jabeen [verfasserIn] Sadaf Zaka [verfasserIn] Jigar V. Desai [verfasserIn] Cornelia Lass-Flörl [verfasserIn] Erika Shor [verfasserIn] Toni Gabaldon [verfasserIn] David S. Perlin [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	Candida glabrata petite toelrance drug resistance

Übergeordnetes Werk:	In: mBio - American Society for Microbiology, 2010, 14(2023), 5
Übergeordnetes Werk:	volume:14 ; year:2023 ; number:5

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1128/mbio.01180-23

Katalog-ID:	DOAJ090977114

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520			\|a ABSTRACT Small colony variants are relatively common among some bacterial species and are associated with poor prognosis and recalcitrant infections. Similarly, Candida glabrata—a major intracellular fungal pathogen—produces small and slow-growing respiratory-deficient colonies, termed “petite.” Despite reports of clinical petite C. glabrata strains, our understanding of petite behavior in the host remains obscure. Moreover, controversies exist regarding in-host petite fitness and its clinical relevance. Herein, we employed whole-genome sequencing (WGS), dual-RNAseq, and extensive ex vivo and in vivo studies to fill this knowledge gap. WGS identified multiple petite-specific mutations in nuclear and mitochondrially encoded genes. Consistent with dual-RNAseq data, petite C. glabrata cells did not replicate inside host macrophages and were outcompeted by their non-petite parents in macrophages and in gut colonization and systemic infection mouse models. The intracellular petites showed hallmarks of drug tolerance and were relatively insensitive to the fungicidal activity of echinocandin drugs. Petite-infected macrophages exhibited a pro-inflammatory and type I IFN-skewed transcriptional program. Interrogation of international C. glabrata blood isolates (n = 1000) showed that petite prevalence varies by country, albeit at an overall low prevalence (0%–3.5%). Collectively, our study sheds new light on the genetic basis, drug susceptibility, clinical prevalence, and host-pathogen responses of a clinically overlooked phenotype in a major fungal pathogen. Importance Candida glabrata is a major fungal pathogen, which is able to lose mitochondria and form small and slow-growing colonies, called “petite.” This attenuated growth rate has created controversies and questioned the clinical importance of petiteness. Herein, we have employed multiple omics technologies and in vivo mouse models to critically assess the clinical importance of petite phenotype. Our WGS identifies multiple genes potentially underpinning petite phenotype. Interestingly, petite C. glabrata cells engulfed by macrophages are dormant and, therefore, are not killed by the frontline antifungal drugs. Interestingly, macrophages infected with petite cells mount distinct transcriptomic responses. Consistent with our ex vivo observations, mitochondrial-proficient parental strains outcompete petites during systemic and gut colonization. Retrospective examination of C. glabrata isolates identified petite prevalence a rare entity, which can significantly vary from country to country. Collectively, our study overcomes the existing controversies and provides novel insights regarding the clinical relevance of petite C. glabrata isolates.
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allfields	10.1128/mbio.01180-23 doi (DE-627)DOAJ090977114 (DE-599)DOAJ7b0745a56b2f4ec6a459e59902a53e67 DE-627 ger DE-627 rakwb eng QR1-502 Amir Arastehfar verfasserin aut Overlooked Candida glabrata petites are echinocandin tolerant, induce host inflammatory responses, and display poor in vivo fitness 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier ABSTRACT Small colony variants are relatively common among some bacterial species and are associated with poor prognosis and recalcitrant infections. Similarly, Candida glabrata—a major intracellular fungal pathogen—produces small and slow-growing respiratory-deficient colonies, termed “petite.” Despite reports of clinical petite C. glabrata strains, our understanding of petite behavior in the host remains obscure. Moreover, controversies exist regarding in-host petite fitness and its clinical relevance. Herein, we employed whole-genome sequencing (WGS), dual-RNAseq, and extensive ex vivo and in vivo studies to fill this knowledge gap. WGS identified multiple petite-specific mutations in nuclear and mitochondrially encoded genes. Consistent with dual-RNAseq data, petite C. glabrata cells did not replicate inside host macrophages and were outcompeted by their non-petite parents in macrophages and in gut colonization and systemic infection mouse models. The intracellular petites showed hallmarks of drug tolerance and were relatively insensitive to the fungicidal activity of echinocandin drugs. Petite-infected macrophages exhibited a pro-inflammatory and type I IFN-skewed transcriptional program. Interrogation of international C. glabrata blood isolates (n = 1000) showed that petite prevalence varies by country, albeit at an overall low prevalence (0%–3.5%). Collectively, our study sheds new light on the genetic basis, drug susceptibility, clinical prevalence, and host-pathogen responses of a clinically overlooked phenotype in a major fungal pathogen. Importance Candida glabrata is a major fungal pathogen, which is able to lose mitochondria and form small and slow-growing colonies, called “petite.” This attenuated growth rate has created controversies and questioned the clinical importance of petiteness. Herein, we have employed multiple omics technologies and in vivo mouse models to critically assess the clinical importance of petite phenotype. Our WGS identifies multiple genes potentially underpinning petite phenotype. Interestingly, petite C. glabrata cells engulfed by macrophages are dormant and, therefore, are not killed by the frontline antifungal drugs. Interestingly, macrophages infected with petite cells mount distinct transcriptomic responses. Consistent with our ex vivo observations, mitochondrial-proficient parental strains outcompete petites during systemic and gut colonization. Retrospective examination of C. glabrata isolates identified petite prevalence a rare entity, which can significantly vary from country to country. Collectively, our study overcomes the existing controversies and provides novel insights regarding the clinical relevance of petite C. glabrata isolates. Candida glabrata petite toelrance drug resistance Microbiology Farnaz Daneshnia verfasserin aut Hrant Hovhannisyan verfasserin aut Diego Fuentes verfasserin aut Nathaly Cabrera verfasserin aut Christopher Quinteros verfasserin aut Macit Ilkit verfasserin aut Nevzat Ünal verfasserin aut Suleyha Hilmioğlu-Polat verfasserin aut Kauser Jabeen verfasserin aut Sadaf Zaka verfasserin aut Jigar V. Desai verfasserin aut Cornelia Lass-Flörl verfasserin aut Erika Shor verfasserin aut Toni Gabaldon verfasserin aut David S. Perlin verfasserin aut In mBio American Society for Microbiology, 2010 14(2023), 5 (DE-627)627613543 (DE-600)2557172-2 21507511 nnns volume:14 year:2023 number:5 https://doi.org/10.1128/mbio.01180-23 kostenfrei https://doaj.org/article/7b0745a56b2f4ec6a459e59902a53e67 kostenfrei https://journals.asm.org/doi/10.1128/mbio.01180-23 kostenfrei https://doaj.org/toc/2150-7511 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023 5
spelling	10.1128/mbio.01180-23 doi (DE-627)DOAJ090977114 (DE-599)DOAJ7b0745a56b2f4ec6a459e59902a53e67 DE-627 ger DE-627 rakwb eng QR1-502 Amir Arastehfar verfasserin aut Overlooked Candida glabrata petites are echinocandin tolerant, induce host inflammatory responses, and display poor in vivo fitness 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier ABSTRACT Small colony variants are relatively common among some bacterial species and are associated with poor prognosis and recalcitrant infections. Similarly, Candida glabrata—a major intracellular fungal pathogen—produces small and slow-growing respiratory-deficient colonies, termed “petite.” Despite reports of clinical petite C. glabrata strains, our understanding of petite behavior in the host remains obscure. Moreover, controversies exist regarding in-host petite fitness and its clinical relevance. Herein, we employed whole-genome sequencing (WGS), dual-RNAseq, and extensive ex vivo and in vivo studies to fill this knowledge gap. WGS identified multiple petite-specific mutations in nuclear and mitochondrially encoded genes. Consistent with dual-RNAseq data, petite C. glabrata cells did not replicate inside host macrophages and were outcompeted by their non-petite parents in macrophages and in gut colonization and systemic infection mouse models. The intracellular petites showed hallmarks of drug tolerance and were relatively insensitive to the fungicidal activity of echinocandin drugs. Petite-infected macrophages exhibited a pro-inflammatory and type I IFN-skewed transcriptional program. Interrogation of international C. glabrata blood isolates (n = 1000) showed that petite prevalence varies by country, albeit at an overall low prevalence (0%–3.5%). Collectively, our study sheds new light on the genetic basis, drug susceptibility, clinical prevalence, and host-pathogen responses of a clinically overlooked phenotype in a major fungal pathogen. Importance Candida glabrata is a major fungal pathogen, which is able to lose mitochondria and form small and slow-growing colonies, called “petite.” This attenuated growth rate has created controversies and questioned the clinical importance of petiteness. Herein, we have employed multiple omics technologies and in vivo mouse models to critically assess the clinical importance of petite phenotype. Our WGS identifies multiple genes potentially underpinning petite phenotype. Interestingly, petite C. glabrata cells engulfed by macrophages are dormant and, therefore, are not killed by the frontline antifungal drugs. Interestingly, macrophages infected with petite cells mount distinct transcriptomic responses. Consistent with our ex vivo observations, mitochondrial-proficient parental strains outcompete petites during systemic and gut colonization. Retrospective examination of C. glabrata isolates identified petite prevalence a rare entity, which can significantly vary from country to country. Collectively, our study overcomes the existing controversies and provides novel insights regarding the clinical relevance of petite C. glabrata isolates. Candida glabrata petite toelrance drug resistance Microbiology Farnaz Daneshnia verfasserin aut Hrant Hovhannisyan verfasserin aut Diego Fuentes verfasserin aut Nathaly Cabrera verfasserin aut Christopher Quinteros verfasserin aut Macit Ilkit verfasserin aut Nevzat Ünal verfasserin aut Suleyha Hilmioğlu-Polat verfasserin aut Kauser Jabeen verfasserin aut Sadaf Zaka verfasserin aut Jigar V. Desai verfasserin aut Cornelia Lass-Flörl verfasserin aut Erika Shor verfasserin aut Toni Gabaldon verfasserin aut David S. Perlin verfasserin aut In mBio American Society for Microbiology, 2010 14(2023), 5 (DE-627)627613543 (DE-600)2557172-2 21507511 nnns volume:14 year:2023 number:5 https://doi.org/10.1128/mbio.01180-23 kostenfrei https://doaj.org/article/7b0745a56b2f4ec6a459e59902a53e67 kostenfrei https://journals.asm.org/doi/10.1128/mbio.01180-23 kostenfrei https://doaj.org/toc/2150-7511 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023 5
allfields_unstemmed	10.1128/mbio.01180-23 doi (DE-627)DOAJ090977114 (DE-599)DOAJ7b0745a56b2f4ec6a459e59902a53e67 DE-627 ger DE-627 rakwb eng QR1-502 Amir Arastehfar verfasserin aut Overlooked Candida glabrata petites are echinocandin tolerant, induce host inflammatory responses, and display poor in vivo fitness 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier ABSTRACT Small colony variants are relatively common among some bacterial species and are associated with poor prognosis and recalcitrant infections. Similarly, Candida glabrata—a major intracellular fungal pathogen—produces small and slow-growing respiratory-deficient colonies, termed “petite.” Despite reports of clinical petite C. glabrata strains, our understanding of petite behavior in the host remains obscure. Moreover, controversies exist regarding in-host petite fitness and its clinical relevance. Herein, we employed whole-genome sequencing (WGS), dual-RNAseq, and extensive ex vivo and in vivo studies to fill this knowledge gap. WGS identified multiple petite-specific mutations in nuclear and mitochondrially encoded genes. Consistent with dual-RNAseq data, petite C. glabrata cells did not replicate inside host macrophages and were outcompeted by their non-petite parents in macrophages and in gut colonization and systemic infection mouse models. The intracellular petites showed hallmarks of drug tolerance and were relatively insensitive to the fungicidal activity of echinocandin drugs. Petite-infected macrophages exhibited a pro-inflammatory and type I IFN-skewed transcriptional program. Interrogation of international C. glabrata blood isolates (n = 1000) showed that petite prevalence varies by country, albeit at an overall low prevalence (0%–3.5%). Collectively, our study sheds new light on the genetic basis, drug susceptibility, clinical prevalence, and host-pathogen responses of a clinically overlooked phenotype in a major fungal pathogen. Importance Candida glabrata is a major fungal pathogen, which is able to lose mitochondria and form small and slow-growing colonies, called “petite.” This attenuated growth rate has created controversies and questioned the clinical importance of petiteness. Herein, we have employed multiple omics technologies and in vivo mouse models to critically assess the clinical importance of petite phenotype. Our WGS identifies multiple genes potentially underpinning petite phenotype. Interestingly, petite C. glabrata cells engulfed by macrophages are dormant and, therefore, are not killed by the frontline antifungal drugs. Interestingly, macrophages infected with petite cells mount distinct transcriptomic responses. Consistent with our ex vivo observations, mitochondrial-proficient parental strains outcompete petites during systemic and gut colonization. Retrospective examination of C. glabrata isolates identified petite prevalence a rare entity, which can significantly vary from country to country. Collectively, our study overcomes the existing controversies and provides novel insights regarding the clinical relevance of petite C. glabrata isolates. Candida glabrata petite toelrance drug resistance Microbiology Farnaz Daneshnia verfasserin aut Hrant Hovhannisyan verfasserin aut Diego Fuentes verfasserin aut Nathaly Cabrera verfasserin aut Christopher Quinteros verfasserin aut Macit Ilkit verfasserin aut Nevzat Ünal verfasserin aut Suleyha Hilmioğlu-Polat verfasserin aut Kauser Jabeen verfasserin aut Sadaf Zaka verfasserin aut Jigar V. Desai verfasserin aut Cornelia Lass-Flörl verfasserin aut Erika Shor verfasserin aut Toni Gabaldon verfasserin aut David S. Perlin verfasserin aut In mBio American Society for Microbiology, 2010 14(2023), 5 (DE-627)627613543 (DE-600)2557172-2 21507511 nnns volume:14 year:2023 number:5 https://doi.org/10.1128/mbio.01180-23 kostenfrei https://doaj.org/article/7b0745a56b2f4ec6a459e59902a53e67 kostenfrei https://journals.asm.org/doi/10.1128/mbio.01180-23 kostenfrei https://doaj.org/toc/2150-7511 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023 5
allfieldsGer	10.1128/mbio.01180-23 doi (DE-627)DOAJ090977114 (DE-599)DOAJ7b0745a56b2f4ec6a459e59902a53e67 DE-627 ger DE-627 rakwb eng QR1-502 Amir Arastehfar verfasserin aut Overlooked Candida glabrata petites are echinocandin tolerant, induce host inflammatory responses, and display poor in vivo fitness 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier ABSTRACT Small colony variants are relatively common among some bacterial species and are associated with poor prognosis and recalcitrant infections. Similarly, Candida glabrata—a major intracellular fungal pathogen—produces small and slow-growing respiratory-deficient colonies, termed “petite.” Despite reports of clinical petite C. glabrata strains, our understanding of petite behavior in the host remains obscure. Moreover, controversies exist regarding in-host petite fitness and its clinical relevance. Herein, we employed whole-genome sequencing (WGS), dual-RNAseq, and extensive ex vivo and in vivo studies to fill this knowledge gap. WGS identified multiple petite-specific mutations in nuclear and mitochondrially encoded genes. Consistent with dual-RNAseq data, petite C. glabrata cells did not replicate inside host macrophages and were outcompeted by their non-petite parents in macrophages and in gut colonization and systemic infection mouse models. The intracellular petites showed hallmarks of drug tolerance and were relatively insensitive to the fungicidal activity of echinocandin drugs. Petite-infected macrophages exhibited a pro-inflammatory and type I IFN-skewed transcriptional program. Interrogation of international C. glabrata blood isolates (n = 1000) showed that petite prevalence varies by country, albeit at an overall low prevalence (0%–3.5%). Collectively, our study sheds new light on the genetic basis, drug susceptibility, clinical prevalence, and host-pathogen responses of a clinically overlooked phenotype in a major fungal pathogen. Importance Candida glabrata is a major fungal pathogen, which is able to lose mitochondria and form small and slow-growing colonies, called “petite.” This attenuated growth rate has created controversies and questioned the clinical importance of petiteness. Herein, we have employed multiple omics technologies and in vivo mouse models to critically assess the clinical importance of petite phenotype. Our WGS identifies multiple genes potentially underpinning petite phenotype. Interestingly, petite C. glabrata cells engulfed by macrophages are dormant and, therefore, are not killed by the frontline antifungal drugs. Interestingly, macrophages infected with petite cells mount distinct transcriptomic responses. Consistent with our ex vivo observations, mitochondrial-proficient parental strains outcompete petites during systemic and gut colonization. Retrospective examination of C. glabrata isolates identified petite prevalence a rare entity, which can significantly vary from country to country. Collectively, our study overcomes the existing controversies and provides novel insights regarding the clinical relevance of petite C. glabrata isolates. Candida glabrata petite toelrance drug resistance Microbiology Farnaz Daneshnia verfasserin aut Hrant Hovhannisyan verfasserin aut Diego Fuentes verfasserin aut Nathaly Cabrera verfasserin aut Christopher Quinteros verfasserin aut Macit Ilkit verfasserin aut Nevzat Ünal verfasserin aut Suleyha Hilmioğlu-Polat verfasserin aut Kauser Jabeen verfasserin aut Sadaf Zaka verfasserin aut Jigar V. Desai verfasserin aut Cornelia Lass-Flörl verfasserin aut Erika Shor verfasserin aut Toni Gabaldon verfasserin aut David S. Perlin verfasserin aut In mBio American Society for Microbiology, 2010 14(2023), 5 (DE-627)627613543 (DE-600)2557172-2 21507511 nnns volume:14 year:2023 number:5 https://doi.org/10.1128/mbio.01180-23 kostenfrei https://doaj.org/article/7b0745a56b2f4ec6a459e59902a53e67 kostenfrei https://journals.asm.org/doi/10.1128/mbio.01180-23 kostenfrei https://doaj.org/toc/2150-7511 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023 5
allfieldsSound	10.1128/mbio.01180-23 doi (DE-627)DOAJ090977114 (DE-599)DOAJ7b0745a56b2f4ec6a459e59902a53e67 DE-627 ger DE-627 rakwb eng QR1-502 Amir Arastehfar verfasserin aut Overlooked Candida glabrata petites are echinocandin tolerant, induce host inflammatory responses, and display poor in vivo fitness 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier ABSTRACT Small colony variants are relatively common among some bacterial species and are associated with poor prognosis and recalcitrant infections. Similarly, Candida glabrata—a major intracellular fungal pathogen—produces small and slow-growing respiratory-deficient colonies, termed “petite.” Despite reports of clinical petite C. glabrata strains, our understanding of petite behavior in the host remains obscure. Moreover, controversies exist regarding in-host petite fitness and its clinical relevance. Herein, we employed whole-genome sequencing (WGS), dual-RNAseq, and extensive ex vivo and in vivo studies to fill this knowledge gap. WGS identified multiple petite-specific mutations in nuclear and mitochondrially encoded genes. Consistent with dual-RNAseq data, petite C. glabrata cells did not replicate inside host macrophages and were outcompeted by their non-petite parents in macrophages and in gut colonization and systemic infection mouse models. The intracellular petites showed hallmarks of drug tolerance and were relatively insensitive to the fungicidal activity of echinocandin drugs. Petite-infected macrophages exhibited a pro-inflammatory and type I IFN-skewed transcriptional program. Interrogation of international C. glabrata blood isolates (n = 1000) showed that petite prevalence varies by country, albeit at an overall low prevalence (0%–3.5%). Collectively, our study sheds new light on the genetic basis, drug susceptibility, clinical prevalence, and host-pathogen responses of a clinically overlooked phenotype in a major fungal pathogen. Importance Candida glabrata is a major fungal pathogen, which is able to lose mitochondria and form small and slow-growing colonies, called “petite.” This attenuated growth rate has created controversies and questioned the clinical importance of petiteness. Herein, we have employed multiple omics technologies and in vivo mouse models to critically assess the clinical importance of petite phenotype. Our WGS identifies multiple genes potentially underpinning petite phenotype. Interestingly, petite C. glabrata cells engulfed by macrophages are dormant and, therefore, are not killed by the frontline antifungal drugs. Interestingly, macrophages infected with petite cells mount distinct transcriptomic responses. Consistent with our ex vivo observations, mitochondrial-proficient parental strains outcompete petites during systemic and gut colonization. Retrospective examination of C. glabrata isolates identified petite prevalence a rare entity, which can significantly vary from country to country. Collectively, our study overcomes the existing controversies and provides novel insights regarding the clinical relevance of petite C. glabrata isolates. Candida glabrata petite toelrance drug resistance Microbiology Farnaz Daneshnia verfasserin aut Hrant Hovhannisyan verfasserin aut Diego Fuentes verfasserin aut Nathaly Cabrera verfasserin aut Christopher Quinteros verfasserin aut Macit Ilkit verfasserin aut Nevzat Ünal verfasserin aut Suleyha Hilmioğlu-Polat verfasserin aut Kauser Jabeen verfasserin aut Sadaf Zaka verfasserin aut Jigar V. Desai verfasserin aut Cornelia Lass-Flörl verfasserin aut Erika Shor verfasserin aut Toni Gabaldon verfasserin aut David S. Perlin verfasserin aut In mBio American Society for Microbiology, 2010 14(2023), 5 (DE-627)627613543 (DE-600)2557172-2 21507511 nnns volume:14 year:2023 number:5 https://doi.org/10.1128/mbio.01180-23 kostenfrei https://doaj.org/article/7b0745a56b2f4ec6a459e59902a53e67 kostenfrei https://journals.asm.org/doi/10.1128/mbio.01180-23 kostenfrei https://doaj.org/toc/2150-7511 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023 5
language	English
source	In mBio 14(2023), 5 volume:14 year:2023 number:5
sourceStr	In mBio 14(2023), 5 volume:14 year:2023 number:5
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Candida glabrata petite toelrance drug resistance Microbiology
isfreeaccess_bool	true
container_title	mBio
authorswithroles_txt_mv	Amir Arastehfar @@aut@@ Farnaz Daneshnia @@aut@@ Hrant Hovhannisyan @@aut@@ Diego Fuentes @@aut@@ Nathaly Cabrera @@aut@@ Christopher Quinteros @@aut@@ Macit Ilkit @@aut@@ Nevzat Ünal @@aut@@ Suleyha Hilmioğlu-Polat @@aut@@ Kauser Jabeen @@aut@@ Sadaf Zaka @@aut@@ Jigar V. Desai @@aut@@ Cornelia Lass-Flörl @@aut@@ Erika Shor @@aut@@ Toni Gabaldon @@aut@@ David S. Perlin @@aut@@
publishDateDaySort_date	2023-01-01T00:00:00Z
hierarchy_top_id	627613543
id	DOAJ090977114
language_de	englisch
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Similarly, Candida glabrata—a major intracellular fungal pathogen—produces small and slow-growing respiratory-deficient colonies, termed “petite.” Despite reports of clinical petite C. glabrata strains, our understanding of petite behavior in the host remains obscure. Moreover, controversies exist regarding in-host petite fitness and its clinical relevance. Herein, we employed whole-genome sequencing (WGS), dual-RNAseq, and extensive ex vivo and in vivo studies to fill this knowledge gap. WGS identified multiple petite-specific mutations in nuclear and mitochondrially encoded genes. Consistent with dual-RNAseq data, petite C. glabrata cells did not replicate inside host macrophages and were outcompeted by their non-petite parents in macrophages and in gut colonization and systemic infection mouse models. The intracellular petites showed hallmarks of drug tolerance and were relatively insensitive to the fungicidal activity of echinocandin drugs. Petite-infected macrophages exhibited a pro-inflammatory and type I IFN-skewed transcriptional program. Interrogation of international C. glabrata blood isolates (n = 1000) showed that petite prevalence varies by country, albeit at an overall low prevalence (0%–3.5%). Collectively, our study sheds new light on the genetic basis, drug susceptibility, clinical prevalence, and host-pathogen responses of a clinically overlooked phenotype in a major fungal pathogen. Importance Candida glabrata is a major fungal pathogen, which is able to lose mitochondria and form small and slow-growing colonies, called “petite.” This attenuated growth rate has created controversies and questioned the clinical importance of petiteness. Herein, we have employed multiple omics technologies and in vivo mouse models to critically assess the clinical importance of petite phenotype. Our WGS identifies multiple genes potentially underpinning petite phenotype. Interestingly, petite C. glabrata cells engulfed by macrophages are dormant and, therefore, are not killed by the frontline antifungal drugs. Interestingly, macrophages infected with petite cells mount distinct transcriptomic responses. Consistent with our ex vivo observations, mitochondrial-proficient parental strains outcompete petites during systemic and gut colonization. Retrospective examination of C. glabrata isolates identified petite prevalence a rare entity, which can significantly vary from country to country. 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callnumber-first	Q - Science
author	Amir Arastehfar
spellingShingle	Amir Arastehfar misc QR1-502 misc Candida glabrata misc petite misc toelrance misc drug resistance misc Microbiology Overlooked Candida glabrata petites are echinocandin tolerant, induce host inflammatory responses, and display poor in vivo fitness
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topic_title	QR1-502 Overlooked Candida glabrata petites are echinocandin tolerant, induce host inflammatory responses, and display poor in vivo fitness Candida glabrata petite toelrance drug resistance
topic	misc QR1-502 misc Candida glabrata misc petite misc toelrance misc drug resistance misc Microbiology
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title	Overlooked Candida glabrata petites are echinocandin tolerant, induce host inflammatory responses, and display poor in vivo fitness
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title_full	Overlooked Candida glabrata petites are echinocandin tolerant, induce host inflammatory responses, and display poor in vivo fitness
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author_browse	Amir Arastehfar Farnaz Daneshnia Hrant Hovhannisyan Diego Fuentes Nathaly Cabrera Christopher Quinteros Macit Ilkit Nevzat Ünal Suleyha Hilmioğlu-Polat Kauser Jabeen Sadaf Zaka Jigar V. Desai Cornelia Lass-Flörl Erika Shor Toni Gabaldon David S. Perlin
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title_sort	overlooked candida glabrata petites are echinocandin tolerant, induce host inflammatory responses, and display poor in vivo fitness
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title_auth	Overlooked Candida glabrata petites are echinocandin tolerant, induce host inflammatory responses, and display poor in vivo fitness
abstract	ABSTRACT Small colony variants are relatively common among some bacterial species and are associated with poor prognosis and recalcitrant infections. Similarly, Candida glabrata—a major intracellular fungal pathogen—produces small and slow-growing respiratory-deficient colonies, termed “petite.” Despite reports of clinical petite C. glabrata strains, our understanding of petite behavior in the host remains obscure. Moreover, controversies exist regarding in-host petite fitness and its clinical relevance. Herein, we employed whole-genome sequencing (WGS), dual-RNAseq, and extensive ex vivo and in vivo studies to fill this knowledge gap. WGS identified multiple petite-specific mutations in nuclear and mitochondrially encoded genes. Consistent with dual-RNAseq data, petite C. glabrata cells did not replicate inside host macrophages and were outcompeted by their non-petite parents in macrophages and in gut colonization and systemic infection mouse models. The intracellular petites showed hallmarks of drug tolerance and were relatively insensitive to the fungicidal activity of echinocandin drugs. Petite-infected macrophages exhibited a pro-inflammatory and type I IFN-skewed transcriptional program. Interrogation of international C. glabrata blood isolates (n = 1000) showed that petite prevalence varies by country, albeit at an overall low prevalence (0%–3.5%). Collectively, our study sheds new light on the genetic basis, drug susceptibility, clinical prevalence, and host-pathogen responses of a clinically overlooked phenotype in a major fungal pathogen. Importance Candida glabrata is a major fungal pathogen, which is able to lose mitochondria and form small and slow-growing colonies, called “petite.” This attenuated growth rate has created controversies and questioned the clinical importance of petiteness. Herein, we have employed multiple omics technologies and in vivo mouse models to critically assess the clinical importance of petite phenotype. Our WGS identifies multiple genes potentially underpinning petite phenotype. Interestingly, petite C. glabrata cells engulfed by macrophages are dormant and, therefore, are not killed by the frontline antifungal drugs. Interestingly, macrophages infected with petite cells mount distinct transcriptomic responses. Consistent with our ex vivo observations, mitochondrial-proficient parental strains outcompete petites during systemic and gut colonization. Retrospective examination of C. glabrata isolates identified petite prevalence a rare entity, which can significantly vary from country to country. Collectively, our study overcomes the existing controversies and provides novel insights regarding the clinical relevance of petite C. glabrata isolates.
abstractGer	ABSTRACT Small colony variants are relatively common among some bacterial species and are associated with poor prognosis and recalcitrant infections. Similarly, Candida glabrata—a major intracellular fungal pathogen—produces small and slow-growing respiratory-deficient colonies, termed “petite.” Despite reports of clinical petite C. glabrata strains, our understanding of petite behavior in the host remains obscure. Moreover, controversies exist regarding in-host petite fitness and its clinical relevance. Herein, we employed whole-genome sequencing (WGS), dual-RNAseq, and extensive ex vivo and in vivo studies to fill this knowledge gap. WGS identified multiple petite-specific mutations in nuclear and mitochondrially encoded genes. Consistent with dual-RNAseq data, petite C. glabrata cells did not replicate inside host macrophages and were outcompeted by their non-petite parents in macrophages and in gut colonization and systemic infection mouse models. The intracellular petites showed hallmarks of drug tolerance and were relatively insensitive to the fungicidal activity of echinocandin drugs. Petite-infected macrophages exhibited a pro-inflammatory and type I IFN-skewed transcriptional program. Interrogation of international C. glabrata blood isolates (n = 1000) showed that petite prevalence varies by country, albeit at an overall low prevalence (0%–3.5%). Collectively, our study sheds new light on the genetic basis, drug susceptibility, clinical prevalence, and host-pathogen responses of a clinically overlooked phenotype in a major fungal pathogen. Importance Candida glabrata is a major fungal pathogen, which is able to lose mitochondria and form small and slow-growing colonies, called “petite.” This attenuated growth rate has created controversies and questioned the clinical importance of petiteness. Herein, we have employed multiple omics technologies and in vivo mouse models to critically assess the clinical importance of petite phenotype. Our WGS identifies multiple genes potentially underpinning petite phenotype. Interestingly, petite C. glabrata cells engulfed by macrophages are dormant and, therefore, are not killed by the frontline antifungal drugs. Interestingly, macrophages infected with petite cells mount distinct transcriptomic responses. Consistent with our ex vivo observations, mitochondrial-proficient parental strains outcompete petites during systemic and gut colonization. Retrospective examination of C. glabrata isolates identified petite prevalence a rare entity, which can significantly vary from country to country. Collectively, our study overcomes the existing controversies and provides novel insights regarding the clinical relevance of petite C. glabrata isolates.
abstract_unstemmed	ABSTRACT Small colony variants are relatively common among some bacterial species and are associated with poor prognosis and recalcitrant infections. Similarly, Candida glabrata—a major intracellular fungal pathogen—produces small and slow-growing respiratory-deficient colonies, termed “petite.” Despite reports of clinical petite C. glabrata strains, our understanding of petite behavior in the host remains obscure. Moreover, controversies exist regarding in-host petite fitness and its clinical relevance. Herein, we employed whole-genome sequencing (WGS), dual-RNAseq, and extensive ex vivo and in vivo studies to fill this knowledge gap. WGS identified multiple petite-specific mutations in nuclear and mitochondrially encoded genes. Consistent with dual-RNAseq data, petite C. glabrata cells did not replicate inside host macrophages and were outcompeted by their non-petite parents in macrophages and in gut colonization and systemic infection mouse models. The intracellular petites showed hallmarks of drug tolerance and were relatively insensitive to the fungicidal activity of echinocandin drugs. Petite-infected macrophages exhibited a pro-inflammatory and type I IFN-skewed transcriptional program. Interrogation of international C. glabrata blood isolates (n = 1000) showed that petite prevalence varies by country, albeit at an overall low prevalence (0%–3.5%). Collectively, our study sheds new light on the genetic basis, drug susceptibility, clinical prevalence, and host-pathogen responses of a clinically overlooked phenotype in a major fungal pathogen. Importance Candida glabrata is a major fungal pathogen, which is able to lose mitochondria and form small and slow-growing colonies, called “petite.” This attenuated growth rate has created controversies and questioned the clinical importance of petiteness. Herein, we have employed multiple omics technologies and in vivo mouse models to critically assess the clinical importance of petite phenotype. Our WGS identifies multiple genes potentially underpinning petite phenotype. Interestingly, petite C. glabrata cells engulfed by macrophages are dormant and, therefore, are not killed by the frontline antifungal drugs. Interestingly, macrophages infected with petite cells mount distinct transcriptomic responses. Consistent with our ex vivo observations, mitochondrial-proficient parental strains outcompete petites during systemic and gut colonization. Retrospective examination of C. glabrata isolates identified petite prevalence a rare entity, which can significantly vary from country to country. Collectively, our study overcomes the existing controversies and provides novel insights regarding the clinical relevance of petite C. glabrata isolates.
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title_short	Overlooked Candida glabrata petites are echinocandin tolerant, induce host inflammatory responses, and display poor in vivo fitness
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Petite-infected macrophages exhibited a pro-inflammatory and type I IFN-skewed transcriptional program. Interrogation of international C. glabrata blood isolates (n = 1000) showed that petite prevalence varies by country, albeit at an overall low prevalence (0%–3.5%). Collectively, our study sheds new light on the genetic basis, drug susceptibility, clinical prevalence, and host-pathogen responses of a clinically overlooked phenotype in a major fungal pathogen. Importance Candida glabrata is a major fungal pathogen, which is able to lose mitochondria and form small and slow-growing colonies, called “petite.” This attenuated growth rate has created controversies and questioned the clinical importance of petiteness. Herein, we have employed multiple omics technologies and in vivo mouse models to critically assess the clinical importance of petite phenotype. Our WGS identifies multiple genes potentially underpinning petite phenotype. Interestingly, petite C. glabrata cells engulfed by macrophages are dormant and, therefore, are not killed by the frontline antifungal drugs. Interestingly, macrophages infected with petite cells mount distinct transcriptomic responses. Consistent with our ex vivo observations, mitochondrial-proficient parental strains outcompete petites during systemic and gut colonization. Retrospective examination of C. glabrata isolates identified petite prevalence a rare entity, which can significantly vary from country to country. 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Overlooked Candida glabrata petites are echinocandin tolerant, induce host inflammatory responses, and display poor in vivo fitness

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