<named-content content-type="genus-species">Aspergillus fumigatus</named-content> In-Host HOG Pathway Mutation for Cystic Fibrosis Lung Microenvironment Persistence

ABSTRACT The prevalence of Aspergillus fumigatus colonization in individuals with cystic fibrosis (CF) and subsequent fungal persistence in the lung is increasingly recognized. However, there is no consensus for clinical management of A. fumigatus in CF individuals, due largely to uncertainty surrou...

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Autores principales:	Brandon S. Ross, Lotus A. Lofgren, Alix Ashare, Jason E. Stajich, Robert A. Cramer
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	Aspergillus fumigatus cystic fibrosis chronic infection hypoxia osmotic stress oxidative stress Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1737e6f344264bb6abe18050705869f7
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spelling	oai:doaj.org-article:1737e6f344264bb6abe18050705869f72021-11-10T18:37:52Z<named-content content-type="genus-species">Aspergillus fumigatus</named-content> In-Host HOG Pathway Mutation for Cystic Fibrosis Lung Microenvironment Persistence10.1128/mBio.02153-212150-7511https://doaj.org/article/1737e6f344264bb6abe18050705869f72021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02153-21https://doaj.org/toc/2150-7511ABSTRACT The prevalence of Aspergillus fumigatus colonization in individuals with cystic fibrosis (CF) and subsequent fungal persistence in the lung is increasingly recognized. However, there is no consensus for clinical management of A. fumigatus in CF individuals, due largely to uncertainty surrounding A. fumigatus CF pathogenesis and virulence mechanisms. To address this gap in knowledge, a longitudinal series of A. fumigatus isolates from an individual with CF were collected over 4.5 years. Isolate genotypes were defined with whole-genome sequencing that revealed both transitory and persistent A. fumigatus in the lung. Persistent lineage isolates grew most readily in a low-oxygen culture environment, and conidia were more sensitive to oxidative stress-inducing conditions than those from nonpersistent isolates. Closely related persistent isolates harbored a unique allele of the high-osmolarity glycerol (HOG) pathway mitogen-activated protein kinase kinase, Pbs2 (pbs2C2). Data suggest this novel pbs2C2 allele arose in vivo and is necessary for the fungal response to osmotic stress in a low-oxygen environment through hyperactivation of the HOG (SakA) signaling pathway. Hyperactivation of the HOG pathway through pbs2C2 comes at the cost of decreased conidial stress resistance in the presence of atmospheric oxygen levels. These novel findings shed light on pathoadaptive mechanisms of A. fumigatus in CF, lay the foundation for identifying persistent A. fumigatus isolates that may require antifungal therapy, and highlight considerations for successful culture of persistent Aspergillus CF isolates. IMPORTANCE Aspergillus fumigatus infection causes a spectrum of clinical manifestations. For individuals with cystic fibrosis (CF), allergic bronchopulmonary aspergillosis (ABPA) is an established complication, but there is a growing appreciation for A. fumigatus airway persistence in CF disease progression. There currently is little consensus for clinical management of A. fumigatus long-term culture positivity in CF. A better understanding of A. fumigatus pathogenesis mechanisms in CF is expected to yield insights into when antifungal therapies are warranted. Here, a 4.5-year longitudinal collection of A. fumigatus isolates from a patient with CF identified a persistent lineage that harbors a unique allele of the Pbs2 mitogen-activated protein kinase kinase (MAPKK) necessary for unique CF-relevant stress phenotypes. Importantly for A. fumigatus CF patient diagnostics, this allele provides increased fitness under CF lung-like conditions at a cost of reduced in vitro growth under standard laboratory conditions. These data illustrate a molecular mechanism for A. fumigatus CF lung persistence with implications for diagnostics and antifungal therapy.Brandon S. RossLotus A. LofgrenAlix AshareJason E. StajichRobert A. CramerAmerican Society for MicrobiologyarticleAspergillus fumigatuscystic fibrosischronic infectionhypoxiaosmotic stressoxidative stressMicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Aspergillus fumigatus cystic fibrosis chronic infection hypoxia osmotic stress oxidative stress Microbiology QR1-502
spellingShingle	Aspergillus fumigatus cystic fibrosis chronic infection hypoxia osmotic stress oxidative stress Microbiology QR1-502 Brandon S. Ross Lotus A. Lofgren Alix Ashare Jason E. Stajich Robert A. Cramer <named-content content-type="genus-species">Aspergillus fumigatus</named-content> In-Host HOG Pathway Mutation for Cystic Fibrosis Lung Microenvironment Persistence
description	ABSTRACT The prevalence of Aspergillus fumigatus colonization in individuals with cystic fibrosis (CF) and subsequent fungal persistence in the lung is increasingly recognized. However, there is no consensus for clinical management of A. fumigatus in CF individuals, due largely to uncertainty surrounding A. fumigatus CF pathogenesis and virulence mechanisms. To address this gap in knowledge, a longitudinal series of A. fumigatus isolates from an individual with CF were collected over 4.5 years. Isolate genotypes were defined with whole-genome sequencing that revealed both transitory and persistent A. fumigatus in the lung. Persistent lineage isolates grew most readily in a low-oxygen culture environment, and conidia were more sensitive to oxidative stress-inducing conditions than those from nonpersistent isolates. Closely related persistent isolates harbored a unique allele of the high-osmolarity glycerol (HOG) pathway mitogen-activated protein kinase kinase, Pbs2 (pbs2C2). Data suggest this novel pbs2C2 allele arose in vivo and is necessary for the fungal response to osmotic stress in a low-oxygen environment through hyperactivation of the HOG (SakA) signaling pathway. Hyperactivation of the HOG pathway through pbs2C2 comes at the cost of decreased conidial stress resistance in the presence of atmospheric oxygen levels. These novel findings shed light on pathoadaptive mechanisms of A. fumigatus in CF, lay the foundation for identifying persistent A. fumigatus isolates that may require antifungal therapy, and highlight considerations for successful culture of persistent Aspergillus CF isolates. IMPORTANCE Aspergillus fumigatus infection causes a spectrum of clinical manifestations. For individuals with cystic fibrosis (CF), allergic bronchopulmonary aspergillosis (ABPA) is an established complication, but there is a growing appreciation for A. fumigatus airway persistence in CF disease progression. There currently is little consensus for clinical management of A. fumigatus long-term culture positivity in CF. A better understanding of A. fumigatus pathogenesis mechanisms in CF is expected to yield insights into when antifungal therapies are warranted. Here, a 4.5-year longitudinal collection of A. fumigatus isolates from a patient with CF identified a persistent lineage that harbors a unique allele of the Pbs2 mitogen-activated protein kinase kinase (MAPKK) necessary for unique CF-relevant stress phenotypes. Importantly for A. fumigatus CF patient diagnostics, this allele provides increased fitness under CF lung-like conditions at a cost of reduced in vitro growth under standard laboratory conditions. These data illustrate a molecular mechanism for A. fumigatus CF lung persistence with implications for diagnostics and antifungal therapy.
format	article
author	Brandon S. Ross Lotus A. Lofgren Alix Ashare Jason E. Stajich Robert A. Cramer
author_facet	Brandon S. Ross Lotus A. Lofgren Alix Ashare Jason E. Stajich Robert A. Cramer
author_sort	Brandon S. Ross
title	<named-content content-type="genus-species">Aspergillus fumigatus</named-content> In-Host HOG Pathway Mutation for Cystic Fibrosis Lung Microenvironment Persistence
title_short	<named-content content-type="genus-species">Aspergillus fumigatus</named-content> In-Host HOG Pathway Mutation for Cystic Fibrosis Lung Microenvironment Persistence
title_full	<named-content content-type="genus-species">Aspergillus fumigatus</named-content> In-Host HOG Pathway Mutation for Cystic Fibrosis Lung Microenvironment Persistence
title_fullStr	<named-content content-type="genus-species">Aspergillus fumigatus</named-content> In-Host HOG Pathway Mutation for Cystic Fibrosis Lung Microenvironment Persistence
title_full_unstemmed	<named-content content-type="genus-species">Aspergillus fumigatus</named-content> In-Host HOG Pathway Mutation for Cystic Fibrosis Lung Microenvironment Persistence
title_sort	<named-content content-type="genus-species">aspergillus fumigatus</named-content> in-host hog pathway mutation for cystic fibrosis lung microenvironment persistence
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/1737e6f344264bb6abe18050705869f7
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<named-content content-type="genus-species">Aspergillus fumigatus</named-content> In-Host HOG Pathway Mutation for Cystic Fibrosis Lung Microenvironment Persistence

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