Dataset Information

Pseudomonas aeruginosa-Derived Volatile Sulfur Compounds Promote Distal Aspergillus fumigatus Growth and a Synergistic Pathogen-Pathogen Interaction That Increases Pathogenicity in Co-infection.

ABSTRACT: Pathogen-pathogen interactions in polymicrobial infections are known to directly impact, often to worsen, disease outcomes. For example, co-infection with Pseudomonas aeruginosa and Aspergillus fumigatus, respectively the most common bacterial and fungal pathogens isolated from cystic fibrosis (CF) airways, leads to a worsened prognosis. Recent studies of in vitro microbial cross-talk demonstrated that P. aeruginosa-derived volatile sulfur compounds (VSCs) can promote A. fumigatus growth in vitro. However, the mechanistic basis of such cross-talk and its physiological relevance during co-infection remains unknown. In this study we combine genetic approaches and GC-MS-mediated volatile analysis to show that A. fumigatus assimilates VSCs via cysteine (CysB)- or homocysteine (CysD)-synthase. This process is essential for utilization of VSCs as sulfur sources, since P. aeruginosa-derived VSCs trigger growth of A. fumigatus wild-type, but not of a ?cysB?cysD mutant, on sulfur-limiting media. P. aeruginosa produces VSCs when infecting Galleria mellonella and co-infection with A. fumigatus in this model results in a synergistic increase in mortality and of fungal and bacterial burdens. Interestingly, the increment in mortality is much greater with the A. fumigatus wild-type than with the ?cysB?cysD mutant. Therefore, A. fumigatus' ability to assimilate P. aeruginosa derived VSCs significantly triggers a synergistic association that increases the pathobiology of infection. Finally, we show that P. aeruginosa can promote fungal growth when growing on substrates that resemble the lung environment, which suggests that this volatile based synergism is likely to occur during co-infection of the human respiratory airways.

SUBMITTER: Scott J

PROVIDER: S-EPMC6794476 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Pseudomonas aeruginosa-Derived Volatile Sulfur Compounds Promote Distal Aspergillus fumigatus Growth and a Synergistic Pathogen-Pathogen Interaction That Increases Pathogenicity in Co-infection.

Scott Jennifer J Sueiro-Olivares Monica M Ahmed Waqar W Heddergott Christoph C Zhao Can C Thomas Riba R Bromley Michael M Latgé Jean-Paul JP Krappmann Sven S Fowler Stephen S Bignell Elaine E Amich Jorge J

Frontiers in microbiology 20191009

Pathogen-pathogen interactions in polymicrobial infections are known to directly impact, often to worsen, disease outcomes. For example, co-infection with Pseudomonas aeruginosa and Aspergillus fumigatus, respectively the most common bacterial and fungal pathogens isolated from cystic fibrosis (CF) airways, leads to a worsened prognosis. Recent studies of in vitro microbial cross-talk demonstrated that P. aeruginosa-derived volatile sulfur compounds (VSCs) can promote ...[more]

PMID: 31649650

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Project description:Aspergillus fumigatus is a major opportunistic fungal pathogen of immunocompromised and immunocompetent hosts. To successfully establish an infection, A. fumigatus needs to use host carbon sources, such as acetate, present in the body fluids and peripheral tissues. However, utilization of acetate as a carbon source by fungi in the context of infection has not been investigated. This work shows that acetate is metabolized via different pathways in A. fumigatus and that acetate utilization is under the regulatory control of a transcription factor (TF), FacB. A. fumigatus acetate utilization is subject to carbon catabolite repression (CCR), although this is only partially dependent on the TF and main regulator of CCR CreA. The available extracellular carbon source, in this case glucose and acetate, significantly affected A. fumigatus virulence traits such as secondary metabolite secretion and cell wall composition, with the latter having consequences for resistance to oxidative stress, antifungal drugs, and human neutrophil-mediated killing. Furthermore, deletion of facB significantly impaired the in vivo virulence of A. fumigatus in both insect and mammalian models of invasive aspergillosis. This is the first report on acetate utilization in A. fumigatus, and this work further highlights the importance of available host-specific carbon sources in shaping fungal virulence traits and subsequent disease outcome, and a potential target for the development of antifungal strategies. IMPORTANCE Aspergillus fumigatus is an opportunistic fungal pathogen in humans. During infection, A. fumigatus is predicted to use host carbon sources, such as acetate, present in body fluids and peripheral tissues, to sustain growth and promote colonization and invasion. This work shows that A. fumigatus metabolizes acetate via different pathways, a process that is dependent on the transcription factor FacB. Furthermore, the type and concentration of the extracellular available carbon source were determined to shape A. fumigatus virulence determinants such as secondary metabolite secretion and cell wall composition. Subsequently, interactions with immune cells are altered in a carbon source-specific manner. FacB is required for A. fumigatus in vivo virulence in both insect and mammalian models of invasive aspergillosis. This is the first report that characterizes acetate utilization in A. fumigatus and highlights the importance of available host-specific carbon sources in shaping virulence traits and potentially subsequent disease outcome.

Project description:Invasive aspergillosis (IA) is a life-threatening infectious disease caused by fungi from the genus Aspergillus, with an associated mortality as high as 90% in certain populations. IA-associated pulmonary lesions are characteristically depleted in oxygen relative to normal lung tissue, and it has been shown that the most common causal agent of IA, Aspergillus fumigatus, must respond to low-oxygen environments for pathogenesis and disease progression. Previous studies have demonstrated marked alterations to the Aspergillus fumigatus transcriptome in response to low-oxygen environments that induce a 'hypoxia response'. Consequently, we hypothesized that these transcriptomic changes would alter the volatile metabolome and generate a volatile hypoxia signature. In the present study, we analyzed the volatile molecules produced by A. fumigatus in both oxygen replete (normoxia) and depleted (hypoxia) environments via headspace solid-phase micro-extraction coupled to two-dimensional gas chromatography-time-of-flight mass spectrometry. Using the machine learning algorithm random forest, we identified 19 volatile molecules that were discriminatory between the four growth conditions assessed in this study (i.e., early hypoxia (1 h), late hypoxia (8 h), early normoxia (1 h), and late normoxia (8 h)), as well as a set of 19 that were discriminatory between late hypoxia cultures and all other growth conditions in aggregate. Nine molecules were common to both comparisons, while the remaining 20 were specific to only one of two. We assigned putative identifications to 13 molecules, of which six were most highly abundant in late hypoxia cultures. Previously acquired transcriptomic data identified putative biochemical pathways induced in hypoxia conditions that plausibly account for the production of a subset of these molecules, including 2,3-butanedione and 3-hydroxy-2-butanone. These two molecules may represent a novel hypoxia fitness pathway in A. fumigatus, and could be useful in the detection of hypoxia-associated A. fumigatus lesions that develop in established IA infections.

Dataset Information

Pseudomonas aeruginosa-Derived Volatile Sulfur Compounds Promote Distal Aspergillus fumigatus Growth and a Synergistic Pathogen-Pathogen Interaction That Increases Pathogenicity in Co-infection.

Publications

<i>Pseudomonas aeruginosa</i>-Derived Volatile Sulfur Compounds Promote Distal <i>Aspergillus fumigatus</i> Growth and a Synergistic Pathogen-Pathogen Interaction That Increases Pathogenicity in Co-infection.

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