rtfA controls development, secondary metabolism, and virulence in Aspergillus fumigatus

Myers, Ryan R.; Smith, Timothy D.; Elsawa, Sherine F.; Tadrist, Souria; Calvo, Ana M.

doi:10.1371/journal.pone.0176702

Cited by 13 publications

(34 citation statements)

References 89 publications

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“…rtfA is indispensable for A. flavus pathogenesis on live plant and animal tissue. Previously, rtfA was extensively characterized in the opportunistic pathogen A. fumigatus, where it was found to affect virulence (45). Based on this and on the high conservation observed in the RtfA deduced amino sequence in both fungi, we hypothesized that rtfA could also regulate virulence in A. flavus.…”

Section: Resultsmentioning

confidence: 90%

“…One factor necessary for successful biofilm formation is the ability of the microorganism to adhere to surfaces (49). Previously, A. fumigatus rtfA was shown to influence the ability of this fungus to adhere to surfaces in the absence of rtfA, causing a delay in this process (45). In the current study, adhesion of wild-type, ΔrtfA mutant, and ΔrtfA-com strains was tested at 24 h, 48 h, and 72 h. The results showed a statistically significant decrease and delay in the ability of the A. flavus ΔrtfA mutant strain to adhere to surfaces with respect to the controls (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Some distinct rtfA-dependent effects were observed in different Aspergillus spp., however. For example, reduction of vegetative growth was observed in the A. nidulans, A. fumigatus, and A. flavus ΔrtfA mutant; however, this decrease was minor in A. flavus (44)(45)(46). Also, the absence of rtfA affected conidiation in the three Aspergillus spp., but differently.…”

Section: Discussionmentioning

confidence: 97%

“…Also, the absence of rtfA affected conidiation in the three Aspergillus spp., but differently. In A. nidulans, the deletion of rtfA resulted in a reduction of conidiation, while in A. fumigatus, it causes hyperconidiation (44,45), and in A. flavus, a loss of rtfA function resulted in an initial delay in the onset of conidiation, followed by hyperconidiation over time (46). The rtfA homologs also present commonalities in the regulation of cleistothecial and sclerotial formation in A. nidulans and A. flavus, respectively; in both cases, a lack of rtfA resulted in impaired production of these structures (44,46).…”

Section: Discussionmentioning

confidence: 99%

“…In Aspergillus nidulans, A. fumigatus, and A. flavus, rtfA regulates the development and production of some secondary metabolites, including AF production in A. flavus (44)(45)(46). In A. fumigatus, rtfA is also involved in virulence (45); however, whether the rtfA homolog in A. flavus is relevant in infection of either plants or animals has not been investigated. In this study, we examined the role of the rtfA gene in A. flavus virulence using two model systems, a peanut seed model for plant infection and Galleria mellonella as an IA infection model in animals.…”

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confidence: 99%

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The Aspergillus flavus rtfA Gene Regulates Plant and Animal Pathogenesis and Secondary Metabolism

Lohmar

Cary

Calvo

2019

Appl Environ Microbiol

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Aspergillus flavus is an opportunistic fungal plant and human pathogen and a producer of mycotoxins, including aflatoxin B1 (AFB1). As part of our ongoing studies to elucidate the biological functions of the A. flavus rtfA gene, we examined its role in the pathogenicity of both plant and animal model systems. rtfA encodes a putative RNA polymerase II (Pol II) transcription elongation factor previously characterized in Saccharomyces cerevisiae, Aspergillus nidulans, and Aspergillus fumigatus, where it was shown to regulate several important cellular processes, including morphogenesis and secondary metabolism. In addition, an initial study in A. flavus indicated that rtfA also influences development and production of AFB1; however, its effect on virulence is unknown. The current study reveals that the rtfA gene is indispensable for normal pathogenicity in plants when using peanut seed as an infection model, as well as in animals, as shown in the Galleria mellonella infection model. Interestingly, rtfA positively regulates several processes known to be necessary for successful fungal invasion and colonization of host tissue, such as adhesion to surfaces, protease and lipase activity, cell wall composition and integrity, and tolerance to oxidative stress. In addition, metabolomic analysis revealed that A. flavus rtfA affects the production of several secondary metabolites, including AFB1, aflatrem, leporins, aspirochlorine, ditryptophenaline, and aflavinines, supporting a role of rtfA as a global regulator of secondary metabolism. Heterologous complementation of an A. flavus rtfA deletion strain with rtfA homologs from A. nidulans or S. cerevisiae fully rescued the wild-type phenotype, indicating that these rtfA homologs are functionally conserved among these three species. IMPORTANCE In this study, the epigenetic global regulator rtfA, which encodes a putative RNA-Pol II transcription elongation factor-like protein, was characterized in the mycotoxigenic and opportunistic pathogen A. flavus. Specifically, its involvement in A. flavus pathogenesis in plant and animal models was studied. Here, we show that rtfA positively regulates A. flavus virulence in both models. Furthermore, rtfA-dependent effects on factors necessary for successful invasion and colonization of host tissue by A. flavus were also assessed. Our study indicates that rtfA plays a role in A. flavus adherence to surfaces, hydrolytic activity, normal cell wall formation, and response to oxidative stress. This study also revealed a profound effect of rtfA on the metabolome of A. flavus, including the production of potent mycotoxins.

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Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The Aspergillus flavus rtfA Gene Regulates Plant and Animal Pathogenesis and Secondary Metabolism

Lohmar

Cary

Calvo

2019

Appl Environ Microbiol

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Dynamic Transcriptomic and Phosphoproteomic Analysis During Cell Wall Stress in Aspergillus nidulans

Chelius

Huso

Reese

et al. 2020

Molecular & Cellular Proteomics

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The fungal cell-wall integrity signaling (CWIS) pathway regulates cellular response to environmental stress to enable wall repair and resumption of normal growth. This complex, interconnected, pathway has been only partially characterized in filamentous fungi. To better understand the dynamic cellular response to wall perturbation, a β-glucan synthase inhibitor (micafungin) was added to a growing A. nidulans shake-flask culture. From this flask, transcriptomic and phosphoproteomic data were acquired over 10 and 120 minutes, respectively. To differentiate statistically-significant dynamic behavior from noise, a multivariate adaptive regression splines (MARS) model was applied to both data sets. Over 1800 genes were dynamically expressed and 430 phosphorylation sites had changing phosphorylation levels upon micafungin exposure. Twelve kinases had altered phosphorylation and phenotypic profiling of all non-essential kinase deletion mutants revealed putative connections between PrkA, Hk-8-4, and Stk19 and the CWIS pathway. Our collective data implicate actin regulation, endocytosis, and septum formation as critical cellular processes responding to activation of the CWIS pathway, and connections between CWIS and calcium, HOG, and SIN signaling pathways.

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Galleria mellonella as a screening tool to study virulence factors of Aspergillus fumigatus

et al. 2021

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The invertebrate Galleria mellonella has increasingly and widely been used in the last few years to study complex host–microbe interactions. Aspergillus fumigatus is one of the most pathogenic fungi causing life-threatening diseases in humans and animals. Galleria mellonella larvae has been proven as a reliable model for the analysis of pathogenesis and virulence factors, enable to screen a large number of A. fumigatus strains. This review describes the different uses of G. mellonella to study A. fumigatus and provides a comparison of the different protocols to trace fungal pathogenicity. The review also includes a summary of the diverse mutants tested in G. mellonella , and their respective contribution to A. fumigatus virulence. Previous investigations indicated that G. mellonella should be considered as an interesting tool even though a mammalian model may be required to complete and verify initial data.

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rtfA controls development, secondary metabolism, and virulence in Aspergillus fumigatus

Cited by 13 publications

References 89 publications

The Aspergillus flavus rtfA Gene Regulates Plant and Animal Pathogenesis and Secondary Metabolism

The Aspergillus flavus rtfA Gene Regulates Plant and Animal Pathogenesis and Secondary Metabolism

Dynamic Transcriptomic and Phosphoproteomic Analysis During Cell Wall Stress in Aspergillus nidulans

Galleria mellonella as a screening tool to study virulence factors of Aspergillus fumigatus

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