LaeA, a Regulator of Morphogenetic Fungal Virulence Factors

Bok, Jin Woo; Balajee, S. Arunmozhi; Marr, Kieren A.; Andes, David R.; Nielsen, Kristian Fog; Frisvad, Jens Christian; Keller, Nancy P.

doi:10.1128/ec.4.9.1574-1582.2005

Cited by 270 publications

(251 citation statements)

References 38 publications

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“…A hint for the general impact of secondary metabolites on virulence derives from investigations on A. fumigatus mutants, which carry a deleted leaA gene. LaeA is a global regulator of secondary metabolism genes, and the deletion of the gene led to reduced virulence in a murine infection model (Bok et al, 2005;Keller et al, 2006). It is therefore possible that not only the growth inhibitory effect of propionyl-CoA, but also the inability to produce certain metabolites, attenuates virulence and leads to a higher susceptibility against the attack of immune effector cells.…”

Section: Discussionmentioning

confidence: 99%

Methylcitrate synthase from Aspergillus fumigatus is essential for manifestation of invasive aspergillosis

et al. 2007

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SummaryInvasive aspergillosis is a life-threatening disease mainly caused by the fungus Aspergillus fumigatus. In immunocompromised individuals conidia are not efficiently inactivated, which can end in invasive fungal growth. However, the metabolic requirements of the fungus are hardly known. Earlier investigations revealed an accumulation of toxic propionyl-CoA in a methylcitrate synthase mutant, when grown on propionyl-CoA-generating carbon sources. During invasive growth propionyl-CoA could derive from proteins, which are released from infected host tissues. We therefore assumed that a methylcitrate synthase mutant might display an attenuated virulence. Here we show that the addition of propionate to cell culture medium enhanced the ability of alveolar macrophages to kill methylcitrate synthase mutant but not wild-type conidia. When tested in a murine infection model, the methylcitrate synthase mutant displayed attenuated virulence and, furthermore, was cleared from tissues when mice survived the first phase of acute infection. The amplification of cDNA from infected mouse lungs confirmed the transcription of the methylcitrate synthase gene during invasion, which leads to the suggestion that amino acids indeed serve as growth-supporting nutrients during invasive growth of A. fumigatus. Thus, blocking of methylcitrate synthase activity abrogates fungal growth and provides a suitable target for new antifungals.

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Section: Discussionmentioning

confidence: 99%

Methylcitrate synthase from Aspergillus fumigatus is essential for manifestation of invasive aspergillosis

et al. 2007

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“…Molecular studies have also been performed to determine the biosynthetic principle of important bioactive polyketides, such as aflatoxin [17][18][19][20][21][22]. Regulatory networks governing secondary metabolism have been gradually uncovered in several fungal species, for example, the central roles of the G protein-cAMP-PKA pathway and the LaeA and VeA protein complex have been determined [19,[23][24][25].…”

mentioning

confidence: 99%

A PKS gene, pks-1, is involved in chaetoglobosin biosynthesis, pigmentation and sporulation in Chaetomium globosum

Hao

Lou

et al. 2012

Sci. China Life Sci.

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Chaetomium globosum is one of the most common fungi in nature. It is best known for producing chaetoglobosins; however, the molecular basis of chaetoglobosin biosynthesis is poorly understood in this fungus. In this study, we utilized RNA interference (RNAi) to characterize a polyketide synthase gene, pks-1, in C. globosum that is involved in the production of chaetoglobosin A. When pks-1 was knocked down by RNAi, the production of chaetoglobosin A dramatically decreased. Knock-down mutants also displayed a pigment-deficient phenotype. These results suggest that the two polyketides, melanin and chaetoglobosin, are likely to share common biosynthetic steps. Most importantly, we found that pks-1 also plays a critical role in sporulation. The silenced mutants of pks-1 lost the ability to produce spores. We propose that polyketides may modulate cellular development via an unidentified action. We also suggest that C. globosum pks-1 is unique because of its triple role in melanin formation, chaetoglobosin biosynthesis and sporulation. This work may shed light on chaetoglobosin biosynthesis and indicates a relationship between secondary metabolism and fungal morphogenesis.

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“…DProtein BBA_05847 was found in areas 3 and 4. dProtein BBA_00443 was found in areas 5 and 6. BbmtrA displayed approximately 30 % identity to the Aspergillus loss of aflR expression (LaeA) putative methyltransferase, characterized in A. nidulans, Aspergillus fumigatus and Aspergillus flavus, that has been shown to regulate the production of a wide range of secondary metabolites including the aflatoxin, sterigmatocytin and other gene clusters (Bok & Keller, 2004;Bok et al, 2005;Keller et al, 2006). Although B. bassiana is not known to produce either of the former two compounds, several genes in the biosynthetic pathways of these compounds have been identified in the genome (Xiao et al, 2012).…”

Section: Bbmtra Contributes To Virulencementioning

confidence: 99%

A putative methyltransferase, mtrA, contributes to development, spore viability, protein secretion and virulence in the entomopathogenic fungus Beauveria bassiana

2014

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The filamentous fungus, Beauveria bassiana, is a ubiquitously distributed insect pathogen, currently used as an alternative to chemical pesticides for pest control. Conidiospores are the means by which the fungus disseminates in the environment, and these cells also represent the infectious agent most commonly used in field applications. Little, however, is known concerning the molecular basis for maintenance of spore viability, a critical feature for survival and persistence. Here, we report on the role of a putative methyltransferase, BbmtrA, in conidial viability, normal fungal growth and development, and virulence, via characterization of a targeted gene knockout strain. Loss of BbmtrA resulted in pleiotropic effects including reduced germination, growth and conidiation, with growing mycelia displaying greater branching than the WT parent. Conidial viability dramatically decreased over time, with ,5 % of the cells remaining viable after 30 days as compared with .80 % of the WT. Reduced production of extracellular proteins was also observed for the DBbmtrA mutant, including protease/peptidases, glycoside hydrolases and the hyd1 hydrophobin. The latter was further confirmed by hyd1 gene expression analysis. Insect bioassays using the greater wax moth, Galleria mellonella, further revealed that the DBbmtrA strain was attenuated in virulence and failed to sporulate on host cadavers. These data support a global role for mtrA in fungal physiological processes.

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LaeA, a Regulator of Morphogenetic Fungal Virulence Factors

Cited by 270 publications

References 38 publications

Methylcitrate synthase from Aspergillus fumigatus is essential for manifestation of invasive aspergillosis

Methylcitrate synthase from Aspergillus fumigatus is essential for manifestation of invasive aspergillosis

A PKS gene, pks-1, is involved in chaetoglobosin biosynthesis, pigmentation and sporulation in Chaetomium globosum

A putative methyltransferase, mtrA, contributes to development, spore viability, protein secretion and virulence in the entomopathogenic fungus Beauveria bassiana

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