A call to arms: Mustering secondary metabolites for success and survival of an opportunistic pathogen

Raffa, Nicholas; Keller, Nancy P.

doi:10.1371/journal.ppat.1007606

Cited by 101 publications

(124 citation statements)

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“…Similarly, deletion of laeA , a positive regulator of several A. fumigatus secondary metabolites, including gliotoxin, also reduces virulence (9, 10). These results establish that gliotoxin, as well as other secondary metabolites, contribute to A. fumigatus virulence (3).…”

Section: Figsupporting

confidence: 59%

“…Aspergillus fumigatus is a major fungal pathogen responsible for hundreds of thousands of infections and deaths each year (1, 2). Several secondary metabolites biosynthesized by A. fumigatus have been shown to be required for disease (3). For example, gliotoxin ( Fig.…”

Section: Figmentioning

confidence: 99%

“…For example, gliotoxin ( Fig. 1A ), a secondary metabolite that belongs to the epipolythiodioxopiperazine (ETP) class of mycotoxins (4), can be detected in the sera of patients with invasive aspergillosis (5) and is known to inhibit the host immune response (3). When the gliP gene, which encodes the major synthetase of the gliotoxin biosynthetic gene cluster, is deleted from A. fumigatus , the mutant strain does not biosynthesize gliotoxin and exhibits attenuated virulence in a non-neutropenic murine model of aspergillosis (6–8).…”

Section: Figmentioning

confidence: 99%

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Gliotoxin, a known virulence factor in the major human pathogen Aspergillus fumigatus, is also biosynthesized by the non-pathogenic relative A. fischeri

Knowles¹,

Mead

Silva

et al. 2019

Preprint

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2Gliotoxin, a known virulence factor in the major human pathogen Aspergillus fumigatus, is 3 also biosynthesized by the non-pathogenic relative A. fischeri 4 5 ABSTRACT 21Aspergillus fumigatus is a major opportunistic human pathogen. Multiple traits contribute to A. 22 fumigatus pathogenicity, including its ability to produce specific secondary metabolites, such as 23 gliotoxin. Gliotoxin is known to inhibit the host immune response, and genetic mutants that 24 inactivate gliotoxin biosynthesis (or secondary metabolism in general) attenuate A. fumigatus 25 virulence. The genome of A. fischeri, a very close non-pathogenic relative of A. fumigatus, 26 contains a biosynthetic gene cluster that exhibits high sequence similarity to the A. fumigatus 27 gliotoxin cluster. However, A. fischeri is not known to produce gliotoxin. To gain further insight 28 into the similarities and differences between the major pathogen A. fumigatus and the non-29 pathogen A. fischeri, we examined whether A. fischeri strain NRRL 181 biosynthesizes gliotoxin 30 and whether its production, and of secondary metabolites more generally, influence its virulence 31 profile. We found that A. fischeri biosynthesizes gliotoxin in the same conditions as A. 32 fumigatus. However, whereas loss of laeA, a master regulator of secondary metabolite 33 production, has been previously shown to reduce the virulence of A. fumigatus, we found that 34 laeA loss (and loss of secondary metabolite production, including gliotoxin) in A. fischeri does 35 not influence its virulence. These results suggest that gliotoxin and secondary metabolite 36 production are virulence factors in the genomic and phenotypic background of the major 37 pathogen A. fumigatus but are much less important in the background of the non-pathogen A. 38 fischeri. We submit that understanding the observed spectrum of pathogenicity across closely 39 related pathogenic and non-pathogenic Aspergillus species will require detailed characterization 40 of their biological, chemical, and genomic similarities and differences. 41 IMPORTANCE 42Aspergillus fumigatus is a major opportunistic fungal pathogen of humans but most of its close 43 relatives are non-pathogenic. Why is that so? This important, yet largely unanswered, question 44 can be addressed by examining how A. fumigatus and its non-pathogenic close relatives are 45 similar or different with respect to virulence-associated traits. We investigated whether 46Aspergillus fischeri, a non-pathogenic close relative of A. fumigatus, can produce gliotoxin, a 47

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Section: Figsupporting

confidence: 59%

Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

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Gliotoxin, a known virulence factor in the major human pathogen Aspergillus fumigatus, is also biosynthesized by the non-pathogenic relative A. fischeri

Knowles¹,

Mead

Silva

et al. 2019

Preprint

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“…Filamentous fungi produce a remarkable diversity of specialized secondary metabolites (SMs), characterized as bioactive molecules of low molecular weight that are not required for the growth of the organism. Production of these SMs can help fungi in their adaptation to different environmental conditions, improving competitiveness against other microbes or with immune responses during infections [12]. These SMs play diverse ecological roles in fungal defense, communication, and virulence [13], and some of them, owing to their toxic activity, are collectively known as mycotoxins.…”

Section: Introductionmentioning

confidence: 99%

Fumagillin, a Mycotoxin of Aspergillus fumigatus: Biosynthesis, Biological Activities, Detection, and Applications

Guruceaga

Perez-Cuesta

Abad‐Diaz‐de‐Cerio

et al. 2019

Toxins

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Fumagillin is a mycotoxin produced, above all, by the saprophytic filamentous fungus Aspergillus fumigatus. This mold is an opportunistic pathogen that can cause invasive aspergillosis, a disease that has high mortality rates linked to it. Its ability to adapt to environmental stresses through the production of secondary metabolites, including several mycotoxins (gliotoxin, fumagillin, pseurotin A, etc.) also seem to play an important role in causing these infections. Since the discovery of the A. fumigatus fumagillin in 1949, many studies have focused on this toxin and in this review we gather all the information currently available. First of all, the structural characteristics of this mycotoxin and the different methods developed for its determination are given in detail. Then, the biosynthetic gene cluster and the metabolic pathway involved in its production and regulation are explained. The activity of fumagillin on its target, the methionine aminopeptidase type 2 (MetAP2) enzyme, and the effects of blocking this enzyme in the host are also described. Finally, the applications that this toxin and its derivatives have in different fields, such as the treatment of cancer and its microsporicidal activity in the treatment of honeybee hive infections with Nosema spp., are reviewed. Therefore, this work offers a complete review of all the information currently related to the fumagillin mycotoxin secreted by A. fumigatus, important because of its role in the fungal infection process but also because it has many other applications, notably in beekeeping, the treatment of infectious diseases, and in oncology. Key Contribution:Fumagillin is a mycotoxin produced during infections caused by A. fumigatus and in the adaptation processes of this species to multiple environmental stresses. In this review; we include detailed information on the fungal mechanisms employed in the production of this mycotoxin and those present in its regulation, how it acts on its target, and how it can be detected, all of which may be useful for diagnosis or the development of new treatments. Its usefulness in different fields is also described; because of its anti-angiogenic activity it is used to attack different types of tumors; at the same time its antibiotic activity is useful against several parasites.

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“…Currently, it is thought that the ability to cause human disease 379 evolved multiple times among species in section Fumigati (Rokas et al, 2020a). Secondary 380 metabolites contribute to the success of the major human pathogen A. fumigatus in the host 381 environment(Raffa and Keller, 2019) and are therefore "cards" of virulence(Casadevall, 2007; 382 Knowles et al, 2020). However, whether the closest relatives of A. fumigatus, A.…”

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confidence: 99%

Biosynthetic gene clusters, secondary metabolite profiles, and cards of virulence in the closest nonpathogenic relatives of Aspergillus fumigatus

Steenwyk

Mead

Knowles

et al. 2020

Preprint

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23Aspergillus fumigatus is a major human pathogen that causes hundreds of thousands of infections 24 yearly with high mortality rates. In contrast, Aspergillus fischeri and the recently described 25Aspergillus oerlinghausenensis, the two species most closely related to A. fumigatus, are not 26 known to be pathogenic. Some of the "cards of virulence" that A. fumigatus possesses are 27 secondary metabolites that impair the host immune system, protect from host immune cell 28 attacks, or acquire key nutrients. Secondary metabolites and the biosynthetic gene clusters 29 (BGCs) that typically encode them often vary within and between fungal species. To gain insight 30 into whether secondary metabolism-associated cards of virulence vary between A. fumigatus, A. 31 oerlinghausenensis, and A. fischeri, we conducted extensive genomic and secondary metabolite 32 profiling analyses. By analyzing multiple A. fumigatus, one A. oerlinghausenensis, and multiple 33A. fischeri strains, we identified both conserved and diverged secondary metabolism-associated 34 cards of virulence. For example, we found that all species and strains examined biosynthesized 35 the major virulence factor gliotoxin, consistent with the conservation of the gliotoxin BGC 36 across genomes. However, species differed in their biosynthesis of fumagillin and pseurotin, 37 both contributors to host tissue damage during invasive aspergillosis; these differences were 38 reflected in sequence divergence of the intertwined fumagillin/pseurotin BGCs across genomes. 39These results delineate the similarities and differences in secondary metabolism-associated cards 40 of virulence between a major fungal pathogen and its nonpathogenic closest relatives, shedding 41 light into the genetic and phenotypic changes associated with the evolution of fungal 42 pathogenicity. 43 Importance 44The major fungal pathogen Aspergillus fumigatus kills tens of thousands each year. In contrast, 45 the two closest relatives of A. fumigatus, namely Aspergillus fischeri and Aspergillus 46 oerlinghausenensis, are not considered pathogenic. A. fumigatus virulence stems, partly, from its 47 ability to produce small molecules called secondary metabolites that have potent activities during 48 infection. In this study, we examined whether A. fumigatus secondary metabolites and the 49 metabolic pathways involved in their production are conserved in A. oerlinghausenensis and A. 50 fischeri. We found that the nonpathogenic close relatives of A. fumigatus produce some, but not 51 all, secondary metabolites thought to contribute to the success of A. fumigatus in causing human 52 disease and that these similarities and differences were reflected in the underlying metabolic 53 pathways involved in their biosynthesis. Compared to its nonpathogenic close relatives, A.

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A call to arms: Mustering secondary metabolites for success and survival of an opportunistic pathogen

Cited by 101 publications

References 45 publications

Gliotoxin, a known virulence factor in the major human pathogen Aspergillus fumigatus, is also biosynthesized by the non-pathogenic relative A. fischeri

Gliotoxin, a known virulence factor in the major human pathogen Aspergillus fumigatus, is also biosynthesized by the non-pathogenic relative A. fischeri

Fumagillin, a Mycotoxin of Aspergillus fumigatus: Biosynthesis, Biological Activities, Detection, and Applications

Biosynthetic gene clusters, secondary metabolite profiles, and cards of virulence in the closest nonpathogenic relatives of Aspergillus fumigatus

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