{"doi":"10.1101/868745","title":"Gliotoxin, a known virulence factor in the major human pathogen\n                  <i>Aspergillus fumigatus</i>\n                  , is also biosynthesized by the non-pathogenic relative\n                  <i>A. fischeri</i>","abstract":"<jats:title>ABSTRACT</jats:title>\n                <jats:p>\n                  <jats:italic>Aspergillus fumigatus</jats:italic>\n                  is a major opportunistic human pathogen. Multiple traits contribute to\n                  <jats:italic>A. fumigatus</jats:italic>\n                  pathogenicity, including its ability to produce specific secondary metabolites, such as gliotoxin. Gliotoxin is known to inhibit the host immune response, and genetic mutants that inactivate gliotoxin biosynthesis (or secondary metabolism in general) attenuate\n                  <jats:italic>A. fumigatus</jats:italic>\n                  virulence. The genome of\n                  <jats:italic>A. fischeri</jats:italic>\n                  , a very close non-pathogenic relative of\n                  <jats:italic>A. fumigatus</jats:italic>\n                  , contains a biosynthetic gene cluster that exhibits high sequence similarity to the\n                  <jats:italic>A. fumigatus</jats:italic>\n                  gliotoxin cluster. However,\n                  <jats:italic>A. fischeri</jats:italic>\n                  is not known to produce gliotoxin. To gain further insight into the similarities and differences between the major pathogen\n                  <jats:italic>A. fumigatus</jats:italic>\n                  and the non-pathogen\n                  <jats:italic>A. fischeri</jats:italic>\n                  , we examined whether\n                  <jats:italic>A. fischeri</jats:italic>\n                  strain NRRL 181 biosynthesizes gliotoxin and whether its production, and of secondary metabolites more generally, influence its virulence profile. We found that\n                  <jats:italic>A. fischeri</jats:italic>\n                  biosynthesizes gliotoxin in the same conditions as\n                  <jats:italic>A. fumigatus</jats:italic>\n                  . However, whereas loss of\n                  <jats:italic>laeA</jats:italic>\n                  , a master regulator of secondary metabolite production, has been previously shown to reduce the virulence of\n                  <jats:italic>A. fumigatus</jats:italic>\n                  , we found that\n                  <jats:italic>laeA</jats:italic>\n                  loss (and loss of secondary metabolite production, including gliotoxin) in\n                  <jats:italic>A. fischeri</jats:italic>\n                  does not influence its virulence. These results suggest that gliotoxin and secondary metabolite production are virulence factors in the genomic and phenotypic background of the major pathogen\n                  <jats:italic>A. fumigatus</jats:italic>\n                  but are much less important in the background of the non-pathogen\n                  <jats:italic>A. fischeri</jats:italic>\n                  . We submit that understanding the observed spectrum of pathogenicity across closely related pathogenic and non-pathogenic\n                  <jats:italic>Aspergillus</jats:italic>\n                  species will require detailed characterization of their biological, chemical, and genomic similarities and differences.\n                </jats:p>\n                <jats:sec>\n                  <jats:title>IMPORTANCE</jats:title>\n                  <jats:p>\n                    <jats:italic>Aspergillus fumigatus</jats:italic>\n                    is a major opportunistic fungal pathogen of humans but most of its close relatives are non-pathogenic. Why is that so? This important, yet largely unanswered, question can be addressed by examining how\n                    <jats:italic>A. fumigatus</jats:italic>\n                    and its non-pathogenic close relatives are similar or different with respect to virulence-associated traits. We investigated whether\n                    <jats:italic>Aspergillus fischeri</jats:italic>\n                    , a non-pathogenic close relative of\n                    <jats:italic>A. fumigatus</jats:italic>\n                    , can produce gliotoxin, a mycotoxin known to contribute to\n                    <jats:italic>A. fumigatus</jats:italic>\n                    virulence. We discovered that the non-pathogenic\n                    <jats:italic>A. fischeri</jats:italic>\n                    produces gliotoxin under the same conditions as the major pathogen\n                    <jats:italic>A. fumigatus</jats:italic>\n                    . However, we also discovered that, in contrast to what has been previously observed in\n                    <jats:italic>A. fumigatus</jats:italic>\n                    , loss of secondary metabolite, including gliotoxin, production in\n                    <jats:italic>A. fischeri</jats:italic>\n                    does not alter its virulence. Our results are consistent with the “cards of virulence” model of opportunistic fungal disease, where the ability to cause disease stems from the combination (“hand”) of individual virulence factors (“cards”), but not from individual factors\n                    <jats:italic>per se</jats:italic>\n                    .\n                  </jats:p>\n                </jats:sec>","journal":null,"year":null,"id":636683,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":329032,"name":"Matthew E. Mead","orcid":"0000-0001-9195-7585","position":1,"is_corresponding":false},{"id":329033,"name":"Lilian Pereira Silva","orcid":"0000-0002-0143-6557","position":2,"is_corresponding":false},{"id":267273,"name":"Huzefa A. Raja","orcid":"0000-0002-0824-9463","position":3,"is_corresponding":false},{"id":108920,"name":"Jacob L. Steenwyk","orcid":"0000-0002-8436-595X","position":4,"is_corresponding":false},{"id":317398,"name":"Gustavo H. Goldman","orcid":"0000-0002-2986-350X","position":5,"is_corresponding":false},{"id":40922,"name":"Antonis Rokas","orcid":"0000-0002-7248-6551","position":6,"is_corresponding":false},{"id":267276,"name":"Nicholas H. Oberlies","orcid":"0000-0002-0354-8464","position":7,"is_corresponding":false},{"id":329031,"name":"Sonja L. Knowles","orcid":"0000-0002-6295-231X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Gliotoxin, a known virulence factor in the major human pathogen\n                  <i>Aspergillus fumigatus</i>\n                  , is also biosynthesized by the non-pathogenic relative\n                  <i>A. fischeri</i>","abstract":"<jats:title>ABSTRACT</jats:title>\n                <jats:p>\n                  <jats:italic>Aspergillus fumigatus</jats:italic>\n                  is a major opportunistic human pathogen. Multiple traits contribute to\n                  <jats:italic>A. fumigatus</jats:italic>\n                  pathogenicity, including its ability to produce specific secondary metabolites, such as gliotoxin. Gliotoxin is known to inhibit the host immune response, and genetic mutants that inactivate gliotoxin biosynthesis (or secondary metabolism in general) attenuate\n                  <jats:italic>A. fumigatus</jats:italic>\n                  virulence. The genome of\n                  <jats:italic>A. fischeri</jats:italic>\n                  , a very close non-pathogenic relative of\n                  <jats:italic>A. fumigatus</jats:italic>\n                  , contains a biosynthetic gene cluster that exhibits high sequence similarity to the\n                  <jats:italic>A. fumigatus</jats:italic>\n                  gliotoxin cluster. However,\n                  <jats:italic>A. fischeri</jats:italic>\n                  is not known to produce gliotoxin. To gain further insight into the similarities and differences between the major pathogen\n                  <jats:italic>A. fumigatus</jats:italic>\n                  and the non-pathogen\n                  <jats:italic>A. fischeri</jats:italic>\n                  , we examined whether\n                  <jats:italic>A. fischeri</jats:italic>\n                  strain NRRL 181 biosynthesizes gliotoxin and whether its production, and of secondary metabolites more generally, influence its virulence profile. We found that\n                  <jats:italic>A. fischeri</jats:italic>\n                  biosynthesizes gliotoxin in the same conditions as\n                  <jats:italic>A. fumigatus</jats:italic>\n                  . However, whereas loss of\n                  <jats:italic>laeA</jats:italic>\n                  , a master regulator of secondary metabolite production, has been previously shown to reduce the virulence of\n                  <jats:italic>A. fumigatus</jats:italic>\n                  , we found that\n                  <jats:italic>laeA</jats:italic>\n                  loss (and loss of secondary metabolite production, including gliotoxin) in\n                  <jats:italic>A. fischeri</jats:italic>\n                  does not influence its virulence. These results suggest that gliotoxin and secondary metabolite production are virulence factors in the genomic and phenotypic background of the major pathogen\n                  <jats:italic>A. fumigatus</jats:italic>\n                  but are much less important in the background of the non-pathogen\n                  <jats:italic>A. fischeri</jats:italic>\n                  . We submit that understanding the observed spectrum of pathogenicity across closely related pathogenic and non-pathogenic\n                  <jats:italic>Aspergillus</jats:italic>\n                  species will require detailed characterization of their biological, chemical, and genomic similarities and differences.\n                </jats:p>\n                <jats:sec>\n                  <jats:title>IMPORTANCE</jats:title>\n                  <jats:p>\n                    <jats:italic>Aspergillus fumigatus</jats:italic>\n                    is a major opportunistic fungal pathogen of humans but most of its close relatives are non-pathogenic. Why is that so? This important, yet largely unanswered, question can be addressed by examining how\n                    <jats:italic>A. fumigatus</jats:italic>\n                    and its non-pathogenic close relatives are similar or different with respect to virulence-associated traits. We investigated whether\n                    <jats:italic>Aspergillus fischeri</jats:italic>\n                    , a non-pathogenic close relative of\n                    <jats:italic>A. fumigatus</jats:italic>\n                    , can produce gliotoxin, a mycotoxin known to contribute to\n                    <jats:italic>A. fumigatus</jats:italic>\n                    virulence. We discovered that the non-pathogenic\n                    <jats:italic>A. fischeri</jats:italic>\n                    produces gliotoxin under the same conditions as the major pathogen\n                    <jats:italic>A. fumigatus</jats:italic>\n                    . However, we also discovered that, in contrast to what has been previously observed in\n                    <jats:italic>A. fumigatus</jats:italic>\n                    , loss of secondary metabolite, including gliotoxin, production in\n                    <jats:italic>A. fischeri</jats:italic>\n                    does not alter its virulence. Our results are consistent with the “cards of virulence” model of opportunistic fungal disease, where the ability to cause disease stems from the combination (“hand”) of individual virulence factors (“cards”), but not from individual factors\n                    <jats:italic>per se</jats:italic>\n                    .\n                  </jats:p>\n                </jats:sec>","is_dataset_classified":null,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19910364","pmcid":null,"openalex_id":"https://openalex.org/W2991909609","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"5F31AT010558-02","title":"Co-culturing to Elicit Chemical Diversity in Fungi"},{"funder_name":"National Science Foundation","grant_id":"1442113","title":"DIMENSIONS: Collaborative Research: The Making of Biodiversity Across the Yeast Subphylum"}],"total_grants":2,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2020,"count":1}],"oa_status":"green","license":"cc-by-nc","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2019/12/08/868745.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2019/12/08/868745.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/868745","host_type":"publisher"},{"url":"https://doi.org/10.1101/868745","host_type":"repository"},{"url":"https://doi.org/10.1128/mbio.03361-19","host_type":""},{"url":"https://dx.doi.org/10.1101/868745","host_type":""},{"url":"http://dx.doi.org/10.1101/868745","host_type":""}],"fields_of_study":["Antifungal resistance and susceptibility","Mycotoxins in Agriculture and Food","Infectious Diseases and Mycology","0301 basic medicine","0303 health sciences","03 medical and health sciences"],"mesh_terms":[],"keywords":["Gliotoxin","Aspergillus fumigatus","Virulence","Biology","Microbiology","Pathogen","Secondary metabolite","Virulence factor","Secondary metabolism","Human pathogen","Genetics","Gene","Biosynthesis"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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