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In otherwise healthy individuals, macrophages are responsible for rapidly phagocytosing and eliminating these conidia, effectively curbing their germination and consequent invasion of pulmonary tissue. However, under some circumstances, the fungus evades phagocyte-mediated immunity and persists in the respiratory tree. Here, we report that<jats:named-content content-type=\"genus-species\">A. fumigatus<\/jats:named-content>escapes macrophage recognition by strategically targeting phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P<jats:sub>3<\/jats:sub>] metabolism through gliotoxin, a potent immunosuppressive mycotoxin. Time-lapse microscopy revealed that, in response to the toxin, macrophages cease to ruffle, undergo abrupt membrane retraction, and fail to phagocytose large targets effectively. Gliotoxin was found to prevent integrin activation and interfere with actin dynamics, both of which are instrumental for phagocytosis; similar effects were noted in immortalized and primary phagocytes. Detailed studies of the underlying molecular mechanisms of toxicity revealed that inhibition of phagocytosis is attributable to impaired accumulation of PtdIns(3,4,5)P<jats:sub>3<\/jats:sub>and the associated dysregulation of downstream effectors, including Rac and\/or Cdc42. Strikingly, in response to the diacylglycerol mimetic phorbol 12-myristate 13-acetate, gliotoxin-treated macrophages reactivate beta integrins, reestablish actin dynamics, and regain phagocytic capacity, despite the overt absence of plasmalemmal PtdIns(3,4,5)P<jats:sub>3<\/jats:sub>. Together, our findings identify phosphoinositide metabolism as a critical upstream target of gliotoxin and also indicate that increased diacylglycerol levels can bypass the requirement for PtdIns(3,4,5)P<jats:sub>3<\/jats:sub>signaling during membrane ruffling and phagocytosis.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold><jats:named-content content-type=\"genus-species\">Aspergillus fumigatus<\/jats:named-content>is the most frequent cause of human infections in the<jats:italic>Aspergillus<\/jats:italic>genus. In immunocompromised populations, invasive aspergillosis (IA) is associated with a mortality rate of up to 90%, and current antifungal therapies have failed to prevent or reverse the infection. Therefore, a deeper understanding of the interactions between<jats:named-content content-type=\"genus-species\">A. fumigatus<\/jats:named-content>and its host is required. In healthy humans, alveolar macrophages can ingest and eliminate fungal spores, thus limiting their germination into mycotoxin-producing hyphae. Our studies reveal that gliotoxin\u2014the most abundant<jats:italic>Aspergillus<\/jats:italic>mycotoxin\u2014undermines the ability of phagocytes to carry out their protective functions. By targeting PtdIns(3,4,5)P<jats:sub>3<\/jats:sub>signaling and downregulating phagocytic immune defenses, the toxin could also exacerbate polymicrobial infections. Notably, we were able to reverse gliotoxin toxicity by addition of diacylglycerol analogues, which may provide the basis for therapeutic interventions.<\/jats:p>","DOI":"10.1128\/mbio.02242-15","type":"journal-article","created":{"date-parts":[[2016,4,6]],"date-time":"2016-04-06T01:13:25Z","timestamp":1459905205000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":62,"title":["Gliotoxin Suppresses Macrophage Immune Function by Subverting Phosphatidylinositol 3,4,5-Trisphosphate Homeostasis"],"prefix":"10.1128","volume":"7","author":[{"given":"Daniel","family":"Schlam","sequence":"first","affiliation":[{"name":"Division of Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada"},{"name":"Faculty of Medicine, Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnathan","family":"Canton","sequence":"additional","affiliation":[{"name":"Division of Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin","family":"Carre\u00f1o","sequence":"additional","affiliation":[{"name":"Division of Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Kopinski","sequence":"additional","affiliation":[{"name":"Division of Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spencer A.","family":"Freeman","sequence":"additional","affiliation":[{"name":"Division of Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Grinstein","sequence":"additional","affiliation":[{"name":"Division of Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada"},{"name":"Faculty of Medicine, Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada"},{"name":"Keenan Research Centre for Biomedical Science, St. Michael\u2019s Hospital, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory D.","family":"Fairn","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada"},{"name":"Keenan Research Centre for Biomedical Science, St. Michael\u2019s Hospital, Toronto, Ontario, Canada"},{"name":"Departments of Surgery and Biochemistry, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1086\/318483"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/513943"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00036-10"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1439-0507.2003.00830.x"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00055-08"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.3109\/13693786.2010.548084"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1080\/02681219880000241"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.42.3.1109-1115.1983"},{"key":"e_1_3_2_10_2","first-page":"57","article-title":"The pathogenesis of experimental pulmonary aspergillosis. 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