title: Pf4 bacteriophage produced by Pseudomonas aeruginosa inhibits Aspergillus fumigatus metabolism via iron sequestration.
abstract: Pseudomonas aeruginosa (Pa) and Aspergillus fumigatus (Af) are major human pathogens known to interact in a variety of disease settings, including airway infections in cystic fibrosis. We recently reported that clinical CF isolates of Pa inhibit the formation and growth of Af biofilms. Here, we report that the bacteriophage Pf4, produced by Pa, can inhibit the metabolic activity of Af biofilms. This phage-mediated inhibition was dose dependent, ablated by phage denaturation, and was more pronounced against preformed Af biofilm rather than biofilm formation. In contrast, planktonic conidial growth was unaffected. Two other phages, Pf1 and fd, did not inhibit Af, nor did supernatant from a Pa strain incapable of producing Pf4. Pf4, but not Pf1, attaches to Af hyphae in an avid and prolonged manner, suggesting that Pf4-mediated inhibition of Af may occur at the biofilm surface. We show that Pf4 binds iron, thus denying Af a crucial resource. Consistent with this, the inhibition of Af metabolism by Pf4 could be overcome with supplemental ferric iron, with preformed biofilm more resistant to reversal. To our knowledge, this is the first report of a bacterium producing a phage that inhibits the growth of a fungus and the first description of a phage behaving as an iron chelator in a biological system.
authors.affiliation: California Institute for Medical Research, San Jose, CA, USA.|Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
authors.forename: Jack C
authors.initials: JC
authors.lastname: Penner
authors.affiliation: California Institute for Medical Research, San Jose, CA, USA.|Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
authors.forename: Jose A G
authors.initials: JAG
authors.lastname: Ferreira
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Secor
authors.affiliation: Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.|Stanford Immunology Program, Stanford University, Stanford, CA, USA.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Sweere
authors.affiliation: Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.|Stanford Immunology Program, Stanford University, Stanford, CA, USA.
authors.forename: Maria K
authors.initials: MK
authors.lastname: Birukova
authors.affiliation: Cell Sciences Imaging Facility (CSIF), Stanford University Medical School, Stanford, CA, &nbsp;USA.
authors.forename: Lydia-Marie
authors.initials: LM
authors.lastname: Joubert
authors.affiliation: Department of Civil & Environmental Engineering, Stanford University, Stanford, CA, USA.
authors.forename: Janus A J
authors.initials: JAJ
authors.lastname: Haagensen
authors.affiliation: Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Garcia
authors.affiliation: Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.|Biomaterial and Advanced Drug Delivery Laboratory, Stanford University, Stanford, CA 94305, &nbsp;USA.
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Malkovskiy
authors.affiliation: Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
authors.forename: Gernot
authors.initials: G
authors.lastname: Kaber
authors.affiliation: California Institute for Medical Research, San Jose, CA, USA.|Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.|Department of Medical Microbiology, Istanbul University, Istanbul, Turkey.
authors.forename: Hasan
authors.initials: H
authors.lastname: Nazik
authors.affiliation: Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Manasherob
authors.affiliation: Department of Civil & Environmental Engineering, Stanford University, Stanford, CA, USA.
authors.forename: Alfred M
authors.initials: AM
authors.lastname: Spormann
authors.affiliation: California Institute for Medical Research, San Jose, CA, USA.|Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
authors.forename: Karl V
authors.initials: KV
authors.lastname: Clemons
authors.affiliation: California Institute for Medical Research, San Jose, CA, USA.|Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Stevens
authors.affiliation: Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.|Stanford Immunology Program, Stanford University, Stanford, CA, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Bollyky
mesh_terms: D001228:Aspergillosis / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000502:physiology* / Q000821:virology; D001435:Bacteriophages / Q000502:physiology*; D018441:Biofilms; D006801:Humans; D007501:Iron / Q000378:metabolism*; D011550:Pseudomonas aeruginosa / Q000821:virology*
chemical_list: D007501:Iron