title: Staphylococcus aureus α toxin potentiates opportunistic bacterial lung infections.
abstract: Broad-spectrum antibiotic use may adversely affect a patient's beneficial microbiome and fuel cross-species spread of drug resistance. Although alternative pathogen-specific approaches are rationally justified, a major concern for this precision medicine strategy is that co-colonizing or co-infecting opportunistic bacteria may still cause serious disease. In a mixed-pathogen lung infection model, we find that the Staphylococcus aureus virulence factor α toxin potentiates Gram-negative bacterial proliferation, systemic spread, and lethality by preventing acidification of bacteria-containing macrophage phagosomes, thereby reducing effective killing of both S. aureus and Gram-negative bacteria. Prophylaxis or early treatment with a single α toxin neutralizing monoclonal antibody prevented proliferation of co-infecting Gram-negative pathogens and lethality while also promoting S. aureus clearance. These studies suggest that some pathogen-specific, antibody-based approaches may also work to reduce infection risk in patients colonized or co-infected with S. aureus and disparate drug-resistant Gram-negative bacterial opportunists.
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Taylor S
authors.initials: TS
authors.lastname: Cohen
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Jamese J
authors.initials: JJ
authors.lastname: Hilliard
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Omari
authors.initials: O
authors.lastname: Jones-Nelson
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Keller
authors.affiliation: Department of Translational Science, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Terrence
authors.initials: T
authors.lastname: O'Day
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Tkaczyk
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: DiGiandomenico
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Hamilton
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Pelletier
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94110, USA. Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Binh An
authors.initials: BA
authors.lastname: Diep
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94110, USA.
authors.forename: Vien T M
authors.initials: VT
authors.lastname: Le
authors.affiliation: Department of Translational Science, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: JoAnn
authors.initials: J
authors.lastname: Suzich
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, MD 20878, USA.
authors.forename: C Kendall
authors.initials: CK
authors.lastname: Stover
authors.affiliation: Department of Infectious Disease, MedImmune, Gaithersburg, MD 20878, USA. sellmanb@medimmune.com.
authors.forename: Bret R
authors.initials: BR
authors.lastname: Sellman
mesh_terms: D000143:Acids / Q000378:metabolism; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D001427:Bacterial Toxins / Q000009:adverse effects*; D002154:Calpain / Q000378:metabolism; D060085:Coinfection / Q000382:microbiology; D004789:Enzyme Activation / Q000187:drug effects; D006460:Hemolysin Proteins / Q000009:adverse effects*; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000473:pathology; D051379:Mice; D050296:Microbial Viability / Q000187:drug effects; D008954:Models, Biological; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D009894:Opportunistic Infections / Q000382:microbiology* / Q000473:pathology; D011014:Pneumonia / Q000382:microbiology / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012141:Respiratory Tract Infections / Q000382:microbiology* / Q000473:pathology; D013203:Staphylococcal Infections / Q000382:microbiology* / Q000473:pathology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development
chemical_list: D000143:Acids; D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D006460:Hemolysin Proteins; C021091:staphylococcal alpha-toxin; D002154:Calpain