Staphylococcus aureus α toxin potentiates opportunistic bacterial lung infections

TS Cohen, JJ Hilliard, O Jones-Nelson… - Science Translational …, 2016 - science.org
TS Cohen, JJ Hilliard, O Jones-Nelson, AE Keller, T O'Day, C Tkaczyk, A DiGiandomenico
Science Translational Medicine, 2016science.org
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 …
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.
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