Research ArticleInfectious Disease

Staphylococcus aureus α toxin potentiates opportunistic bacterial lung infections

Science Translational Medicine  09 Mar 2016:
Vol. 8, Issue 329, pp. 329ra31
DOI: 10.1126/scitranslmed.aad9922

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Toxic eviction

There are many benefits to a good roommate, but the wrong choice can be toxic. Now, Cohen et al. examine the effects of co-habitation on lung infection. They found that α toxin produced by Staphylococcus aureus can worsen lung co-infection by Gram-negative bacteria by preventing acidification of bacteria-containing phagosomes, increasing proliferation, spread, and lethality. However, early treatment or prophylaxis with a neutralizing antibody to α toxin prevented this effect and promoted S. aureus clearance in a humanized mouse model. If this eviction occurs in humans, this approach may reduce co-infection risk in patients colonized with S. aureus.

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.

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