calpain and Respiratory-Tract-Infections

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.

Topics: Acids; Animals; Antibodies, Bacterial; Antibodies, Monoclonal; Bacterial Toxins; Calpain; Coinfection; Enzyme Activation; Hemolysin Proteins; Humans; Killer Cells, Natural; Lysosomes; Macrophages, Alveolar; Mice; Microbial Viability; Models, Biological; Neutrophils; Opportunistic Infections; Pneumonia; Pseudomonas aeruginosa; Respiratory Tract Infections; Staphylococcal Infections; Staphylococcus aureus