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Abstract
SummaryMacrophages are critical effectors of the early innate response to bacteria in tissues. Phagocytosis and killing of bacteria are interrelated functions essential for bacterial clearance but the rate‐limiting step when macrophages are challenged with large numbers of the major medical pathogen Staphylococcus aureus is unknown. We show that macrophages have a finite capacity for intracellular killing and fail to match sustained phagocytosis with sustained microbial killing when exposed to large inocula of S. aureus (Newman, SH1000 and USA300 strains). S. aureus ingestion by macrophages is associated with a rapid decline in bacterial viability immediately after phagocytosis. However, not all bacteria are killed in the phagolysosome, and we demonstrate reduced acidification of the phagolysosome, associated with failure of phagolysosomal maturation and reduced activation of cathepsin D. This results in accumulation of viable intracellular bacteria in macrophages. We show macrophages fail to engage apoptosis‐associated bacterial killing. Ultittop mately macrophages with viable bacteria undergo cell lysis, and viable bacteria are released and can be internalized by other macrophages. We show that cycles of lysis and reuptake maintain a pool of viable intracellular bacteria over time when killing is overwhelmed and demonstrate intracellular persistence in alveolar macrophages in the lungs in a murine model.
Highlights
Staphylococcus aureus is a major cause of infectious disease contributing both to community-associated and hospital-associated infection (Fluit et al, 2000; Wisplinghoff et al, 2004)
Phagocytosis and killing of bacteria are interrelated functions essential for bacterial clearance but the ratelimiting step when macrophages are challenged with large numbers of the major medical pathogen Staphylococcus aureus is unknown
We show that macrophages have a finite capacity for intracellular killing and fail to match sustained phagocytosis with sustained microbial killing when exposed to large inocula of S. aureus (Newman, SH1000 and USA300 strains)
Summary
Staphylococcus aureus is a major cause of infectious disease contributing both to community-associated and hospital-associated infection (Fluit et al, 2000; Wisplinghoff et al, 2004). The emergence of high-level antimicrobial resistance and in particular methicillinresistant S. aureus strains further challenges the clinical approach. These infections involve all ages, and the emergence of community-acquired methicillin-resistant S. aureus has represented a particular medical challenge (Herold et al, 1998). A more complete understanding of how this pathogen avoids host immune responses is clearly warranted if more effective treatment approaches are to be developed to combat the evolution of antimicrobial resistant strains
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