Abstract
Although considered to be an extracellular pathogen, Staphylococcus aureus is able to invade a variety of mammalian, non-professional phagocytes and can also survive engulfment by professional phagocytes such as neutrophils and monocytes. In both of these cell types S. aureus promptly escapes from the endosomes/phagosomes and proliferates within the cytoplasm, which quickly leads to host cell death. In this report we show that S. aureus interacted with human monocyte-derived macrophages in a very different way to those of other mammalian cells. Upon phagocytosis by macrophages, S. aureus persisted intracellularly in vacuoles for 3–4 days before escaping into the cytoplasm and causing host cell lysis. Until the point of host cell lysis the infected macrophages showed no signs of apoptosis or necrosis and were functional. They were able to eliminate intracellular staphylococci if prestimulated with interferon-γ at concentrations equivalent to human therapeutic doses. S. aureus survival was dependent on the alternative sigma factor B as well as the global regulator agr, but not SarA. Furthermore, isogenic mutants deficient in α-toxin, the metalloprotease aureolysin, protein A, and sortase A were efficiently killed by macrophages upon phagocytosis, although with different kinetics. In particular α-toxin was a key effector molecule that was essential for S. aureus intracellular survival in macrophages. Together, our data indicate that the ability of S. aureus to survive phagocytosis by macrophages is determined by multiple virulence factors in a way that differs considerably from its interactions with other cell types. S. aureus persists inside macrophages for several days without affecting the viability of these mobile cells which may serve as vehicles for the dissemination of infection.
Highlights
S. aureus is a leading etiologic agent of nosocomial and communityacquired infectious diseases
We found that significant numbers of S. aureus cells which had avoided killing during the first 4–5 days post-phagocytosis were suddenly able to lyse the macrophages in which no signs of apoptosis or necrosis were previously demonstrated
Contrary to this we have found that the phagocytosis of opsonised S. aureus strain Newman by human monocyte-derived macrophages (hMDMs) in ratios bacteria to macrophages of up to 50:1, led to a prolonged, survival of bacteria in phagocytes that did not affect the viability of the host cells
Summary
S. aureus is a leading etiologic agent of nosocomial and communityacquired infectious diseases. The pathogenesis of staphylococcal disease usually proceeds from a local infection (e.g., wound infection, furuncle and cellulitis) to systemic dissemination (bacteremia) and to metastatic infections (e.g., endocarditis, osteomyelitis and septic arthritis). The public health concern regarding staphylococcal infections is magnified by the increasing prevalence of multiply antibiotic resistant strains such as methicillin-resistant S. aureus (MRSA) and glycopeptide-insensitive S. aureus (GISA) [3]. The appearance of vancomycin-resistant strains (VRSA) suggests the possibility of a return to a pre-antibiotic era where 80% of bloodstream infections were fatal. A comprehensive understanding of the pathogenic pathways exerted by S. aureus is urgently needed to aid the design of new therapeutic and preventive treatments
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