Characterization of a new cytotoxin that contributes to Staphylococcus aureus pathogenesis

Abstract

SUMMARY Staphylococcus aureus is an important pathogen that continues to be a significant global health threat due to the prevalence of methicillin resistant S. aureus strains (MRSA). The pathogenesis of this organism is partly attributed to the production of a large repertoire of cytotoxins that target and kill innate immune cells, which provide the first line of defense against S. aureus infection. Here we demonstrate that leukocidin A/B (LukAB) is required and sufficient for the ability of S. aureus, including MRSA, to kill human neutrophils, macrophages and dendritic cells. LukAB targets the plasma membrane of host cells resulting in cellular swelling and subsequent cell death. We found that S. aureus lacking lukAB are severely impaired in their ability to kill phagocytes during bacteria-phagocyte interaction, which in turn renders the lukAB-negative staphylococci more susceptible to killing by neutrophils. Notably, we show that lukAB is expressed in vivo within abscesses in a murine infection model and that it contributes significantly to pathogenesis of MRSA in an animal hosts. Collectively, these results extend our understanding of how S. aureus avoids phagocyte-mediated clearance, and underscore LukAB as an important factor that contributes to staphylococcal pathogenesis.

Differential regulation of staphylococcal virulence by the sensor kinase SaeS in response to neutrophil-derived stimuli

“…SaeRS regulates transcription of multiple toxins, including γ-toxin (hlgA, hlgB, hlgC), LukSF-PVL, and LukAB/LukGH, which have been shown to contribute to PMN lysis (26)(27)(28)(29)(30)(31). Additionally, transcription of the saePQRS operon and SaeR target genes are activated in response to PMN phagocytosis and PMN components (32)(33)(34).…”

Staphylococcus aureusLukAB cytotoxin kills human neutrophils by targeting the CD11b subunit of the integrin Mac-1

“…A single S. aureus strain can produce up to five different leukotoxins including two versions of γ-hemolysin (HlgAB and HlgCB), leukocidin E/D (LukED), Panton-Valentine leukocidin (PVL), and leukocidin A/B (LukAB, also known as LukGH) (4)(5)(6). The sequence similarity among these leukocidins ranges from 60% to 80% with the exception of LukAB, which is only 30-40% similar to the others (9,10). LukAB is the most recently identified member of the bicomponent leukocidin family (9,10).…”

“…The sequence similarity among these leukocidins ranges from 60% to 80% with the exception of LukAB, which is only 30-40% similar to the others (9,10). LukAB is the most recently identified member of the bicomponent leukocidin family (9,10). This toxin contributes to the cytotoxicity of clinical isolates toward innate immune cells and has been shown to play an important role in the success of S. aureus in both ex vivo and in vivo models of infection (9,11).…”

“…LukAB is the most recently identified member of the bicomponent leukocidin family (9,10). This toxin contributes to the cytotoxicity of clinical isolates toward innate immune cells and has been shown to play an important role in the success of S. aureus in both ex vivo and in vivo models of infection (9,11). LukAB specifically targets phagocytes such as polymorphonuclear cells (PMNs or neutrophils) (9)(10)(11)(12), which are an integral part of the host innate immune response to S. aureus (13).…”

“…This toxin contributes to the cytotoxicity of clinical isolates toward innate immune cells and has been shown to play an important role in the success of S. aureus in both ex vivo and in vivo models of infection (9,11). LukAB specifically targets phagocytes such as polymorphonuclear cells (PMNs or neutrophils) (9)(10)(11)(12), which are an integral part of the host innate immune response to S. aureus (13). The capacity to kill PMNs is conserved among all leukocidins (4,5), although the actions of LukED (14) and Hlg (15) are not limited to phagocytes (5).…”