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Counter inhibition between leukotoxins attenuates Staphylococcus aureus virulence.

Yoong P, Torres VJ - Nat Commun (2015)

Bottom Line: Despite extensive sequence conservation, each leukotoxin has unique properties, including disparate cellular receptors and species specificities.Using in vivo murine models of infection, we show that LukSF-PV negatively influences S. aureus virulence and colonization by inhibiting LukED.Thus, while S. aureus leukotoxins can certainly injure immune cells, the discovery of leukotoxin antagonism suggests that they may also play a role in reducing S. aureus virulence and maintaining infection without killing the host.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.

ABSTRACT
Staphylococcus aureus subverts host defences by producing a collection of virulence factors including bi-component pore-forming leukotoxins. Despite extensive sequence conservation, each leukotoxin has unique properties, including disparate cellular receptors and species specificities. How these toxins collectively influence S. aureus pathogenesis is unknown. Here we demonstrate that the leukotoxins LukSF-PV and LukED antagonize each other's cytolytic activities on leukocytes and erythrocytes by forming inactive hybrid complexes. Remarkably, LukSF-PV inhibition of LukED haemolytic activity on both human and murine erythrocytes prevents the release of nutrients required for in vitro bacterial growth. Using in vivo murine models of infection, we show that LukSF-PV negatively influences S. aureus virulence and colonization by inhibiting LukED. Thus, while S. aureus leukotoxins can certainly injure immune cells, the discovery of leukotoxin antagonism suggests that they may also play a role in reducing S. aureus virulence and maintaining infection without killing the host.

No MeSH data available.


Related in: MedlinePlus

Models of leukotoxin antagonism.On leukocytes, an ‘F' subunit from an ‘inert' leukotoxin can associate with an ‘S' subunit bound to that cell in a receptor dependent manner, giving rise to inactive hybrid complexes. Thus, the ‘S' subunit is sequestered from its cognate ‘F' partner, preventing the formation of pores in those cells. In RBCs, the formation of inactive hybrid complexes is different as the ‘F' subunits interact with RBCs in what appears to be a receptor-independent manner, and is a prerequisite for haemolysis. Antagonism of LukED-mediated haemolysis in RBCs is observed by each LukS-PV or LukF-PV, although inhibition is enhanced in the presence of both LukS-PV and LukF-PV subunits.
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f5: Models of leukotoxin antagonism.On leukocytes, an ‘F' subunit from an ‘inert' leukotoxin can associate with an ‘S' subunit bound to that cell in a receptor dependent manner, giving rise to inactive hybrid complexes. Thus, the ‘S' subunit is sequestered from its cognate ‘F' partner, preventing the formation of pores in those cells. In RBCs, the formation of inactive hybrid complexes is different as the ‘F' subunits interact with RBCs in what appears to be a receptor-independent manner, and is a prerequisite for haemolysis. Antagonism of LukED-mediated haemolysis in RBCs is observed by each LukS-PV or LukF-PV, although inhibition is enhanced in the presence of both LukS-PV and LukF-PV subunits.

Mentions: Leukotoxin antagonism occurs in instances where a leukotoxin cannot target a certain cell type for lysis, but it can in turn interact with an active leukotoxin preventing the active toxin from exerting its cytotoxic effects. Interestingly, leukotoxin antagonism was also observed on human neutrophils, which are susceptible to all S. aureus leukotoxins, albeit to differing degrees. On leukocytes, we propose a model whereby an ‘inert' ‘F' subunit can form an inactive hybrid complex with a ‘S' subunit bound to that cell, thereby preventing the ‘S' subunit from pairing with its cognate ‘F' partner to form pores in that cell (Fig. 5). Interaction of leukotoxins with RBCs, however, appear to be different, with nonspecific binding of ‘F' subunits being a prerequisite for haemolysis (Supplementary Fig. 5A)48. Unlike leukotoxin inhibition of leukocyte lysis by an ‘inert' ‘F' subunit, LukS-PV and LukF-PV alone can equally inhibit LukED haemolysis, although inhibition is enhanced in the presence of both subunits (Fig. 5 and Supplementary Fig. 5B). Because the interaction of leukotoxins with RBCs is still not well understood, the mechanism of leukotoxin antagonism on these cells remains to be fully elucidated.


Counter inhibition between leukotoxins attenuates Staphylococcus aureus virulence.

Yoong P, Torres VJ - Nat Commun (2015)

Models of leukotoxin antagonism.On leukocytes, an ‘F' subunit from an ‘inert' leukotoxin can associate with an ‘S' subunit bound to that cell in a receptor dependent manner, giving rise to inactive hybrid complexes. Thus, the ‘S' subunit is sequestered from its cognate ‘F' partner, preventing the formation of pores in those cells. In RBCs, the formation of inactive hybrid complexes is different as the ‘F' subunits interact with RBCs in what appears to be a receptor-independent manner, and is a prerequisite for haemolysis. Antagonism of LukED-mediated haemolysis in RBCs is observed by each LukS-PV or LukF-PV, although inhibition is enhanced in the presence of both LukS-PV and LukF-PV subunits.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4562310&req=5

f5: Models of leukotoxin antagonism.On leukocytes, an ‘F' subunit from an ‘inert' leukotoxin can associate with an ‘S' subunit bound to that cell in a receptor dependent manner, giving rise to inactive hybrid complexes. Thus, the ‘S' subunit is sequestered from its cognate ‘F' partner, preventing the formation of pores in those cells. In RBCs, the formation of inactive hybrid complexes is different as the ‘F' subunits interact with RBCs in what appears to be a receptor-independent manner, and is a prerequisite for haemolysis. Antagonism of LukED-mediated haemolysis in RBCs is observed by each LukS-PV or LukF-PV, although inhibition is enhanced in the presence of both LukS-PV and LukF-PV subunits.
Mentions: Leukotoxin antagonism occurs in instances where a leukotoxin cannot target a certain cell type for lysis, but it can in turn interact with an active leukotoxin preventing the active toxin from exerting its cytotoxic effects. Interestingly, leukotoxin antagonism was also observed on human neutrophils, which are susceptible to all S. aureus leukotoxins, albeit to differing degrees. On leukocytes, we propose a model whereby an ‘inert' ‘F' subunit can form an inactive hybrid complex with a ‘S' subunit bound to that cell, thereby preventing the ‘S' subunit from pairing with its cognate ‘F' partner to form pores in that cell (Fig. 5). Interaction of leukotoxins with RBCs, however, appear to be different, with nonspecific binding of ‘F' subunits being a prerequisite for haemolysis (Supplementary Fig. 5A)48. Unlike leukotoxin inhibition of leukocyte lysis by an ‘inert' ‘F' subunit, LukS-PV and LukF-PV alone can equally inhibit LukED haemolysis, although inhibition is enhanced in the presence of both subunits (Fig. 5 and Supplementary Fig. 5B). Because the interaction of leukotoxins with RBCs is still not well understood, the mechanism of leukotoxin antagonism on these cells remains to be fully elucidated.

Bottom Line: Despite extensive sequence conservation, each leukotoxin has unique properties, including disparate cellular receptors and species specificities.Using in vivo murine models of infection, we show that LukSF-PV negatively influences S. aureus virulence and colonization by inhibiting LukED.Thus, while S. aureus leukotoxins can certainly injure immune cells, the discovery of leukotoxin antagonism suggests that they may also play a role in reducing S. aureus virulence and maintaining infection without killing the host.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.

ABSTRACT
Staphylococcus aureus subverts host defences by producing a collection of virulence factors including bi-component pore-forming leukotoxins. Despite extensive sequence conservation, each leukotoxin has unique properties, including disparate cellular receptors and species specificities. How these toxins collectively influence S. aureus pathogenesis is unknown. Here we demonstrate that the leukotoxins LukSF-PV and LukED antagonize each other's cytolytic activities on leukocytes and erythrocytes by forming inactive hybrid complexes. Remarkably, LukSF-PV inhibition of LukED haemolytic activity on both human and murine erythrocytes prevents the release of nutrients required for in vitro bacterial growth. Using in vivo murine models of infection, we show that LukSF-PV negatively influences S. aureus virulence and colonization by inhibiting LukED. Thus, while S. aureus leukotoxins can certainly injure immune cells, the discovery of leukotoxin antagonism suggests that they may also play a role in reducing S. aureus virulence and maintaining infection without killing the host.

No MeSH data available.


Related in: MedlinePlus