Abstract
Bacterial superantigens (SAgs) cause Vβ-dependent T-cell proliferation leading to immune dysregulation associated with the pathogenesis of life-threatening infections such as toxic shock syndrome, and necrotizing pneumonia. Previously, we demonstrated that staphylococcal enterotoxin-like toxin X (SElX) from Staphylococcus aureus is a classical superantigen that exhibits T-cell activation in a Vβ-specific manner, and contributes to the pathogenesis of necrotizing pneumonia. Here, we discovered that SElX can also bind to neutrophils from human and other mammalian species and disrupt IgG-mediated phagocytosis. Site-directed mutagenesis of the conserved sialic acid-binding motif of SElX abolished neutrophil binding and phagocytic killing, and revealed multiple glycosylated neutrophil receptors for SElX binding. Furthermore, the neutrophil binding-deficient mutant of SElX retained its capacity for T-cell activation demonstrating that SElX exhibits mechanistically independent activities on distinct cell populations associated with acquired and innate immunity, respectively. Finally, we demonstrated that the neutrophil-binding activity rather than superantigenicity is responsible for the SElX-dependent virulence observed in a necrotizing pneumonia rabbit model of infection. Taken together, we report the first example of a SAg, that can manipulate both the innate and adaptive arms of the human immune system during S. aureus pathogenesis.
Highlights
Staphylococcus aureus is an opportunistic pathogen responsible for a wide array of human diseases in both the hospital and community settings [1]
We discovered that staphylococcal enterotoxin-like toxin X (SElX) binds to neutrophils via multiple glycosylated neutrophil surface receptors, inhibiting phagocytosis and contributing to the pathogenesis of severe lung infection
SElX binds to neutrophils and monocytes from multiple mammalian species In order to test the hypothesis that SElX can bind to human leukocytes, recombinant SElX was incubated with human leukocytes isolated from healthy donors
Summary
Staphylococcus aureus is an opportunistic pathogen responsible for a wide array of human diseases in both the hospital and community settings [1]. The diversity of disease types and the strain-dependent variation in pathogenic potential is due in part to the large array of virulence factors that are produced by S. aureus [1]. The staphylococcal superantigens (SAgs) are a family of at least 26 secreted proteins that modulate the immune system by stimulating dysregulated T-cell proliferation [2,3,4], contributing to a variety of different diseases including toxic shock syndrome, necrotizing pneumonia and Kawasaki disease [2]. The diversity of SAgs produced by S. aureus strains facilitates interaction with the large repertoire of variable-β chains (Vβ) found in the T-cell receptor leading to dysregulation of a critical component of the adaptive immune response [2, 5]. Very high concentrations of SElX were required for a relatively low-affinity interaction suggesting that CD162 may not be the main neutrophil receptor involved [15]
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