The Staphylococcus aureus superantigen SElX is a bifunctional toxin that inhibits neutrophil function

Tuffs, Stephen W.; James, David B. A.; Bestebroer, Jovanka; Richards, Amy C.; Goncheva, Mariya I.; O’Shea, Marie A.; Wee, Bryan A.; Seo, Keun Seok; Schlievert, Patrick M.; Lengeling, Andreas; Strijp, Jos A. van; Torres, Victor J.; Fitzgerald, J. Ross

doi:10.1371/journal.ppat.1006461

Cited by 39 publications

(38 citation statements)

References 62 publications

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“…In addition to TSS, staphylococcal SAgs have been strongly associated with a number of other diseases including life-threatening conditions such as pneumonia and endocarditis [ 3 ]. SAgs in severe S. aureus- mediated pneumonia are likely to over activate the immune system, induce damage to the pulmonary epithelium, and subvert neutrophil activation resulting in serve inflammatory pathology [ 3 , 74 , 75 ]. Specifically, SEB, SEC, SElX and TSST-1 have all been shown to contribute to mortality in a rabbit model of necrotizing pneumonia [ 38 , 74 , 75 ].…”

Section: Staphylococcal Superantigens and Diseasementioning

confidence: 99%

“…SAgs in severe S. aureus- mediated pneumonia are likely to over activate the immune system, induce damage to the pulmonary epithelium, and subvert neutrophil activation resulting in serve inflammatory pathology [ 3 , 74 , 75 ]. Specifically, SEB, SEC, SElX and TSST-1 have all been shown to contribute to mortality in a rabbit model of necrotizing pneumonia [ 38 , 74 , 75 ]. Rabbit models of S. aureus infection have also demonstrated that SAgs can contribute to the disease process in the development of infective endocarditis, augmenting the formation and persistence of microbial heart valve vegetations [ 55 , 76 ].…”

Section: Staphylococcal Superantigens and Diseasementioning

confidence: 99%

“…Therefore, it is possible that these toxins have evolved alternative roles during infection. This has been demonstrated to be the case for SElX, which was shown to bind to and inhibit the function of neutrophils, and this activity was distinct from the ability of the toxin to induce T cell proliferation [ 54 , 75 ]. SElX is quite distinct from other members of the SAg family in that it does not form the classic two domain SAg structure [ 54 ].…”

Section: Superantigens In S Aureus Pathogenesimentioning

confidence: 99%

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Manipulation of Innate and Adaptive Immunity by Staphylococcal Superantigens

2018

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Staphylococcal superantigens (SAgs) constitute a family of potent exotoxins secreted by Staphylococcus aureus and other select staphylococcal species. SAgs function to cross-link major histocompatibility complex (MHC) class II molecules with T cell receptors (TCRs) to stimulate the uncontrolled activation of T lymphocytes, potentially leading to severe human illnesses such as toxic shock syndrome. The ubiquity of SAgs in clinical S. aureus isolates suggests that they likely make an important contribution to the evolutionary fitness of S. aureus. Although the apparent redundancy of SAgs in S. aureus has not been explained, the high level of sequence diversity within this toxin family may allow for SAgs to recognize an assorted range of TCR and MHC class II molecules, as well as aid in the avoidance of humoral immunity. Herein, we outline the major diseases associated with the staphylococcal SAgs and how a dysregulated immune system may contribute to pathology. We then highlight recent research that considers the importance of SAgs in the pathogenesis of S. aureus infections, demonstrating that SAgs are more than simply an immunological diversion. We suggest that SAgs can act as targeted modulators that drive the immune response away from an effective response, and thus aid in S. aureus persistence.

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Section: Staphylococcal Superantigens and Diseasementioning

confidence: 99%

Section: Staphylococcal Superantigens and Diseasementioning

confidence: 99%

Section: Superantigens In S Aureus Pathogenesimentioning

confidence: 99%

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Manipulation of Innate and Adaptive Immunity by Staphylococcal Superantigens

2018

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“…These toxins are preferentially directed against immune cells to induce inflammation and cell death. With respect to superantigens, different models have demonstrated enhanced activation and cytotoxicity against the immune system that contributes to lung infection [32,33]. The efficient bacterial defense against immune cells is of particular importance during lung infection, as immune cells are abundantly recruited to lung tissue during infection and the interaction of S. aureus with the immune system appears to be a key factor in the pathogenesis of pneumonia [34].…”

Section: Discussionmentioning

confidence: 99%

Staphylococcus aureus Pneumonia: Preceding Influenza Infection Paves the Way for Low-Virulent Strains

Deinhardt‐Emmer

Haupt

Garcia-Moreno

et al. 2019

Toxins

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Staphylococcus aureus is a facultative pathogenic bacterium that colonizes the nasopharyngeal area of healthy individuals, but can also induce severe infection, such as pneumonia. Pneumonia caused by mono- or superinfected S. aureus leads to high mortality rates. To establish an infection, S. aureus disposes of a wide variety of virulence factors, which can vary between clinical isolates. Our study aimed to characterize pneumonia isolates for their virulent capacity. For this, we analyzed isolates from colonization, pneumonia due to S. aureus, and pneumonia due to S. aureus/influenza virus co-infection. A total of 70 strains were analyzed for their virulence genes and the host–pathogen interaction was analyzed through functional assays in cell culture systems. Strains from pneumonia due to S. aureus mono-infection showed enhanced invasion and cytotoxicity against professional phagocytes than colonizing and co-infecting strains. This corresponded to the high presence of cytotoxic components in pneumonia strains. By contrast, strains obtained from co-infection did not exhibit these virulence characteristics and resembled strains from colonization, although they caused the highest mortality rate in patients. Taken together, our results underline the requirement of invasion and toxins to cause pneumonia due to S. aureus mono-infection, whereas in co-infection even low-virulent strains can severely aggravate pneumonia.

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“…Recently, it was discovered that SE l X has a unique sialic acid-binding motif. This motif allows SE l X to interact with adhesion molecules on neutrophils involved in immune recognition and cell activation (Langley et al, 2017 ; Tuffs et al, 2017 ). Importantly, the ability of SE l X to bind neutrophils, which are considered the first line of defense against S. aureus (Spaan et al, 2013 ), was crucial for disease progression in a rabbit model of necrotizing pneumonia.…”

Section: The Enterotoxins Are Immunomodulators Of Multiple Immune Celmentioning

confidence: 99%

Basis of Virulence in Enterotoxin-Mediated Staphylococcal Food Poisoning

2018

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The Staphylococcus aureus enterotoxins are a superfamily of secreted virulence factors that share structural and functional similarities and possess potent superantigenic activity causing disruptions in adaptive immunity. The enterotoxins can be separated into two groups; the classical (SEA-SEE) and the newer (SEG-SElY and counting) enterotoxin groups. Many members from both these groups contribute to the pathogenesis of several serious human diseases, including toxic shock syndrome, pneumonia, and sepsis-related infections. Additionally, many members demonstrate emetic activity and are frequently responsible for food poisoning outbreaks. Due to their robust tolerance to denaturing, the enterotoxins retain activity in food contaminated previously with S. aureus. The genes encoding the enterotoxins are found mostly on a variety of different mobile genetic elements. Therefore, the presence of enterotoxins can vary widely among different S. aureus isolates. Additionally, the enterotoxins are regulated by multiple, and often overlapping, regulatory pathways, which are influenced by environmental factors. In this review, we also will focus on the newer enterotoxins (SEG-SElY), which matter for the role of S. aureus as an enteropathogen, and summarize our current knowledge on their prevalence in recent food poisoning outbreaks. Finally, we will review the current literature regarding the key elements that govern the complex regulation of enterotoxins, the molecular mechanisms underlying their enterotoxigenic, superantigenic, and immunomodulatory functions, and discuss how these activities may collectively contribute to the overall manifestation of staphylococcal food poisoning.

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The Staphylococcus aureus superantigen SElX is a bifunctional toxin that inhibits neutrophil function

Cited by 39 publications

References 62 publications

Manipulation of Innate and Adaptive Immunity by Staphylococcal Superantigens

Manipulation of Innate and Adaptive Immunity by Staphylococcal Superantigens

Staphylococcus aureus Pneumonia: Preceding Influenza Infection Paves the Way for Low-Virulent Strains

Basis of Virulence in Enterotoxin-Mediated Staphylococcal Food Poisoning

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