Staphylococcus aureus toxin suppresses antigen-specific T cell responses

Lee, Brandon; Olaniyi, Reuben; Kwieciński, Jakub; Wardenburg, Juliane Bubeck

doi:10.1172/jci130728

Cited by 31 publications

(33 citation statements)

References 33 publications

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“…In comparison with wild-type S. aureus , infection with a Hla deletion mutant resulted in greater expansion of antigen- specific memory T cells. Interestingly, maternal immunization with Hla resulted in enhanced development of memory T cells in pups following post-natal infection, supporting the idea that early exposure to Hla interferes with the development of immunological memory ( 35 ). Bonifacius et al have recently reported that Hla induced direct death of Th1-polarized cells, while Th17 cells were relatively resistant.…”

Section: Expansion Of Naïve To Memory and Effector T Cells In mentioning

confidence: 52%

“…Therefore, similar to the bicomponent leukotoxins, Hla expression can disrupt antigen presentation to T cells by directly killing APCs and by inhibiting differentiation of T cells to effector and memory cells ( 34 ). Primary infection in C57BL/6 mice with Hla-producing S. aureus impaired protection against recurrent infection ( 35 ). This was attributed, at least in part, to direct toxicity of Hla to dendritic cells, whose numbers were decreased following skin infection with wild type S. aureus , but not an Hla mutant ( 35 ).…”

Section: S Aureus and Antigen Presenting Cellsmentioning

confidence: 99%

“…Primary infection in C57BL/6 mice with Hla-producing S. aureus impaired protection against recurrent infection ( 35 ). This was attributed, at least in part, to direct toxicity of Hla to dendritic cells, whose numbers were decreased following skin infection with wild type S. aureus , but not an Hla mutant ( 35 ). Consistent with this notion, anti-Hla IgG protects against necrosis in the skin and lungs ( 36 , 37 ), but the effects of antibody on immune cell toxicity are not yet clear and may depend on the site of infection ( 37 ).…”

Section: S Aureus and Antigen Presenting Cellsmentioning

confidence: 99%

“…Similarly, Hla induces programmed cell death of human T cells during USA300 infection ( 95 ). In a mouse model, expression of Hla during primary infection results in abrogated memory T cell responses, at least in part due to direct toxicity on T cells ( 35 ). In comparison with wild-type S. aureus , infection with a Hla deletion mutant resulted in greater expansion of antigen- specific memory T cells.…”

Section: Expansion Of Naïve To Memory and Effector T Cells In mentioning

confidence: 99%

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Evasion of Immunological Memory by S. aureus Infection: Implications for Vaccine Design

Teymournejad

Montgomery

2021

Front. Immunol.

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Recurrent S. aureus infections are common, suggesting that natural immune responses are not protective. All candidate vaccines tested thus far have failed to protect against S. aureus infections, highlighting an urgent need to better understand the mechanisms by which the bacterium interacts with the host immune system to evade or prevent protective immunity. Although there is evidence in murine models that both cellular and humoral immune responses are important for protection against S. aureus, human studies suggest that T cells are critical in determining susceptibility to infection. This review will use an “anatomic” approach to systematically outline the steps necessary in generating a T cell-mediated immune response against S. aureus. Through the processes of bacterial uptake by antigen presenting cells, processing and presentation of antigens to T cells, and differentiation and proliferation of memory and effector T cell subsets, the ability of S. aureus to evade or inhibit each step of the T-cell mediated response will be reviewed. We hypothesize that these interactions result in the redirection of immune responses away from protective antigens, thereby precluding the establishment of “natural” memory and potentially inhibiting the efficacy of vaccination. It is anticipated that this approach will reveal important implications for future design of vaccines to prevent these infections.

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Section: Expansion Of Naïve To Memory and Effector T Cells In mentioning

confidence: 52%

Section: S Aureus and Antigen Presenting Cellsmentioning

confidence: 99%

Section: S Aureus and Antigen Presenting Cellsmentioning

confidence: 99%

Section: Expansion Of Naïve To Memory and Effector T Cells In mentioning

confidence: 99%

See 2 more Smart Citations

Evasion of Immunological Memory by S. aureus Infection: Implications for Vaccine Design

Teymournejad

Montgomery

2021

Front. Immunol.

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“…During infections, neutrophils, monocytes, macrophages, dendritic cells, and memory T cells are thought to be targeted by the leukocidins ( Spaan et al, 2017 ). A close relative of the bicomponent leukocidins, α-toxin, also exhibits leukocidal activity and was recently shown to suppress antigen-specific T cell responses ( Lee et al, 2020 ). Although these toxins suppress host adaptive immunity against S. aureus, exposure to these virulence factors during the initial infection is crucial for the development of neutralizing antibodies ( Zhao et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Targeting leukocidin-mediated immune evasion protects mice from Staphylococcus aureus bacteremia

Tam

Lacey

Devlin

et al. 2020

Journal of Experimental Medicine

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Staphylococcus aureus is responsible for various diseases in humans, and recurrent infections are commonly observed. S. aureus produces an array of bicomponent pore-forming toxins that target and kill leukocytes, known collectively as the leukocidins. The contribution of these leukocidins to impair the development of anti–S. aureus adaptive immunity and facilitate reinfection is unclear. Using a murine model of recurrent bacteremia, we demonstrate that infection with a leukocidin mutant results in increased levels of anti–S. aureus antibodies compared with mice infected with the WT parental strain, indicating that leukocidins negatively impact the generation of anti–S. aureus antibodies in vivo. We hypothesized that neutralizing leukocidin-mediated immune subversion by vaccination may shift this host-pathogen interaction in favor of the host. Leukocidin-immunized mice produce potent leukocidin-neutralizing antibodies and robust Th1 and Th17 responses, which collectively protect against bloodstream infections. Altogether, these results demonstrate that blocking leukocidin-mediated immune evasion can promote host protection against S. aureus bloodstream infection.

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A Dual‐Action Molecule Suppresses S. aureus Infection as an Inhibitor Targeting Hla Pore Formation and TLR2 Signaling

Wang

Jiang

et al. 2022

Advanced Biology

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including pneumonia, sepsis and meningitis, and other chronic infections. [1] Novel antibiotics are the most favorable choice, however, the lack of innovative antibiotic development coupled with the frequent emergence of resistant strains may send us back to a preantibiotic era. Increasing evidence suggests that the excessive use of broad-spectrum antibiotics is associated with the risk of many metabolic and inflammatory diseases and some potential diseases related to the disruption of microbiota. [2][3] The rising prevalence of multidrug-resistant and highly virulent strains increases the urgent need for new therapies independent of antibacterial activity.S. aureus produces diverse exotoxins to facilitate its colonization and spreading during infection, and one of the most well-characterized exotoxins is Hla, a typical β-barrel pore-forming cytotoxin expressed by almost all clinical isolates. [4] Hla plays indispensable role in the pathogenesis of invasive infections, phagosome escape, and partially the triggering of the immune response. [5] Hla-induced activation of a disintegrin and metalloproteinase 10 is a critical mechanism of barrier disruption that greatly contributes to the pathogenesis of lethal S. aureus infections by enabling effective spreading. [6] Hla pore-dependent activation of NOD-like receptor protein 3 inflammasome is a successful example of pathogens exploiting host inflammatory signaling by enhancing the pathogenesis of severe S. aureus infection via inducing necrosis. [7] Moreover, Hla is exploited to manipulate adaptive immunity against S. aureus, suppressing the antigen-specific memory T cell response by disturbing DC-T cell crosstalk. [8] Notably, the pore formation activity of Hla is required for these cellular events as the inactive mutant H35L retains the ability to bind the membrane while impaired pore formation fails to act in these cases. The critical role of Hla in S. aureus pathogenesis renders it a developing therapeutic target for virulence-specific strategies aiming to attenuate the pathogenicity of S. aureus rather than directly kill bacteria.Host innate immune response is the first line of defense against S. aureus infection, promoting bacterial clearance and limiting the inciting injury of infection and systemic spreading through neutrophil chemotaxis, phagocytosis and inflammation. [9] However, inflammation is a double-edged sword. In most Antibiotic resistance is the greatest challenge for the treatment of Staphylococcus aureus (S. aureus) infection under the global antibiotic resistance crisis. With the bottleneck period of the development of new antibiotics, novel alternative agents are urgently in need. In this study, the small molecule amentoflavone is identified as a dual-action inhibitor of Hla, a pore-forming virulence determinant particularly important for S. aureus pathogenicity and Toll-like receptor 2 (TLR2) signaling, which triggers inflammation response upon recognizing pathogen-associated molecular patterns. Amentoflavone treatment conferred effective protec...

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Staphylococcus aureus toxin suppresses antigen-specific T cell responses

Cited by 31 publications

References 33 publications

Evasion of Immunological Memory by S. aureus Infection: Implications for Vaccine Design

Evasion of Immunological Memory by S. aureus Infection: Implications for Vaccine Design

Targeting leukocidin-mediated immune evasion protects mice from Staphylococcus aureus bacteremia

A Dual‐Action Molecule Suppresses S. aureus Infection as an Inhibitor Targeting Hla Pore Formation and TLR2 Signaling

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