Targeting leukocidin-mediated immune evasion protects mice from <i>Staphylococcus aureus</i> bacteremia

Tam, Kayan; Lacey, Keenan A.; Devlin, Joseph C.; Coffre, Maryaline; Sommerfield, Alexis; Chan, Rita; O’Malley, Aidan; Koralov, Sergei B.; Loke, P’ng; Torres, Victor J.

doi:10.1084/jem.20190541

Cited by 22 publications

(15 citation statements)

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“…These findings raise the question of whether the other biochemical observations regarding erythrocyte targeting described here and elsewhere also apply to endothelial targeting. Moreover, the identification of the LukE DR1 as critical for toxin activity pinpoints a domain that could be used to elicit protective immune responses in the form of neutralizing antibodies (41). These are interesting questions for further research.…”

Section: Discussionmentioning

confidence: 99%

“…aureus leukocidins play many roles in facilitating pathogenesis (7,9,32,(42)(43)(44)(45). Further, the leukocidins are promising vaccine targets (41,46). Thus, understanding the biochemistry of leukocidin interactions with host receptors and cells is an important area of research to continue as these studies may facilitate the development of novel S. aureus therapeutics and vaccines.…”

Section: Discussionmentioning

confidence: 99%

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Identification of a domain critical for Staphylococcus aureus LukED receptor targeting and lysis of erythrocytes

Vasquez

Lubkin

Reyes‐Robles

et al. 2020

Journal of Biological Chemistry

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Leukocidin ED (LukED) is a pore forming toxin produced by Staphylococcus aureus which lyses host cells and promotes virulence of the bacteria. LukED enables S. aureus to acquire iron by lysing erythrocytes, which is dependent on targeting the host receptor Duffy antigen receptor for chemokines (DARC). The toxin also targets DARC on the endothelium contributing to the lethality observed during bloodstream infection in mice. LukED is comprised of two monomers, LukE and LukD. LukE binds to DARC and facilitates hemolysis, but the closely related Panton-Valentine Leukocidin S (LukS-PV) does not bind to DARC and is not hemolytic. The interaction of LukE with DARC, and the role this plays in hemolysis, are incompletely characterized. To determine the domain(s) of LukE that are critical for DARC binding, we studied the hemolytic function of LukE-LukS-PV chimeras, in which areas of sequence divergence (divergence regions or DRs) were swapped between the toxins. We found that two regions of LukE’s rim domain contribute to hemolysis, namely residues 57-75 (DR1) and residues 182-196 (DR4). Interestingly, LukE DR1 is sufficient to render LukS-PV capable of DARC binding and hemolysis. Further, LukE, by binding DARC through DR1, promotes the recruitment of LukD to erythrocytes, likely by facilitating LukED oligomer formation. Finally, we show that LukE targets murine Darc through DR1 in vivo to cause host lethality. These findings expand our biochemical understanding of the LukE-DARC interaction and the role that this toxin-receptor pair plays in S. aureus pathophysiology.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of a domain critical for Staphylococcus aureus LukED receptor targeting and lysis of erythrocytes

Vasquez

Lubkin

Reyes‐Robles

et al. 2020

Journal of Biological Chemistry

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“…Related bicomponent toxins, LukED and HlgAB, target similar cells in mice as LukAB does in humans, making LukED and HlgAB more impactful in preclinical mouse models ( Spaan et al, 2017 ). In mice, immunization with LukED and HlgAB antigens induces stronger anti-LukED and anti-HlgAB antibody responses relative to infection with wild-type S. aureus and improves survival upon subsequent challenge with S. aureus ( Tam et al, 2020 ).…”

Section: Antivirulence Strategiesmentioning

confidence: 99%

Antivirulence Strategies for the Treatment of Staphylococcus aureus Infections: A Mini Review

2021

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Staphylococcus aureus is a Gram-positive bacterium capable of infecting nearly all host tissues, causing severe morbidity and mortality. Widespread antimicrobial resistance has emerged among S. aureus clinical isolates, which are now the most frequent causes of nosocomial infection among drug-resistant pathogens. S. aureus produces an array of virulence factors that enhance in vivo fitness by liberating nutrients from the host or evading host immune responses. Staphylococcal virulence factors have been identified as viable therapeutic targets for treatment, as they contribute to disease pathogenesis, tissue injury, and treatment failure. Antivirulence strategies, or treatments targeting virulence without direct toxicity to the inciting pathogen, show promise as an adjunctive therapy to traditional antimicrobials. This Mini Review examines recent research on S. aureus antivirulence strategies, with an emphasis on translational studies. While many different virulence factors have been investigated as therapeutic targets, this review focuses on strategies targeting three virulence categories: pore-forming toxins, immune evasion mechanisms, and the S. aureus quorum sensing system. These major areas of S. aureus antivirulence research demonstrate broad principles that may apply to other human pathogens. Finally, challenges of antivirulence research are outlined including the potential for resistance, the need to investigate multiple infection models, and the importance of studying antivirulence in conjunction with traditional antimicrobial treatments.

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“…Conventional mouse models are the most frequently used systems for investigating a variety of S. aureus diseases, e.g., skin and soft tissue infections [ 77 , 78 ], bacteremia [ 79 , 80 ], sepsis [ 81 , 82 ], peritonitis [ 83 , 84 ], pneumonia [ 85 , 86 ], osteomyelitis [ 87 , 88 ], and endocarditis [ 89 , 90 ]. Although these models led to important advancements in our understanding of host–pathogen interaction, as well as to the identification of key virulence factors and potential treatment strategies for S. aureus infections, scientists have had to deal with failures of human clinical trials based on mouse models, with vaccination studies being a prime example [ 91 , 92 , 93 ].…”

Section: Implications Of Staphylococcal Host Adaptation For Murinementioning

confidence: 99%

Staphylococcus aureus Host Tropism and Its Implications for Murine Infection Models

Mrochen

Oliveira

Raafat

et al. 2020

IJMS

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Staphylococcus aureus (S. aureus) is a pathobiont of humans as well as a multitude of animal species. The high prevalence of multi-resistant and more virulent strains of S. aureus necessitates the development of new prevention and treatment strategies for S. aureus infection. Major advances towards understanding the pathogenesis of S. aureus diseases have been made using conventional mouse models, i.e., by infecting naïve laboratory mice with human-adapted S.aureus strains. However, the failure to transfer certain results obtained in these murine systems to humans highlights the limitations of such models. Indeed, numerous S. aureus vaccine candidates showed promising results in conventional mouse models but failed to offer protection in human clinical trials. These limitations arise not only from the widely discussed physiological differences between mice and humans, but also from the lack of attention that is paid to the specific interactions of S. aureus with its respective host. For instance, animal-derived S. aureus lineages show a high degree of host tropism and carry a repertoire of host-specific virulence and immune evasion factors. Mouse-adapted S.aureus strains, humanized mice, and microbiome-optimized mice are promising approaches to overcome these limitations and could improve transferability of animal experiments to human trials in the future.

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

Cited by 22 publications

References 64 publications

Identification of a domain critical for Staphylococcus aureus LukED receptor targeting and lysis of erythrocytes

Identification of a domain critical for Staphylococcus aureus LukED receptor targeting and lysis of erythrocytes

Antivirulence Strategies for the Treatment of Staphylococcus aureus Infections: A Mini Review

Staphylococcus aureus Host Tropism and Its Implications for Murine Infection Models

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