Staphylococcus aureus Leukocidins Target Endothelial DARC to Cause Lethality in Mice

Lubkin, Ashira; Lee, Warren L.; Alonzo, Francis; Wang, Changsen; Aligo, Jason; Keller, Matthew D.; Girgis, Natasha; Reyes‐Robles, Tamara; Chan, Rita; O’Malley, Aidan; Buckley, Peter T.; Vozhilla, Nicollaq; Vasquez, Marilyn; Su, Johnny; Sugiyama, Michael G.; Yeung, Stephen T.; Coffre, Maryaline; Bajwa, Sofia; Chen, Eric; Martin, Patricia; Kim, Sang Yong; Loomis, Cynthia A.; Worthen, G. Scott; Shopsin, Bo; Khanna, Kamal M.; Weinstock, Daniel; Lynch, A. Simon; Koralov, Sergei B.; Loke, P’ng; Cadwell, Ken; Torres, Victor J.

doi:10.1016/j.chom.2019.01.015

Cited by 27 publications

(40 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S. aureus leukocidins play many roles in facilitating pathogenesis (7,9,32,(42)(43)(44)(45). Further, the leukocidins are promising vaccine targets (41,46).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to facilitating hemolysis, LukED targeting of Darc (the murine homolog of DARC) also contributes to lethality during S. aureus bloodstream infections in mice. In fact, when LukED is injected intravenously, the toxin targets murine Darc on endothelial cells to cause rapid lethality through derangements in the distribution of vascular fluid (32). To further investigate the role of the LukE DR1 in targeting Darc in vivo, we employed this toxin challenge model using Swiss Webster mice.…”

Section: Luke Dr1 -Darc Interaction In Vivomentioning

confidence: 99%

“…Swiss-Webster mice were purchased from Envigo. C57BL/6J Darc-/-mice were provided by Dr. G. Scott Worthen (University of Pennsylvania), rederived and bred in-house at NYU School of Medicine as described previously (32). C57BL/6J controls were purchased from The Jackson Laboratory and bred in-house.…”

Section: Murine Toxin Challengementioning

confidence: 99%

See 2 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…S. aureus leukocidins play many roles in facilitating pathogenesis (7,9,32,(42)(43)(44)(45). Further, the leukocidins are promising vaccine targets (41,46).…”

Section: Discussionmentioning

confidence: 99%

Section: Luke Dr1 -Darc Interaction In Vivomentioning

confidence: 99%

See 1 more Smart Citation

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Leukocidins blunt the development of broadly neutralizing antibody responses against S. aureus While all the leukocidins exhibit strong tropism toward human leukocytes, LukED and HlgAB are also active in murine models of S. aureus BSI DuMont et al, 2013;Lubkin et al, 2019;Reyes-Robles et al, 2013;Spaan et al, 2013Spaan et al, , 2015Spaan et al, , 2014. Thus, we focused on the role of LukED and HlgAB in S. aureus-mediated immune subversion in vivo.…”

Section: Resultsmentioning

confidence: 99%

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

Tam

Lacey

Devlin

et al. 2020

Journal of Experimental Medicine

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…LukED is unique among the leukocidins in that it shows an increased tropism toward murine leukocytes. Studies indicate there is an increased potency towards mouse phagocytes using both in vitro and in vivo mouse models, including systemic and intravenous models [ 61 , 62 , 63 , 64 ].…”

Section: Role Of S Aureus Toxins In Human Disementioning

confidence: 99%

Epidemiological and Clinical Evidence for the Role of Toxins in S. aureus Human Disease

Bennett

Thomsen

2020

Toxins

View full text Add to dashboard Cite

Staphylococcus aureus asymptomatically colonizes approximately 30–50% of the population and is a leading cause of bacteremia, bone/joint infections, and skin infections in the US. S. aureus has become a major public health threat due to antibiotic resistance and an increasing number of failed vaccine attempts. To develop new anti-staphylococcal preventive therapies, it will take a more thorough understanding of the current role S. aureus virulence factors play in contributing to human disease. This review focuses on the clinical association of individual toxins with S. aureus infection as well as attempted treatment options. Further understanding of these associations will increase understanding of toxins and their importance to S. aureus pathogenesis.

show abstract

Staphylococcus aureus Leukocidins Target Endothelial DARC to Cause Lethality in Mice

Cited by 27 publications

References 46 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

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

Epidemiological and Clinical Evidence for the Role of Toxins in S. aureus Human Disease

Contact Info

Product

Resources

About