Critical role of alpha-toxin and protective effects of its neutralization by a human antibody in acute bacterial skin and skin structure infections

Vien T.M. Le, Christine Tkaczyk, Sally Chau, Renee L. Rao, Etyene Castro Dip, Eliane P. Pereira-Franchi, Lily Cheng, Sally Lee, Holly Koelkebeck, Jamese J. Hilliard, Xiang Qing Yu, Vivekananda Datta, Vien Nguyen, William Weiss, Laszlo Prokai, Terrence O'Day, C. Kendall Stover, Bret R. Sellman, Binh An Diep

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Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) causes large-scale epidemics of acute bacterial skin and skin structure infections (ABSSSI) within communities across the United States. Animal models that reproduce ABSSSI as they occur in humans are urgently needed to test new therapeutic strategies. Alpha-toxin plays a critical role in a variety of staphylococcal infection models in mice, but its role in the pathogenesis of ABSSSI remains to be elucidated in rabbits, which are similar to humans in their susceptibility to S. aureus superantigens and certain bicomponent pore-forming leukocidins. We report here a new rabbit model of ABSSSI and show that those infected with a mutant deficient in expression of alpha-toxin (Δhla) developed a small dermonecrotic lesion, whereas those infected with isogenic USA300 MRSA wild-type or complemented Δhla strains developed ABSSSI that mimic the severe infections that occur in humans, including the large central dermonecrotic core surrounded by erythema, induration, and marked subcutaneous hemorrhage. More importantly, immunoprophylaxis with MEDI4893∗, an anti-alpha-toxin human monoclonal antibody, significantly reduced the severity of disease caused by a USA300 wild-type strain to that caused by the Δhla mutant, indicating that this toxin could be completely neutralized during infection. Thus, this study illustrates a potential high standard for the development of new immunotherapeutic agents in which a toxin-neutralizing antibody provides protection to the same degree achieved with a toxin gene knockout. When MEDI4893∗ was administered as adjunctive therapy with a subtherapeutic dose of linezolid, the combination was significantly more efficacious than either agent alone in reducing the severity of ABSSSI.

Original languageEnglish
Pages (from-to)5640-5648
Number of pages9
JournalAntimicrobial agents and chemotherapy
Volume60
Issue number10
DOIs
StatePublished - 1 Oct 2016

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Skin
Antibodies
Infection
Linezolid
Methicillin-Resistant Staphylococcus aureus
Leukocidins
Rabbits
Staphylococcal Infections
Superantigens
Gene Knockout Techniques
Erythema
Neutralizing Antibodies
Staphylococcus aureus
Animal Models
Monoclonal Antibodies
Hemorrhage
Therapeutics

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Le, Vien T.M. ; Tkaczyk, Christine ; Chau, Sally ; Rao, Renee L. ; Dip, Etyene Castro ; Pereira-Franchi, Eliane P. ; Cheng, Lily ; Lee, Sally ; Koelkebeck, Holly ; Hilliard, Jamese J. ; Yu, Xiang Qing ; Datta, Vivekananda ; Nguyen, Vien ; Weiss, William ; Prokai, Laszlo ; O'Day, Terrence ; Stover, C. Kendall ; Sellman, Bret R. ; Diep, Binh An. / Critical role of alpha-toxin and protective effects of its neutralization by a human antibody in acute bacterial skin and skin structure infections. In: Antimicrobial agents and chemotherapy. 2016 ; Vol. 60, No. 10. pp. 5640-5648.
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abstract = "Methicillin-resistant Staphylococcus aureus (MRSA) causes large-scale epidemics of acute bacterial skin and skin structure infections (ABSSSI) within communities across the United States. Animal models that reproduce ABSSSI as they occur in humans are urgently needed to test new therapeutic strategies. Alpha-toxin plays a critical role in a variety of staphylococcal infection models in mice, but its role in the pathogenesis of ABSSSI remains to be elucidated in rabbits, which are similar to humans in their susceptibility to S. aureus superantigens and certain bicomponent pore-forming leukocidins. We report here a new rabbit model of ABSSSI and show that those infected with a mutant deficient in expression of alpha-toxin (Δhla) developed a small dermonecrotic lesion, whereas those infected with isogenic USA300 MRSA wild-type or complemented Δhla strains developed ABSSSI that mimic the severe infections that occur in humans, including the large central dermonecrotic core surrounded by erythema, induration, and marked subcutaneous hemorrhage. More importantly, immunoprophylaxis with MEDI4893∗, an anti-alpha-toxin human monoclonal antibody, significantly reduced the severity of disease caused by a USA300 wild-type strain to that caused by the Δhla mutant, indicating that this toxin could be completely neutralized during infection. Thus, this study illustrates a potential high standard for the development of new immunotherapeutic agents in which a toxin-neutralizing antibody provides protection to the same degree achieved with a toxin gene knockout. When MEDI4893∗ was administered as adjunctive therapy with a subtherapeutic dose of linezolid, the combination was significantly more efficacious than either agent alone in reducing the severity of ABSSSI.",
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Le, VTM, Tkaczyk, C, Chau, S, Rao, RL, Dip, EC, Pereira-Franchi, EP, Cheng, L, Lee, S, Koelkebeck, H, Hilliard, JJ, Yu, XQ, Datta, V, Nguyen, V, Weiss, W, Prokai, L, O'Day, T, Stover, CK, Sellman, BR & Diep, BA 2016, 'Critical role of alpha-toxin and protective effects of its neutralization by a human antibody in acute bacterial skin and skin structure infections', Antimicrobial agents and chemotherapy, vol. 60, no. 10, pp. 5640-5648. https://doi.org/10.1128/AAC.00710-16

Critical role of alpha-toxin and protective effects of its neutralization by a human antibody in acute bacterial skin and skin structure infections. / Le, Vien T.M.; Tkaczyk, Christine; Chau, Sally; Rao, Renee L.; Dip, Etyene Castro; Pereira-Franchi, Eliane P.; Cheng, Lily; Lee, Sally; Koelkebeck, Holly; Hilliard, Jamese J.; Yu, Xiang Qing; Datta, Vivekananda; Nguyen, Vien; Weiss, William; Prokai, Laszlo; O'Day, Terrence; Stover, C. Kendall; Sellman, Bret R.; Diep, Binh An.

In: Antimicrobial agents and chemotherapy, Vol. 60, No. 10, 01.10.2016, p. 5640-5648.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Critical role of alpha-toxin and protective effects of its neutralization by a human antibody in acute bacterial skin and skin structure infections

AU - Le, Vien T.M.

AU - Tkaczyk, Christine

AU - Chau, Sally

AU - Rao, Renee L.

AU - Dip, Etyene Castro

AU - Pereira-Franchi, Eliane P.

AU - Cheng, Lily

AU - Lee, Sally

AU - Koelkebeck, Holly

AU - Hilliard, Jamese J.

AU - Yu, Xiang Qing

AU - Datta, Vivekananda

AU - Nguyen, Vien

AU - Weiss, William

AU - Prokai, Laszlo

AU - O'Day, Terrence

AU - Stover, C. Kendall

AU - Sellman, Bret R.

AU - Diep, Binh An

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Methicillin-resistant Staphylococcus aureus (MRSA) causes large-scale epidemics of acute bacterial skin and skin structure infections (ABSSSI) within communities across the United States. Animal models that reproduce ABSSSI as they occur in humans are urgently needed to test new therapeutic strategies. Alpha-toxin plays a critical role in a variety of staphylococcal infection models in mice, but its role in the pathogenesis of ABSSSI remains to be elucidated in rabbits, which are similar to humans in their susceptibility to S. aureus superantigens and certain bicomponent pore-forming leukocidins. We report here a new rabbit model of ABSSSI and show that those infected with a mutant deficient in expression of alpha-toxin (Δhla) developed a small dermonecrotic lesion, whereas those infected with isogenic USA300 MRSA wild-type or complemented Δhla strains developed ABSSSI that mimic the severe infections that occur in humans, including the large central dermonecrotic core surrounded by erythema, induration, and marked subcutaneous hemorrhage. More importantly, immunoprophylaxis with MEDI4893∗, an anti-alpha-toxin human monoclonal antibody, significantly reduced the severity of disease caused by a USA300 wild-type strain to that caused by the Δhla mutant, indicating that this toxin could be completely neutralized during infection. Thus, this study illustrates a potential high standard for the development of new immunotherapeutic agents in which a toxin-neutralizing antibody provides protection to the same degree achieved with a toxin gene knockout. When MEDI4893∗ was administered as adjunctive therapy with a subtherapeutic dose of linezolid, the combination was significantly more efficacious than either agent alone in reducing the severity of ABSSSI.

AB - Methicillin-resistant Staphylococcus aureus (MRSA) causes large-scale epidemics of acute bacterial skin and skin structure infections (ABSSSI) within communities across the United States. Animal models that reproduce ABSSSI as they occur in humans are urgently needed to test new therapeutic strategies. Alpha-toxin plays a critical role in a variety of staphylococcal infection models in mice, but its role in the pathogenesis of ABSSSI remains to be elucidated in rabbits, which are similar to humans in their susceptibility to S. aureus superantigens and certain bicomponent pore-forming leukocidins. We report here a new rabbit model of ABSSSI and show that those infected with a mutant deficient in expression of alpha-toxin (Δhla) developed a small dermonecrotic lesion, whereas those infected with isogenic USA300 MRSA wild-type or complemented Δhla strains developed ABSSSI that mimic the severe infections that occur in humans, including the large central dermonecrotic core surrounded by erythema, induration, and marked subcutaneous hemorrhage. More importantly, immunoprophylaxis with MEDI4893∗, an anti-alpha-toxin human monoclonal antibody, significantly reduced the severity of disease caused by a USA300 wild-type strain to that caused by the Δhla mutant, indicating that this toxin could be completely neutralized during infection. Thus, this study illustrates a potential high standard for the development of new immunotherapeutic agents in which a toxin-neutralizing antibody provides protection to the same degree achieved with a toxin gene knockout. When MEDI4893∗ was administered as adjunctive therapy with a subtherapeutic dose of linezolid, the combination was significantly more efficacious than either agent alone in reducing the severity of ABSSSI.

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DO - 10.1128/AAC.00710-16

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