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
N1 - Funding Information:
This work was supported by U.S. Public Health Service grant NIH R01 AI087674 and a MedImmune, LLC, grant. The following authors are employed by MedImmune, LLC: Christine Tkaczyk, Lily Cheng, Sally Lee, Holly Koelkebeck, Jamese J. Hilliard, Xiang Qing Yu, Terrence O'Day, C. Kendall Stover, and Bret R. Sellman. Patent 2014/0072,577 describing MEDI4893∗, an anti-alpha-toxin human monoclonal antibody, used in this work has been filed by MedImmune, LLC. This work, including the efforts of Binh An Diep, was funded by HHS | National Institutes of Health (NIH) (R01 AI087674). This work was supported by U.S. Public Health Service grant NIH R01 AI087674 and a MedImmune, LLC, grant.
Publisher Copyright:
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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.
UR - http://www.scopus.com/inward/record.url?scp=84992343795&partnerID=8YFLogxK
U2 - 10.1128/AAC.00710-16
DO - 10.1128/AAC.00710-16
M3 - Article
C2 - 27401576
AN - SCOPUS:84992343795
SN - 0066-4804
VL - 60
SP - 5640
EP - 5648
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 10
ER -