Targeting Alpha Toxin and ClfA with a Multimechanistic Monoclonal-Antibody-Based Approach for Prophylaxis of Serious <named-content content-type="genus-species">Staphylococcus aureus</named-content> Disease

ABSTRACT Staphylococcus aureus produces numerous virulence factors, each contributing different mechanisms to bacterial pathogenesis in a spectrum of diseases. Alpha toxin (AT), a cytolytic pore-forming toxin, plays a key role in skin and soft tissue infections and pneumonia, and a human anti-AT mon...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: C. Tkaczyk, M. M. Hamilton, A. Sadowska, Y. Shi, C.S. Chang, P. Chowdhury, R. Buonapane, X. Xiao, P. Warrener, J. Mediavilla, B. Kreiswirth, J. Suzich, C. K. Stover, B. R. Sellman
Formato: article
Lenguaje:EN
Publicado: American Society for Microbiology 2016
Materias:
Acceso en línea:https://doaj.org/article/6e74eeed87f04363a6e71d969cd1965a
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:6e74eeed87f04363a6e71d969cd1965a
record_format dspace
spelling oai:doaj.org-article:6e74eeed87f04363a6e71d969cd1965a2021-11-15T15:50:16ZTargeting Alpha Toxin and ClfA with a Multimechanistic Monoclonal-Antibody-Based Approach for Prophylaxis of Serious <named-content content-type="genus-species">Staphylococcus aureus</named-content> Disease10.1128/mBio.00528-162150-7511https://doaj.org/article/6e74eeed87f04363a6e71d969cd1965a2016-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00528-16https://doaj.org/toc/2150-7511ABSTRACT Staphylococcus aureus produces numerous virulence factors, each contributing different mechanisms to bacterial pathogenesis in a spectrum of diseases. Alpha toxin (AT), a cytolytic pore-forming toxin, plays a key role in skin and soft tissue infections and pneumonia, and a human anti-AT monoclonal antibody (MAb), MEDI4893*, has been shown to reduce disease severity in dermonecrosis and pneumonia infection models. However, interstrain diversity and the complex pathogenesis of S. aureus bloodstream infections suggests that MEDI4893* alone may not provide adequate protection against S. aureus sepsis. Clumping factor A (ClfA), a fibrinogen binding protein, is an important virulence factor facilitating S. aureus bloodstream infections. Herein, we report on the identification of a high-affinity anti-ClfA MAb, 11H10, that inhibits ClfA binding to fibrinogen, prevents bacterial agglutination in human plasma, and promotes opsonophagocytic bacterial killing (OPK). 11H10 prophylaxis reduced disease severity in a mouse bacteremia model and was dependent on Fc effector function and OPK. Additionally, prophylaxis with 11H10 in combination with MEDI4893* provided enhanced strain coverage in this model and increased survival compared to that obtained with the individual MAbs. The MAb combination also reduced disease severity in murine dermonecrosis and pneumonia models, with activity similar to that of MEDI4893* alone. These results indicate that an MAb combination targeting multiple virulence factors provides benefit over a single MAb neutralizing one virulence mechanism by providing improved efficacy, broader strain coverage, and protection against multiple infection pathologies. IMPORTANCE Alternative strategies to broad-spectrum antibiotics are required to combat the antibiotic resistance epidemic. Previous attempts at active or passive immunization against Staphylococcus aureus targeting single antigens have failed in clinical trials despite positive preclinical data. To provide broad disease and isolate coverage, an effective immunization strategy likely must target multiple virulence mechanisms of the pathogen. Herein, we tested a multimechanistic MAb combination targeting alpha toxin (AT) and clumping factor A (ClfA) that neutralizes AT-mediated cytotoxicity, blocks fibrinogen binding by ClfA, prevents bacterial agglutination, targets the bacteria for opsonophagocytic killing, and provides broad isolate coverage in a lethal-bacteremia model. Although each MAb alone was effective in bacteremia against some individual isolates, the MAb combination provided improved protection against other isolates. These results illustrate the importance of targeting multiple virulence mechanisms and highlight the potential for an MAb combination targeting AT and ClfA to effectively prevent S. aureus disease.C. TkaczykM. M. HamiltonA. SadowskaY. ShiC.S. ChangP. ChowdhuryR. BuonapaneX. XiaoP. WarrenerJ. MediavillaB. KreiswirthJ. SuzichC. K. StoverB. R. SellmanAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 3 (2016)
institution DOAJ
collection DOAJ
language EN
topic Microbiology
QR1-502
spellingShingle Microbiology
QR1-502
C. Tkaczyk
M. M. Hamilton
A. Sadowska
Y. Shi
C.S. Chang
P. Chowdhury
R. Buonapane
X. Xiao
P. Warrener
J. Mediavilla
B. Kreiswirth
J. Suzich
C. K. Stover
B. R. Sellman
Targeting Alpha Toxin and ClfA with a Multimechanistic Monoclonal-Antibody-Based Approach for Prophylaxis of Serious <named-content content-type="genus-species">Staphylococcus aureus</named-content> Disease
description ABSTRACT Staphylococcus aureus produces numerous virulence factors, each contributing different mechanisms to bacterial pathogenesis in a spectrum of diseases. Alpha toxin (AT), a cytolytic pore-forming toxin, plays a key role in skin and soft tissue infections and pneumonia, and a human anti-AT monoclonal antibody (MAb), MEDI4893*, has been shown to reduce disease severity in dermonecrosis and pneumonia infection models. However, interstrain diversity and the complex pathogenesis of S. aureus bloodstream infections suggests that MEDI4893* alone may not provide adequate protection against S. aureus sepsis. Clumping factor A (ClfA), a fibrinogen binding protein, is an important virulence factor facilitating S. aureus bloodstream infections. Herein, we report on the identification of a high-affinity anti-ClfA MAb, 11H10, that inhibits ClfA binding to fibrinogen, prevents bacterial agglutination in human plasma, and promotes opsonophagocytic bacterial killing (OPK). 11H10 prophylaxis reduced disease severity in a mouse bacteremia model and was dependent on Fc effector function and OPK. Additionally, prophylaxis with 11H10 in combination with MEDI4893* provided enhanced strain coverage in this model and increased survival compared to that obtained with the individual MAbs. The MAb combination also reduced disease severity in murine dermonecrosis and pneumonia models, with activity similar to that of MEDI4893* alone. These results indicate that an MAb combination targeting multiple virulence factors provides benefit over a single MAb neutralizing one virulence mechanism by providing improved efficacy, broader strain coverage, and protection against multiple infection pathologies. IMPORTANCE Alternative strategies to broad-spectrum antibiotics are required to combat the antibiotic resistance epidemic. Previous attempts at active or passive immunization against Staphylococcus aureus targeting single antigens have failed in clinical trials despite positive preclinical data. To provide broad disease and isolate coverage, an effective immunization strategy likely must target multiple virulence mechanisms of the pathogen. Herein, we tested a multimechanistic MAb combination targeting alpha toxin (AT) and clumping factor A (ClfA) that neutralizes AT-mediated cytotoxicity, blocks fibrinogen binding by ClfA, prevents bacterial agglutination, targets the bacteria for opsonophagocytic killing, and provides broad isolate coverage in a lethal-bacteremia model. Although each MAb alone was effective in bacteremia against some individual isolates, the MAb combination provided improved protection against other isolates. These results illustrate the importance of targeting multiple virulence mechanisms and highlight the potential for an MAb combination targeting AT and ClfA to effectively prevent S. aureus disease.
format article
author C. Tkaczyk
M. M. Hamilton
A. Sadowska
Y. Shi
C.S. Chang
P. Chowdhury
R. Buonapane
X. Xiao
P. Warrener
J. Mediavilla
B. Kreiswirth
J. Suzich
C. K. Stover
B. R. Sellman
author_facet C. Tkaczyk
M. M. Hamilton
A. Sadowska
Y. Shi
C.S. Chang
P. Chowdhury
R. Buonapane
X. Xiao
P. Warrener
J. Mediavilla
B. Kreiswirth
J. Suzich
C. K. Stover
B. R. Sellman
author_sort C. Tkaczyk
title Targeting Alpha Toxin and ClfA with a Multimechanistic Monoclonal-Antibody-Based Approach for Prophylaxis of Serious <named-content content-type="genus-species">Staphylococcus aureus</named-content> Disease
title_short Targeting Alpha Toxin and ClfA with a Multimechanistic Monoclonal-Antibody-Based Approach for Prophylaxis of Serious <named-content content-type="genus-species">Staphylococcus aureus</named-content> Disease
title_full Targeting Alpha Toxin and ClfA with a Multimechanistic Monoclonal-Antibody-Based Approach for Prophylaxis of Serious <named-content content-type="genus-species">Staphylococcus aureus</named-content> Disease
title_fullStr Targeting Alpha Toxin and ClfA with a Multimechanistic Monoclonal-Antibody-Based Approach for Prophylaxis of Serious <named-content content-type="genus-species">Staphylococcus aureus</named-content> Disease
title_full_unstemmed Targeting Alpha Toxin and ClfA with a Multimechanistic Monoclonal-Antibody-Based Approach for Prophylaxis of Serious <named-content content-type="genus-species">Staphylococcus aureus</named-content> Disease
title_sort targeting alpha toxin and clfa with a multimechanistic monoclonal-antibody-based approach for prophylaxis of serious <named-content content-type="genus-species">staphylococcus aureus</named-content> disease
publisher American Society for Microbiology
publishDate 2016
url https://doaj.org/article/6e74eeed87f04363a6e71d969cd1965a
work_keys_str_mv AT ctkaczyk targetingalphatoxinandclfawithamultimechanisticmonoclonalantibodybasedapproachforprophylaxisofseriousnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentdisease
AT mmhamilton targetingalphatoxinandclfawithamultimechanisticmonoclonalantibodybasedapproachforprophylaxisofseriousnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentdisease
AT asadowska targetingalphatoxinandclfawithamultimechanisticmonoclonalantibodybasedapproachforprophylaxisofseriousnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentdisease
AT yshi targetingalphatoxinandclfawithamultimechanisticmonoclonalantibodybasedapproachforprophylaxisofseriousnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentdisease
AT cschang targetingalphatoxinandclfawithamultimechanisticmonoclonalantibodybasedapproachforprophylaxisofseriousnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentdisease
AT pchowdhury targetingalphatoxinandclfawithamultimechanisticmonoclonalantibodybasedapproachforprophylaxisofseriousnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentdisease
AT rbuonapane targetingalphatoxinandclfawithamultimechanisticmonoclonalantibodybasedapproachforprophylaxisofseriousnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentdisease
AT xxiao targetingalphatoxinandclfawithamultimechanisticmonoclonalantibodybasedapproachforprophylaxisofseriousnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentdisease
AT pwarrener targetingalphatoxinandclfawithamultimechanisticmonoclonalantibodybasedapproachforprophylaxisofseriousnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentdisease
AT jmediavilla targetingalphatoxinandclfawithamultimechanisticmonoclonalantibodybasedapproachforprophylaxisofseriousnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentdisease
AT bkreiswirth targetingalphatoxinandclfawithamultimechanisticmonoclonalantibodybasedapproachforprophylaxisofseriousnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentdisease
AT jsuzich targetingalphatoxinandclfawithamultimechanisticmonoclonalantibodybasedapproachforprophylaxisofseriousnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentdisease
AT ckstover targetingalphatoxinandclfawithamultimechanisticmonoclonalantibodybasedapproachforprophylaxisofseriousnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentdisease
AT brsellman targetingalphatoxinandclfawithamultimechanisticmonoclonalantibodybasedapproachforprophylaxisofseriousnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentdisease
_version_ 1718427463449575424