Critical Role of Alpha-Toxin and Protective Effects of Its Neutralization by a Human Antibody in Acute Bacterial Skin and Skin Structure Infections

Abstract

g 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 (⌬hla) developed a small dermonecrotic lesion, whereas those infected with isogenic USA300 MRSA wild-type or complemented ⌬hla 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-alphatoxin human monoclonal antibody, significantly reduced the severity of disease caused by a USA300 wild-type strain to that caused by the ⌬hla 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.

Multimechanistic Monoclonal Antibodies (MAbs) Targeting Staphylococcus aureus Alpha-Toxin and Clumping Factor A: Activity and Efficacy Comparisons of a MAb Combination and an Engineered Bispecific Antibody Approach

“…Although alpha-toxin is a key virulence determinant in S. aureus pneumonia and skin and soft-tissue infections (20,26), bloodstream infections are likely more complex, with a more complicated interplay of virulence determinants involved (27)(28)(29)(30)(31). Consistent with this hypothesis, prophylaxis with an anti-alpha-toxin IgG alone significantly reduced disease severity in S. aureus pneumonia and skin infection models in mice and rabbits (6,8,20,21,26,(32)(33)(34) but did not protect against challenge by all isolates tested in a lethal bacteremia model (Table 2) (9). However, passive immunization with MEDI4893* combined with anti-ClfA MAb 11H10 or SAR114 provided improved strain coverage, indicating that targeting multiple virulence factors may be necessary to protect against systemic S. aureus diseases such as bacteremia ( Table 2; Fig.…”

α-Toxin Induces Platelet Aggregation and Liver Injury during Staphylococcus aureus Sepsis

“…The latter would kill the bacteria but fail to neutralize the effects of the secreted AT that could be blocked by a toxin neutralizing antibody. Multiple studies from independent laboratories with different anti-AT mAbs have demonstrated additive or synergistic protective activity with multiple antibiotics in different S. aureus animal infection models (Foletti et al, 2013; Hua et al, 2015; Hua et al, 2014; Le et al, 2016). The results herein offer one possible explanation as to how targeting AT may contribute to enhanced protection from acute lethality on top of traditional antibiotic antibacterial activity.…”

α-Toxin Regulates Local Granulocyte Expansion from Hematopoietic Stem and Progenitor Cells in Staphylococcus aureus–Infected Wounds

“…Given its importance in exacerbating infection severity, AT has been a clinical target, employing both monoclonal antibodies and small molecules. These therapies have had a marked effect on reducing disease severity in mouse and rabbit models of S. aureus skin infection(33–35). Still, it is unclear whether targeting AT in an active or passive vaccination strategy will be effective as a single antigen, because S. aureus produces many other virulence factors that evade host defenses(36).…”