Abstract
Staphylococcus aureus can cause devastating and life-threatening infections. With the increase in multidrug resistant strains, novel therapies are needed. Limited success with active and passive immunization strategies have been attributed to S. aureus immune evasion. Here, we report on a monoclonal antibody, 514G3, that circumvents a key S. aureus evasion mechanism by targeting the cell wall moiety Protein A (SpA). SpA tightly binds most subclasses of immunoglobulins via their Fc region, neutralizing effector function. The organism can thus shield itself with a protective coat of serum antibodies and render humoral immunity ineffective. The present antibody reactivity was derived from an individual with natural anti-SpA antibody titers. The monoclonal antibody is of an IgG3 subclass, which differs critically from other immunoglobulin subclasses since its Fc is not bound by SpA. Moreover, it targets a unique epitope on SpA that allows it to bind in the presence of serum antibodies. Consequently, the antibody opsonizes S. aureus and maintains effector function to enable natural immune mediated clearance. The data presented here provide evidence that 514G3 antibody is able to successfully rescue mice from S. aureus mediated bacteremia.
Highlights
IntroductionThe specific roles of these authors are articulated in the Staphylococcus aureus is found in the nose and on the skin of 25–30% of healthy adults[1]
The plasma was fractionated and the immunoglobulins were subjected to immunoprecipitation on magnetic beads coated with SpA peptides (S1 File, and S1 Table)
Since full length WT SpA binds immunoglobulins via their Fc and VH3 framework regions, and prevent the identification of anti-SpA antibodies that bind via the CDRs, the SpA peptides used for immunoprecipitation were designed from regions on the SpA outside the Fcγ and Fab
Summary
The specific roles of these authors are articulated in the Staphylococcus aureus is found in the nose and on the skin of 25–30% of healthy adults[1]. In a person with a weakened immune system, if it manages to breach the periphery, S. aureus infections can be serious or even fatal[2,3,4]. Fatal infections are often associated with bacteremia, which, before the widespread use of antibiotics, had a 65–70% mortality rate. Even with best practices and latest antibiotics, there is 20–40% mortality within 30 days of bacteremia[5] due to antibiotic-resistant strains[6,7,8,9]
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