Abstract
Staphylococcus aureus is a common commensal and frequent opportunistic pathogen that causes invasive infections that often recur. Co-evolution with the host has led to the development of toxins that affect diverse immune cell types. Recent reports have highlighted the contributions of staphylococcal protein A (SpA). This small oligomeric secreted protein contains 4–5 homologous domains with two distinct immunoglobulin-binding sites; one for IgG Fc domains, while a separate site binds an evolutionarily conserved surface on Fab encoded by VHIII clan related genes. The Fab-binding site has been implicated in in vivo supraclonal VHIII-BCR targeted B-cell depletion by an activation induced death pathway. Yet the concept of a superantigen for B lymphocytes poses a seeming paradox. Unlike TCR that are expressed only in a membrane-associated form, BCR are expressed in both a membrane BCR form and in secreted Ig forms, which permeate virtually every part of the body at high levels. We therefore asked, why circulating immunoglobulin do not block the superantigen properties of SpA? Herein, we show that soluble IgG molecules are not in vivo inhibitors of these B-cell superantigen effects but are instead essential for potentiating these properties. We also show that the Fc subclass of circulating IgG is an indirect critical determinant of the B-cell superantigen effect. In contrast, host FcγR and complement are not required for SpA mediated in vivo B-cell depletion. Unexpectedly, after VHIII-IgG2a pretreatment SpA challenge resulted in fatal anaphylactic reactions, which we speculate may have involved FcγR interactions with mast cells and basophils. Cumulatively, our findings illuminate a cunning and potent molecular strategy by which a bacterial toxin effectively confounds the contributions of host B-lymphocytes to immune defenses.
Highlights
Staphylococcus aureus is estimated to cause over half a million cases of invasive infection, with more than 10,000 deaths annually in the United States, in some years exceeding those attributed to influenza, viral hepatitis, and HIV/AIDS together [1, 2]
Recombinant murine VHIII IgG1, IgG2a or IgG3 were generated with the variable regions of the anti-PC TEPC15 parental clone [51], while the VHI isotype control IgG express antibody genes from the anti-Hen Egg Lysozyme (HEL) D1.3 mAb [52], which were generated by transfection of CHO cells and subsequent cloning and expansion, using the OptiVEC system (Invitrogen, Thermo Fischer)
In the current studies we have elucidated the nature of IgG complexes that are required for the superantigen properties of staphylococcal protein A (SpA)
Summary
Staphylococcus aureus is estimated to cause over half a million cases of invasive infection, with more than 10,000 deaths annually in the United States, in some years exceeding those attributed to influenza, viral hepatitis, and HIV/AIDS together [1, 2]. S. aureus is a ubiquitous commensal, with an estimated 30% of the population continuously colonized [3] and intermittent colonization of many more [4]. Antibiotic-resistant strains, including methicillin-resistant S. aureus (MRSA), are increasing causes of community-acquired as well as hospital-acquired infections [5]. S. aureus has a remarkable ability to evade host defenses through release of virulence factors, which can impair and/or deplete a range of different cell types [11,12,13]. Even though functional antibodies and the complement system are known to play critical roles in defense [14, 15], in vivo experimental models have shown that mice with competent B cells and antibody responses can fare worse in containing and clearing S. aureus infection than do B-cell deficient mice [16,17,18]
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