Diverted on the way to memory

The finding that protein A of Staphylococcus aureus diverts the immune response so that it ineffectively responds to other structures from the bacterium explains the failure of ongoing attempts to develop working S. aureus vaccines.

Staphylococcus aureus is a global pathogen of great importance, causing thousands of deaths each year in the United States alone. The main problems with S. aureus infections are frequent resistance to antibiotics and the large repertoire of molecules produced by the pathogen to subvert human immune defences^1,2. Notably, there is no protective immunity towards S. aureus, meaning that previous S. aureus infection does not defend an individual against subsequent infections. Writing in the Journal of Experimental Medicine, Pauli et al.³ describe a mechanism by which one S. aureus molecule, protein A, overwhelms the host's immune machinery through excessively stimulating certain immune responses while suppressing reactivity toward other key virulence determinants of the bacterium. These findings explain the weak protective immune responses and lack of immunological memory observed with S. aureus infections.

The human immune system has two ways to combat bacterial invaders. One is innate immunity, so-called because the response mechanisms involved do not require adaptation; rather, the immune cells recognize structures that are evolutionarily conserved among pathogens, resulting in the pathogens' quick elimination. S. aureus has a large repertoire of 'weapons' to subvert this aspect of human immune defence — such as toxins that kill white blood cells — and the battle between the bacterium and the innate immune response determines whether an S. aureus invasion develops into a longer-lasting infection.

The other system is adaptive immunity, which mostly involves T cells and B cells. In B cells, adaptive immune responses lead to genetic rearrangements that result in differentiation into plasma cells, which produce antibodies that are specific to certain structures (antigens) and that trigger mechanisms to remove the pathogens expressing those structures. About 10% of plasma cells survive after an infection is cleared; these 'memory B cells' provide protective immunity against further infections with the same pathogen. Adaptive responses kick in about a week after the initial infection and normally provide long-lasting immunity.

In the case of S. aureus, the role of adaptive immunity is poorly understood, but it is clear that long-lasting protective memory is not generated. This is not only reflected by recurring S. aureus infections, but also by the fact that vaccine development against S. aureus has always failed at the stage of clinical trials⁴. Although the mechanisms underlying this situation are still being unravelled, protein A, which is located on the surface of S. aureus cells, is believed to have a key role. Protein A contains repetitive sequences consisting of two parts: one binds to the Fc (constant) part of human antibodies and the other binds to the Fab (variable) antibody region. This Fab-region binding is 'superantigenic', meaning that it is nonspecific and has excessive potential to stimulate immune responses⁵.

Binding of protein A to the Fc region was reported many years ago⁶ and results in what has been called a 'camouflage coat' of nonspecific antibodies on the S. aureus surface that prevents binding of specific antibodies and thus a targeted immune response. Pauli et al.³ now show that the superantigenic binding of protein A to the Fab domain is so overwhelming that it strongly hampers the production of antibodies to other S. aureus antigens (Fig. 1).

Figure 1: Protein-A-dependent immune evasion.

Protein A of Staphylococcus aureus contains a region of repetitive domains, part of which binds to the Fab region of antibodies in a nonspecific, 'superantigenic' manner. Pauli et al.³ propose that this superantigenic binding biases the B-cell immune response to S. aureus towards protein A. They observe that, of the B cells that differentiate to become antibody-producing plasmablasts during an S. aureus infection, the majority bind to, and produce antibodies against, protein A; very few B cells that bind to other S. aureus antigens undergo this differentiation process. This means that the memory B cells that remain after an infection, and that are 'primed' to mount immune responses to repeat infections, will also be mostly specific for protein A. This may explain the lack of protective memory against S. aureus infections, because such protection requires immune activity against multiple virulence determinants of the bacterium.

To reach this conclusion, the authors characterized the antigen specificity of plasmablasts — an immature form of plasma B cells that are produced only during infections and that play a crucial part in active immune responses — in large cohorts of people with and without S. aureus infections. They found that, in principle, nothing was wrong with the plasmablast response in the infected individuals, inasmuch as the cells underwent normal maturation on exposure to S. aureus antigens. However, when the investigators isolated the antibody-encoding genes of the responding plasmablasts, they found that almost all targeted protein A, and very few were specific for other S. aureus toxins or cell-surface virulence determinants. On the basis of these results, Pauli et al. propose that the superantigenic action of protein A prevents the production of specific and effective antibodies to other S. aureus antigens.

Unfortunately, mouse models cannot be used to substantiate this proposal, because the murine immune response differs considerably in details of adaptive immunity that matter in this case⁷. However, it has been shown in a mouse model that protein A contributes significantly to immune evasion⁸ and that monoclonal antibodies against protein A neutralize the Fc-binding and Fab-binding activities of protein A⁹. These studies suggest that protein A would be a valuable target for the development of vaccines against S. aureus. However, it is commonly thought that a successful S. aureus vaccine will need to be multivalent — in other words, it will need to target several of the many molecules that the bacterium uses for virulence and immune evasion. For example, the vaccine should also include strategies to address the fact that S. aureus produces several toxins that can circumvent immune elimination even when specific antibody responses are mounted¹⁰. Pauli and colleagues' findings suggest that, by adding protein A-specific components in such preparations, we may finally be able to develop a working S. aureus vaccine.