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The Advantages of Being a Superantigen

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Science Translational Medicine  10 Dec 2014:
Vol. 6, Issue 266, pp. 266ec211
DOI: 10.1126/scitranslmed.aaa3457

Staphylococcus aureus causes an array of ailments—chronic and recurrent skin and soft tissue infections, pneumonia, infective endocarditis, septicemia, and osteomyelitis, among others. Host defense against this pathogen is complex and involves the generation of cellular and humoral immune responses. Furthermore, S. aureus infection decreases antibody production in murine models of infection. But humans who are naturally infected with S. aureus develop skewed antibody responses to the bacteria’s most well-characterized virulence factor, Protein A (SpA). The molecular mechanism involved in the generation of epitope-specific antibody production during S. aureus infection in human remains unknown. Now, Pauli et al. investigate why humans produce protective antibodies and immune memory to S. aureus infection.

The authors phenotypically characterized the epitopes and responses in activated B cells, called plasmablasts (PBs), from infected patients. Using a variety of high-throughput approaches, the authors found that PB responses are SpA-specific and little to no responses were found against many other clinically relevant virulence factors, with the exception of SpAKK (an inactive bacterial protein structurally related to SpA). These results indicate a preferential induction of SpA-reactive B cells in their group of patients. Furthermore, these responses were specific to a single antibody type and displayed evidence of selected regions responsible for affinity-maturation against SpA. The authors propose that S. aureus uses SpA to dominate expansion of variable heavy 3 (VH3) idiotype B in germinal centers—immune structures responsible for the generation of high-affinity, T cell–dependent antibody responses—thus preventing the production of specific and effective antibody responses to other staphylococcal antigens.

The chronic or repeated nature of S. aureus infection in human populations suggests that patients cannot mount a protective antibody response even when serological responses to S. aureus antigens are detected. Nonspecific expansion and activation of PBs by SpA allow S. aureus to prevent protective humoral immune responses and the generation of sufficient memory to avoid future infections. Thus, improved Staphylococcus aureus vaccination strategies should take into consideration the use of inactive toxins, such as SpAKK to improve antibody responses.

N. Pauli et al., Staphylococcus aureus infection induces protein A–mediated immune evasion in humans. J. Exp. Med. 211, 2331–2339 (2014).[Full Text]

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