Staphylococcal and streptococcal superantigens: molecular, biological and clinical aspects.

Superantigens (SAgs) include a class of certain bacterial and viral proteins exhibiting highly potent lymphocyte-transforming (mitogenic) activity towards human and or other mammalian T lymphocytes. Unlike conventional antigens, SAgs bind to certain regions of major histocompatibility complex (MHC) class II molecules of antigen-presenting cells (APCs) outside the classical antigen-binding groove and concomitantly bind in their native form to T cells at specific motifs of the variable region of the beta chain (Vbeta) of the T cell receptor (TcR). This interaction triggers the activation (proliferation) of the targeted T lymphocytes and leads to the in vivo or in vitro release of high amounts of various cytokines and other effectors by immune cells. Each SAg interacts specifically with a characteristic set of Vbeta motifs. The review summarizes our current knowledge on S. aureus and S. pyogenes superantigen proteins. The repertoire of the staphylococcal and streptococcal SAgs comprises 24 and 8 proteins, respectively. The staphylococcal SAgs include (i) the classical enterotoxins A, B, C (and antigenic variants), D, E, and the recently discovered enterotoxins G to Q, (ii) toxic shock syndrome toxin-1, (iii) exfoliatins A and B. The streptococcal SAgs include the classical pyrogenic exotoxins A and C and the newly identified pyrogenic toxins, G, H, I, J, SMEZ, and SSA. The structural and genomic aspects of these toxins and their molecular relatedness are described as well as the available 3-D crystal structure of some of them and that of certain of their complexes with MHC class II molecules and the TcR, respectively. The pathophysiological properties and clinical disorders related to these SAgs are reviewed.

Protection against tetanus toxin after intragastric administration of two recombinant lactic acid bacteria: impact of strain viability and in vivo persistence.

Non-pathogenic lactic acid bacteria (LAB) are attractive as live carriers to deliver protective antigens to the mucosal immune system. Both persisting and non-persisting strains of lactic acid bacteria have been evaluated and seem to work equally well by the systemic and nasal routes of administration. However, it is not known if persistence and viability of the strain play a critical role when immunizing by the oral route. To address this question, recombinant LAB strains, able to persist (Lactobacillus plantarum NCIMB8826/pMEC127) or not (Lactococcus lactis MG1363/pMEC46) in the gastro-intestinal tract of mice and producing equivalent amounts of the tetanus toxin fragment C (TTFC) were compared to each other. A very strong ELISA TTFC-specific and protective humoral response was elicited by either live or UV-inactivated recombinant Lb. plantarum strains. In a similar protocol, recombinant Lc. lactis seemed to be somewhat less efficient than the former host. It is thus tempting to propose that the difference in the capacity of the bacterial vector to persist in the gastro-intestinal tract impacts on its immunogenicity and on the level of protection it may induce. Protection was slightly superior after administration of live strains.

Enhanced mucosal delivery of antigen with cell wall mutants of lactic acid bacteria.

The potential of recombinant lactic acid bacteria (LAB) to deliver heterologous antigens to the immune system and to induce protective immunity has been best demonstrated by using the C subunit of tetanus toxin (TTFC) as a model antigen. Two types of LAB carriers have mainly been used, Lactobacillus plantarum and Lactococcus lactis, which differ substantially in their abilities to resist passage through the stomach and to persist in the mouse gastrointestinal tract. Here we analyzed the effect of a deficiency in alanine racemase, an enzyme that participates in cell wall synthesis, in each of these bacterial carriers. Recombinant wild-type and mutant strains of L. plantarum NCIMB8826 and L. lactis MG1363 producing TTFC intracellularly were constructed and used in mouse immunization experiments. Remarkably, we observed that the two cell wall mutant strains were far more immunogenic than their wild-type counterparts when the intragastric route was used. However, intestinal TTFC-specific immunoglobulin A was induced only after immunization with the recombinant L. plantarum mutant strain. Moreover, the alanine racemase mutant of either LAB strain allowed induction of a much stronger serum TTFC-specific immune response after immunization via the vagina, which is a quite different ecosystem than the gastrointestinal tract. The design and use of these mutants thus resulted in a major improvement in the mucosal delivery of antigens exhibiting vaccine properties.