Études chimiques et immunologiques des capsules polysaccharidiques de Streptococcus suis

Streptococcus suis is one of the most important porcine bacterial pathogens and is responsible for substantial economic losses to the swine industry. Moreover, it is also a zoonotic agent representing serious risks to human health. This bacterium causes a variety of clinical signs, of which meningitis, sudden death, and septic shock are the most frequent. Furthermore, no efficient vaccine is available to protect against infections caused by S. suis.  Being encapsulated, S. suis is classified into 35 serotypes based on the antigenicity of their capsular polysaccharide (CPS). However, only the structure of the serotype 2 CPS is known to date. Immunologically, purified CPSss generally behave as T-independent antigens, making them very poor immunogens. Indeed, this has been previously demonstrated to be the case for the serotype 2 CPS. Paradoxically, anti-CPS antibodies are strongly opsonizing and protective, making them attractive targets for vaccine development.  Therefore, the objectives of this thesis are, firstly, to further characterize the chemical composition and structure of the S. suis CPSs from different serotypes, and secondly, to study the immunostimulatory and immunogenic properties of these additional CPSs. Moreover, this thesis will attempt to increase the serotype 2 CPS immunogenicity for potential use it as a vaccine antigen.  In a first step, a review of the literature provided an updated and global view of S. suis infections in swine and humans and identified the most important serotypes. With these epidemiological data in hand, we then purified the CPSs of selected serotypes, which allowed us to determine the structures for eight additional CPSs (1, 1/2, 3, 7, 8, 9, 14, and 18).  The knowledge obtained regarding the structure of theses CPSs allowed us to then evaluate their antigenicity and immunogenicity. We demonstrated for the first time that serotype 3 is highly immunogenic S. suis CPS, as it induces an opsonizing response composed of IgG and IgM by a T-independent mechanism.  In addition, we have developped for the first time a glycoconjugate vaccine composed of serotype 2 CPS conjugated to tetanus toxoid in order to obtain a protective T-dependent antibody response. A proof of concept performed with pigs demonstrated protection conferred by our glycoconjugate vaccine against S. suis, and more importantly the potential of glycoconjugate vaccines in the fight against invasive bacterial infections in veterinary medicine. Finally, immunogenicity studies performed in mice with this glycoconjugate vaccine allowed us to evaluate the effect of the animal model and adjuvant choice on the anti-CPS response. It also allowed us to produce three new monoclonal antibodies that enabled us to study, among other aspects, the humoral mechanisms involved in S. suis clearance by opsonophagocytosis.    Consequently, the work conducted during this thesis will serve to highlight the importance of anti-CPS antibodies in the protection against invasive bacterial diseases.

Keyphrases: Streptococcus suis, Structures, Porc, Serotype, Capsular polysaccharide, Glycoconjugate vaccine, Antibody response, Opsonophagocytosis, Immunogenicity, Mouse, Swine