Staphylococcal virulence. Towards vaccination against infectious arthritis and sepsis

Abstract

Staphylococcus aureus is a common cause of disease in humans representing a particular threat to immunocompromised patients. Several potential virulence factors have been described. The emergence of antibiotic resistant strains has prompted the development of new therapeutic and prophylactic regimens. Fundamental knowledge of staphylococcal virulence factors and their role in disease will enable the rational design of specific therapeutics. The aims of this thesis are to elucidate the role of particular staphylococcal virulence factors in septic arthritis and septicaemia, and to assess the efficacy of the use of recombinant antistaphylococcal vaccines. A set of isogenic S. aureus strains was used in a murine model to assess the role of defined virulence factors in the pathogenesis, of sepsis and arthritis. This set of mutants included strain defective in: a) global virulence regulator gene b) capsular polysaccharide genes; c) alpha- beta- and gamma-hemolysin genes. Induction of protective antibodies via vaccination may provide an effective means of preventing sepsis and septic arthritis. Collagen adhesin is expressed by most staphylococcal strains inducing septic arthritis. Vaccination with a recombinant fragment of collagen adhesin protected mice against sepsis-induced death. Antibodies against this fragment interfered with bacterial binding to host tissue and promoted phagocytic uptake and intracellular killing of bacteria. Superantigens produced by many S. aureus strains are potent stimulators of host inflammatory response. Induction of immunity against native superantigens is not feasible, since this would trigger severe inflammation, potentially leading to septic shock. Vaccination of mice with an engineered enterotoxin, devoid of superantigenic properties, significantly increased survival following challenge with S. aureus. In summary, this thesis defines bacterial components crucial to staphylococcal pathogenesis and indicates potential candidate antigens which might be incorporated into a future vaccine against septic arthritis and sepsis. Ideally, this vaccine would be multifactorial and should inhibit bacterial adhesion to matrix proteins, promote phagocytosis, and neutralise toxins