Unfolding the immune response against Staphylococcus aureus-mediated systemic sequelae of skin recurrences

Staphylococcal protein A (SpA) is a surface-associated virulence factor of Staphylococcus aureus (S. aureus) which binds human immunoglobulins via both Fc and Fab fragment masking the pathogen to the host immune system. This activity interacts with the normal maturation of the host immune system during an infection and allows S. aureus to cause recurrent infections as, for example, skin recurrences. Skin recurrences are not only bothersome superficial infections that require continuous treatments, but may also evolve in more complicated and systemic complications. Immunization with SpA protects animals against S. aureus systemic infections unmasking the pathogen to the host immune system, which turns out to recognize bacterial antigens otherwise hidden by SpA activity. The aim of this project was to assess the protective effect of SpAmut against skin recurrences and systemic complications in a mouse model of Skin and Soft Tissues Infections (SSTIs) set up in C57BL/6 mice, which are naturally susceptible to re-infections with S. aureus. Vaccination with SpAmut adjuvanted with AS01 (SpAmut/AS01) was able to limit bacterial spreading from the skin through the blood, abrogating S. aureus infiltration to the kidneys (target for systemic disease). S. aureus-specific protein microarrays were used to compare sera of mice vaccinated with SpAmut/AS01 and then infected with those of mice only infected for their ability to recognize a selection of S. aureus antigens. Vaccination with SpAmut/AS01 was able to unmask several S. aureus antigens to the immune system during SSTIs in mice. Interestingly, mice infected with S. aureus did not develop measurable antibodies against the mutated version of SpA, whereas infection in vaccinated mice significantly increased the avidity of antibodies against SpAmut induced by previous immunization. Furthermore, only sera from vaccinated and infected mice allowed internalization of S. aureus by human phagocytes in vitro, suggesting a functional role in mediating the in vivo observed protection. Overall, these data support the essential role of vaccination with SpA, an immunomodulator antigen of S. aureus, in the induction of a functional specific antibody response during recurrences, contributing to the control of systemic bacterial dissemination, one of the main complications developed during S. aureus-mediated SSTIs.