The pathogenic role of adenosine synthase A in Staphylococcus aureus infection and the development of vaccine against its infection

Abstract

Staphylococcus aureus (S. aureus) is an opportunistic human pathogen, which widely spreads in hospitals and communities. Patients infected by S. aureus display a variety of clinical manifestations range from localized skin and soft tissue infections to systemic infections like bacteremia. Of note is that prior infection of S. aureus does not confer protection against subsequent infection, therefore leading to a relatively high proportion of patients suffering from recurrent infection. The lack of optimal adaptive immunity may primarily contribute to the reinfection. Although recent studies have shed light on the role of cellular immunity in recurrent infections of S. aureus, the mechanism by which S. aureus evades host T cell responses remains mostly unexplored. A better understanding of how S. aureus evades host immunity will facilitate the development of treatment and vaccination against S. aureus infection.

This study demonstrates that a potent S. aureus virulence factor, adenosine synthase A (AdsA), can impede the development of optimal Th17 responses by interfering with NLRP3 inflammasome mediated IL-1β production. In vitro infection experiments confirm that AdsA can specifically inhibit NLRP3 inflammasome activation in macrophages and dendritic cells. From a mechanistic view, AdsA thwarts the NLRP3 inflammasome activation by facilitating the production of adenosine, which can interfere with the priming signal and downregulate the expression of NLRP3 through the adenosine/A2aR pathway. Furthermore, in mice and dendritic cell infection assays, S. aureus dampens Th1/Th17 immunity by limiting the induction of IL-1β and other Th polarizing cytokines via AdsA. In a murine infection model, pharmacological inhibition of the A2a receptor improves S. aureus-specific Th17 responses, whereas NLRP3 and caspase-1 inhibitor downregulate these responses. Overall, our results reveal that AdsA contributes to recurrent S. aureus infection by restraining protective Th1/Th17 responses.

In this study, attempts are also made to develop a multiple components vaccine named as Sta-V5, incorporating five conserved antigens, AdsA, EsxA and EsxB, PmtA and PmtC, which play different roles in the pathogenesis of S. aureus infection. The immunization of Sta-V5 confers broad protection against multiple epidemiologically relevant S. aureus isolates in five different murine infection models. The vaccine not only elicits functional antibodies that mediate opsonophagocytic killing of S. aureus but also mounts potent S. aureus specific cellular immunity. Additionally, our data suggest that γδ T cells participate in the protective immunity induced by Sta-V5 in a murine skin infection model.

In summary, this study provides an insight into the mechanism by which S. aureus subverts protective immune responses via the AdsA/IL-1β/Th17 axis, leading to recurrent infection. Furthermore, it also provides a multicomponent vaccine that can elicit potent adaptive immunity against S. aureus infection.