Deciphering the immune-modulating effect of Staphylococcus aureus protein A (SpA) on the functional antibody response

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While Staphylococcus aureus is commonly found as part of the human commensal flora it is also a major opportunistic pathogen causing significant illness and burden on healthcare systems. The increasing incidence of antimicrobial resistant infection including methicillin-resistant Staphylococcus aureus (MRSA) and the failure of effective prevention approaches means that it remains a high-priority target for the development of new therapeutics and vaccines [1].Human immune responses to S. aureus often appear dysregulated due to an array of immune-modulator bacterial virulence factors. These factors block immune cell chemotaxis, complement activation, phagocytic uptake and oxidative killing, and facilitate pathogen replication. This results in disruption of normal B and T cell function, preventing the establishment of otherwise protective immune responses [2]. Central to the disruption of B cell survival and function is S. aureus protein A (SpA), an immunoglobulin (Ig)-binding virulence factor, which subsequently impairs the humoral response. As a cell wall-associated protein, SpA is either expressed on the bacterial surface or secreted. By sequestering immunoglobulin through the Fc portion, SpA causes disruption of opsonophagocytosis resulting in bacterial persistence. Another key function of SpA is to impair the B cell response by binding the Fab region of VH3-type B cell receptor and acting as a superantigen. In mice, B cells targeted by this superantigen initially undergo massive activation, followed by apoptosis and cell death [3]. SpA is also associated with the transient extrafollicular expansion of short-lived VH3-biased B cells followed by reduction of protective secondary anti-S. aureus antibody response and of the pool of bone marrow-resident long-lived antigen-specific plasma cells [4]. Moreover, analysis of human B cells revealed a similar VH3-dominant response both during natural infection and in the memory compartment of healthy individuals [5, 6]. It is currently unknown to what extent these effects are relevant to the functional human response to infection and what is the impact of this biased antibody response to the establishment of protective defenses. The aim of this PhD project is to understand the immune-modulating effect of S. aureus protein A on the functional response to infection in humans. Using clinical samples obtained from healthy donors, individuals recovering from S. aureus infection and other sources, you will characterize the mechanisms underlying SpA-mediated evasion of a functional antibody response. Understanding this mechanism will be vital to deciphering the virulence of S. aureus and other microorganisms.