Staphylococcus aureus Protein A Disrupts Immunity Mediated by Long-Lived Plasma Cells

Abstract

Infection with Staphylococcus aureus does not induce long-lived protective immunity for reasons that are not completely understood. Human and murine vaccine studies support a role for antibodies in protecting against recurring infections, but S. aureus modulates the B cell response through expression of Staphylococcal Protein A (SpA), a surface protein that drives polyclonal B cell expansion and induces cell death in the absence of co-stimulation. In this murine study, we show that SpA altered the fate of plasmablasts and plasma cells (PCs) by enhancing the short-lived extrafollicular response and reducing the pool of bone marrow (BM)-resident long-lived PCs (LLPCs). The absence of LLPCs was associated with a rapid decline in antigen-specific, class-switched antibody. In contrast, when previously inoculated mice were challenged with isogenic Δspa S. aureus, cells proliferated in the BM survival niches and sustained long-term antibody titers. The effects of SpA on PC fate were limited to the secondary response, as antibody levels and the formation of B cell memory occurred normally during the primary response in mice inoculated with either WT or Δspa S. aureus. Thus, failure to establish long-term protective antibody titers against S. aureus was not a consequence of diminished formation of B cell memory; instead, SpA reduced the proliferative capacity of PCs that entered the BM, diminishing the number of cells in the long-lived pool.

Development of Systemic Immune Dysregulation in a Rat Trauma Model with Biomaterial-Associated Infection

“…This is supported by our data showing a significant increase in IL-10 in the infected group compared to the collagen only group (47,48). Following this expansion, S. aureus immune evasion mechanisms subsequently lead to an ablation of B cells, in particular the long-term plasma cells, thus increasing the risk for chronic and recurring infection (49), which is supported by our data showing a continual decline in B cells in the infection group after a peak at Day 7.…”

Essential Domain-Dependent Roles Within Soluble IgG for in vivo Superantigen Properties of Staphylococcal Protein A: Resolving the B-Cell Superantigen Paradox

“…The total amount of SpA at harvest in a representative animal was estimated to at least equal the doses that cause targeted B-cell depletion in our infusion studies ( 45 ). In a recent report, the SpA released during experimental S. aureus infection in a mouse model was shown to induce responses that included high-levels of extra-follicular plasmablasts that peaked only at 6 weeks after inoculation ( 67 ). The potential effects of SpA on germinal center reactions and anamnestic responses have not yet been considered, although the above described findings do highlight the challenges inherent to fully characterizing the kinetics and anatomic distribution of the SpA that is released during infection.…”

Розвиток Імунної Відповіді При Стафілококовій Пневмонії (Частина 8)

“…Keener и соавт. [30] было показано, что протеин SpA Staphylococcus aureus изменяет судьбу плазмокластов и плазмати-ческих клеток, способствуя повышению уровня вы-живания экстрафолликулярных короткоживущих плазматических клеток и сокращению пула долго-живущих плазматических клеток. Отсутствие дол-гоживущих плазматических клеток ассоциируется с быстрым снижением титра антигенспецифических антистафилококковых антител.…”