A Novel Role for Plasmin-Mediated Degradation of Opsonizing Antibody in the Evasion of Host Immunity by Virulent, but Not Attenuated, Francisella tularensis

Abstract

Opsonization by Abs represents a critical component of the host immune response against many pathogens. The mechanisms by which virulent microbes evade this protective response are not completely understood. In disease mediated by Francisella tularensis, Ab can effectively protect against infections with attenuated strains, for example, LVS, but not virulent strains such as SchuS4. Thus, it is likely that SchuS4 has mechanisms, which are not present in LVS, that allow evasion of opsonization by Ab, dampening the protective effects of these host molecules. Here we demonstrate that evasion of Ab-mediated opsonization and phagocytosis by the highly virulent SchuS4 is associated with its ability to bind the host serine protease plasmin. SchuS4, but not the closely related LVS, bound active plasmin. Plasmin bound SchuS4 degraded exogenous and opsonizing Abs, whereas LVS failed to do so. Furthermore, plasmin-mediated inhibition of Ab opsonization by SchuS4 also inhibited Ab-mediated uptake of this bacterium by macrophages. Ab-mediated uptake of uncoated and opsonized SchuS4 elicited a strong proinflammatory response in infected macrophages. However, plasmin-coated, opsonized SchuS4 poorly elicited production of these protective proinflammatory cytokines. This unique host-pathogen interplay is a novel immune evasion strategy utilized by virulent F. tularensis, and it provides one explanation for the ability of Ab to protect against attenuated, but not virulent, strains of F. tularensis. This mechanism may also represent a more common hereto unrecognized strategy by which virulent bacteria evade detection and clearance by Ig.