The mechanisms and functions of the Yersinia pseudotuberculosis outer membrane adhesins invasin and YadA in phagocytic uptake and systemic infections

Invasin and YadA are two outer membrane adhesins expressed by enteropathogenic yersiniae that interact with beta1 integrin cell receptors. While invasin binds directly to beta1 integrins with high affinity, YadA was proposed to bind indirectly through extracellular matrix (ECM) components. We have compared Y. pseudotuberculosis inv and yadA mutants for their ability to activate phagocytic signaling pathways in macrophages. From these studies, we propose a model whereby invasin promotes efficient phagocytic uptake due to direct "high affinity" interactions with integrin receptors while YadA can independently promote phagocytosis through integrin clustering in the context of a crosslinked fibrillar ECM network.; We hypothesized that invasin- and YadA- mediated interactions with macrophages in culture would have implications for tissue colonization and clearance of Y. pseudotuberculosis during systemic infections in mice. To test this hypothesis, adhesin mutants were injected intravenously into Balb/c mice and bacterial colonization and immune cell infiltration were measured in various tissues. Consistent with data from tissue culture experiments, studies in the mouse suggest that the outcome of Y. pseudotuberculosis infections is dependent on the expression of invasin and YadA on the bacterial surface and the micro environment of specific tissues. Our findings support the hypothesis that the loss of invasin and YadA expression in Y. pestis, which occurred as a consequence of reductive evolution from Y. pseudotuberculosis, may contribute to evasion of the host immune response and enhanced virulence.; One of the molecules that we found to be activated in macrophages upon Y. pseudotuberculosis binding was focal adhesin kinase (FAK). FAK, which is a protein tyrosine kinase, plays a role in numerous cellular processes that can contribute to the innate immune response during bacterial infections. We have begun to investigate how FAK contributes to the innate immune response by intravenous infection of wild type mice and mice that are deficient for FAK expression in macrophages and neutrophils with Y. pseudotuberuculosis . Preliminary evidence suggests that FAK expression in these phagocytes, together with tissue specific microenvironments and the elaboration of bacterial virulence factors and adhesins all contribute to the balance between colonization and immune clearance of Y. pseudotuberculosis in the mouse.