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* Department Genetics of Microorganisms, Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany;
Max von Pettenkofer Institute, Ludwig-Maximilians University München, München, Germany;
Research Center for Infectious Diseases and
Department of Obstetrics and Gynecology, University of Würzburg, Würzburg, Germany; and
¶ Department of Microbial Pathogenesis, Helmholtz Center for Infection Research, Braunschweig, Germany
Dendritic cells (DCs) ingest and process bacteria for presenting their Ags to T cells. PavA (pneumococcal adherence and virulence factor A) is a key virulence determinant of pneumococci under in vivo conditions and was shown to modulate adherence of pneumococci to a variety of nonprofessional phagocytic host cells. Here, we demonstrated the role of PavA for the interaction of human DCs with live pneumococci and analyzed the induced host cell responses upon ingestion of viable pneumococci. Expression of PavA protected pneumococci against recognition and actin cytoskeleton-dependent phagocytosis by DCs compared with isogenic pavA mutants. A major proportion of internalized pneumococci were found in membrane-bound phagosomes. Pneumococcal phagocytosis promotes maturation of DCs, and both wild-type pneumococci and PavA-deficient pneumococci triggered production of proinflammatory cytokines such as IL-1β, IL-6, IL-8, IL-12, and TNF-
and antiinflammatory IL-10. However, cytokine production was delayed and reduced when DCs encounter pneumococci lacking PavA, which also results in a less efficient activation of the adaptive immune response. Strikingly, purified PavA reassociates to pneumococci but not DCs and reduced phagocytosis of the pavA mutant to levels similar to those of wild-type pneumococci. Additionally, pavA mutants covered with exogenously provided PavA protein induced a DC cytokine profile similar to wild-type pneumococci. In conclusion, these results suggest that PavA is key factor for live pneumococci to escape phagocytosis and to induce optimal cytokine productions by DCs and adaptive immune responses as well.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by the Bundesministerium für Bildung und Forschung (CAPNETZ C8; to S.H.) and the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 479, Teilprojekt A7, DFG HA 3125/2-1 and 4-1).
2 Address correspondence and reprint requests to Dr. Sven Hammerschmidt, Department Genetics of Microorganisms, Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University Greifswald, Friedrich Ludwig Jahn Strasse 15a, D-17487 Greifswald, Germany. E-mail address: sven.hammerschmidt{at}uni-greifswald.de
3 Abbreviations used in this paper: DC, dendritic cell; BMDC, bone marrow-derived dendritic cell; CLSM, confocal laser scanning microscopy; CPS, capsular polysaccharide; FESEM, field emission electron microscopy; iDC, immature dendritic cell; Lamp1, lysosomal-associated membrane protein 1; MBP, maltose-binding protein; MOI, multiplicity of infection; OxMi, oxidative mitogenesis; PavA, pneumococcal adherence and virulence factor A; TEM, transmission electron microscopy.
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