Pneumococcal Interaction with Human Dendritic Cells: Phagocytosis, Survival, and Induced Adaptive Immune Response Are Manipulated by PavA

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 iso-genic 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-1 beta, IL-6, IL-8, IL-12, and TNF-alpha 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 Journal of Immunology, 2009, 183: 1952-1963.