Role ofd-Alanylation ofStreptococcus gordoniiLipoteichoic Acid in Innate and Adaptive Immunity

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Abstract
In recent years, there has been considerable interest in using the oral commensal gram-positive bacteriumStreptococcus gordoniias a live vaccine vector. The present study investigated the role ofd-alanylation of lipoteichoic acid (LTA) in the interaction ofS. gordoniiwith the host innate and adaptive immune responses. A mutant strain defective ind-alanylation was generated by inactivation of thedltAgene in a recombinant strain ofS. gordonii(PM14) expressing a fragment of the S1 subunit of pertussis toxin. The mutant strain was found to be more susceptible to killing by polymyxin B, nisin, magainin II, and human β defensins than the parent strain. When it was examined for binding to murine bone marrow-derived dendritic cells (DCs), thedltAmutant exhibited 200- to 400-fold less binding than the parent but similar levels of binding were shown for Toll-like receptor 2 (TLR2) knockout DCs and HEp-2 cells. In a mouse oral colonization study, the mutant showed a colonization ability similar to that of the parent and was not able to induce a significant immune response. The mutant induced significantly less interleukin 12p70 (IL-12p70) and IL-10 than the parent from DCs. LTA purified from the bacteria induced tumor necrosis factor-alpha and IL-6 production from wild-type DCs but not from TLR2 knockout DCs, and the mutant LTA induced a significantly smaller amount of these two cytokines. These results show thatd-alanylation of LTA inS. gordoniiplays a role in the interaction with the host immune system by contributing to the relative resistance to host defense peptides and by modulating cytokine production by DCs.

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