TREPONEMA-PALLIDUM AND BORRELIA-BURGDORFERI LIPOPROTEINS AND SYNTHETIC LIPOPEPTIDES ACTIVATE MONOCYTIC CELLS VIA A CD14-DEPENDENT PATHWAY DISTINCT FROM THAT USED BY LIPOPOLYSACCHARIDE

Lipoproteins of Treponema pallidum and Borrelia burgdorferi possess po tent proinflammatory properties and, thus, have been implicated as maj or proinflammatory agonists in syphilis and Lyme disease. Here we used purified B. burgdorferi outer surface protein A (OspA) and synthetic lipopeptides corresponding to the N-termini of OspA and the 47-kDa maj or lipoprotein immunogen of T. pallidum to clarify the contribution of CD14 to monocytic cell activation by spirochetal lipoproteins and lip opeptides. As with LPS, mouse anti-human CD14 Abs blocked the activati on of 1,25-dihydroxyvitamin D-3-matured human myelomonocytic THP-1 cel ls by OspA and the two lipopeptides. The existence of a CD14-dependent pathway was corroborated by using undifferentiated THP-I cells transf ected with CD14 and peritoneal macrophages from CD14-deficient BALB/c mice. Unlike LPS, cell activation by lipoproteins and lipopeptides was serum independent and was not augmented by exogenous LPS-binding prot ein. Two observations constituted evidence that LPS and lipoprotein/li popeptide signaling proceed via distinct transducing elements downstre am of CD14: 1) CHO cells transfected with CD14 were exquisitely sensit ive to LPS but were lipoprotein/lipopeptide nonresponsive; and 2) subs toichiometric amounts of deacylated LPS that block LPS signaling at a site distal to CD14 failed to antagonize activation by lipoproteins an d lipopeptides. The combined results demonstrate that spirochetal lipo proteins and lipopeptides use a CD14-dependent pathway that differs in at least two fundamental respects from the well-characterized LPS rec ognition pathway.