Novel engagement of CD14 and multiple toll-like receptors by group B streptococci

Group B streptococcus (GBS) imposes a major health threat to newborn infant s. Little is known about the molecular basis of GBS-induced sepsis. Both he at-inactivated whole GBS bacteria and a heat-labile soluble factor released by GBS during growth (GBS-F) induce nuclear translocation of NF-kappaB, th e secretion of TNF-alpha, and the formation of NO in mouse macrophages. Mac rophages from mice with a targeted disruption of MyD88 failed to secrete TN F-alpha in response to both heat-inactivated whole bacteria and GBS-F, sugg esting that Toll-like receptors (TLRs) are involved in different aspects of GBS recognition. Immune cell activation by whole bacteria differed profoun dly from that by secreted GBS-F. Whole GBS activated macrophages independen tly of TLR2 and TLR6, whereas a response to the secreted GBS-F was not obse rved in macrophages from TLR2-deficient animals. In addition to TLR2, TLR6 and CD14 expression were essential for GBS-F responses, whereas TLR1 and TL R4 or MD-2 did not appear to be involved. Heat lability distinguished GBS-F from peptidoglycan and lipoproteins. GBS mutants deficient in capsular pol ysaccharide or beta -hemolysin had GBS-F activity comparable to that of wil d-type streptococci. We suggest that CD14 and TLR2 and TLR6 function as cor eceptors for secreted microbial products derived from GBS and that cell wal l components of GBS are recognized by TLRs distinct from TLR1, 2, 4, or 6.