Novel Engagement of CD14 and Multiple Toll-Like Receptors by Group B Streptococci

Abstract

Group B streptococcus (GBS) imposes a major health threat to newborn infants. Little is known about the molecular basis of GBS-induced sepsis. Both heat-inactivated whole GBS bacteria and a heat-labile soluble factor released by GBS during growth (GBS-F) induce nuclear translocation of NF-κB, the secretion of TNF-α, and the formation of NO in mouse macrophages. Macrophages from mice with a targeted disruption of MyD88 failed to secrete TNF-α in response to both heat-inactivated whole bacteria and GBS-F, suggesting that Toll-like receptors (TLRs) are involved in different aspects of GBS recognition. Immune cell activation by whole bacteria differed profoundly from that by secreted GBS-F. Whole GBS activated macrophages independently of TLR2 and TLR6, whereas a response to the secreted GBS-F was not observed in macrophages from TLR2-deficient animals. In addition to TLR2, TLR6 and CD14 expression were essential for GBS-F responses, whereas TLR1 and TLR4 or MD-2 did not appear to be involved. Heat lability distinguished GBS-F from peptidoglycan and lipoproteins. GBS mutants deficient in capsular polysaccharide or β-hemolysin had GBS-F activity comparable to that of wild-type streptococci. We suggest that CD14 and TLR2 and TLR6 function as coreceptors for secreted microbial products derived from GBS and that cell wall components of GBS are recognized by TLRs distinct from TLR1, 2, 4, or 6.

Type I IFN Signaling Is Crucial for Host Resistance against Different Species of Pathogenic Bacteria

“…We found, however, that, in addition to live bacteria, low (0.1 g/ml), but not high (Ն10 g/ml), doses of heatkilled bacteria can also induce IFN-␣␤ expression in macrophages (our unpublished observations). Heat-killed GBS were previously found to induce TNF-␣ via a pathway involving MyD88, an adaptor protein that is involved in signaling by most TLRs (54). Studies are underway to determine whether MyD88 or TLRs are involved in GBS-induced IFN-␣␤ expression.…”

Ganglioside GD1a Is an Essential Coreceptor for Toll-like Receptor 2 Signaling in Response to the B subunit of Type IIb Enterotoxin

“…For this purpose we used CHO-K1 cells, which do not synthesize GD1a or other complex gangliosides (13). CHO-K1 cells, moreover, lack functional endogenous TLR2 but transcribe TLR1 and TLR6, either of which is capable of cooperative signaling with TLR2 in TLR2-transfected CHO-K1 cells (23,24). We have, therefore, transfected CHO-K1 cells with human TLR2 to allow reconstitution of TLR2/TLR1 cooperative signaling, required for maximal cell activation by LT-IIb-B 5 (7).…”

Recognition of Staphylococcus aureus-derived peptidoglycan (PGN) but not intact bacteria is mediated by CD14 in microglia

“…However, recent evidence also supports a role for mCD14 in the recognition of gram-positive PAMPs such as PGN and lipoteichoic acid (Cleveland et al, 1996;Dziarski et al, 2000a;Gupta et al, 1996). With respect to gram-positive bacterial antigens, mCD14 is thought to interact with either TLR2/TLR1 or TLR2/TLR6 heterodimers to induce cell activation and subsequent effector functions (Henneke et al, 2001;Kielian et al, 2002;Manukyan et al, 2005;Schroder et al, 2003;Weber et al, 2003). Soluble CD14 can also bind both PGN and LPS (Dziarski, 2003;Gupta et al, 1996;Hailman et al, 1994); however, these complexes have disparate effects on cell activation in mCD14-negative cells.…”