Group B streptococcus (GBS) is the most important cause of neonatal
sepsis, which is mediated in part by
TLR2. However, GBS components that potently induce
cytokines via
TLR2 are largely unknown. We found that GBS strains of the same
serotype differ in released factors that activate
TLR2. Several lines of
genetic and biochemical evidence indicated that
lipoteichoic acid (LTA), the most widely studied
TLR2 agonist in
Gram-positive bacteria, was not essential for
TLR2 activation. We thus examined the role of GBS
lipoproteins in this process by inactivating two genes essential for
bacterial lipoprotein (BLP) maturation: the prolipoprotein diacylglyceryl
transferase gene (lgt) and the
lipoprotein signal peptidase gene (lsp). We found that Lgt modification of the
N-terminal sequence called lipobox was not critical for Lsp cleavage of BLPs. In the absence of lgt and lsp,
lipoprotein signal peptides were processed by the type I
signal peptidase. Importantly, both the Deltalgt and the Deltalsp
mutant were
impaired in
TLR2 activation. In contrast to released factors, fixed Deltalgt and Deltalsp GBS cells exhibited normal
inflammatory activity indicating that
extracellular toxins and
cell wall components activate
phagocytes through independent pathways. In addition, the Deltalgt
mutant exhibited increased lethality in a model of neonatal GBS
sepsis. Notably, LTA comprised little, if any,
inflammatory potency when extracted from Deltalgt GBS. In conclusion, mature BLPs, and not LTA, are the major
TLR2 activating factors from GBS and significantly contribute to GBS
sepsis.
