Bordetella pertussis lipid A recognition by Toll-like Receptor 4 and MD-2 is dependent on distinct charged and uncharged interfaces [Microbiology]

April 2nd, 2015 by Maeshima, N., Evans-Atkinson, T., Hajjar, A. M., Fernandez, R. C.

Lipid A in LPS activates innate immunity through the Toll-like Receptor 4 (TLR4)-MD-2 complex on host cells. Variation in lipid A has significant consequences for TLR4 activation and thus may be a means by which Gram-negative bacteria modulate host immunity. However, although even minor changes in lipid A structure have been shown to affect downstream immune responses, the mechanism by which the TLR4-MD-2 receptor complex recognizes these changes is not well understood. We have previously shown that strain BP338 of the human pathogen Bordetella pertussis, the causative agent of whooping cough, modifies its lipid A by the addition of glucosamine moieties that promote TLR4 activation in human, but not mouse, macrophages. Using site-directed mutagenesis and an NFκB reporter assay screen, we have identified several charged amino acid residues in TLR4 and MD-2 that are important for these species-specific responses: some of these are novel for responses to penta-acyl B. pertussis LPS and their mutation does not affect the response to hexa-acylated Escherichia coli LPS or tetra-acylated lipid IVA. We additionally show evidence that suggests that recognition of penta-acylated B. pertussis lipid A is dependent on uncharged amino acids in TLR4 and MD-2, and that this is true for both human and mouse TLR4-MD-2 receptors. Taken together, we have demonstrated that the TLR4-MD-2 receptor complex recognizes variation in lipid A molecules using multiple sites for receptor-ligand interaction, and propose that host-specific immunity to a particular Gram-negative bacteria is, at least in part, mediated by very subtle tuning of one of the earliest interactions at the host-pathogen interface.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on Bordetella pertussis lipid A recognition by Toll-like Receptor 4 and MD-2 is dependent on distinct charged and uncharged interfaces [Microbiology]