The Lipid A Phosphate Position Determines Differential Host Toll-Like Receptor 4 Responses to Phylogenetically Related Symbiotic and Pathogenic Bacteria

Abstract

The human symbiont Bacteroides thetaiotaomicron promotes intestinal function and health, whereas the phylogenetically related pathogen Porphyromonas gingivalis is associated with the chronic oral inflammatory disease periodontitis. Although both B. thetaiotaomicron and P. gingivalis synthesize lipopolysaccharides (LPS) consisting of penta-acylated, monophosphorylated lipid A in addition to immunologically silent, nonphosphorylated lipid A, they elicit strikingly distinct Toll-like receptor 4 (TLR4) responses. We show that the phosphate position of penta-acylated, monophosphorylated lipid A is a key feature for determining the differential TLR4 responses elicited by these evolutionarily related bacteria. B. thetaiotaomicron produces TLR4-stimulatory lipid A bearing a 1-phosphate, in contrast to P. gingivalis, which produces TLR4-evasive lipid A bearing a 4-phosphate. Confirming these observations, recombinant Escherichia coli LPS containing penta-acylated, 1-phosphorylated lipid A is more TLR4 stimulatory than LPS containing 4-phosphorylated lipid A. The specific capacity of a Gram-negative bacterium to alert or evade the host innate immune defense system through TLR4-dependent signaling is currently recognized as a critical aspect defining the relationship between the host and the bacterium. We propose that the distinct lipid A phosphate positions observed for the B. thetaiotaomicron and P. gingivalis LPS contributes to the manifestation of these bacteria as commensal or pathogen within the human host.

Minor Modifications to the Phosphate Groups and the C3′ Acyl Chain Length of Lipid A in Two Bordetella pertussis Strains, BP338 and 18-323, Independently Affect Toll-like Receptor 4 Protein Activation

“…Coats et al (29) suggest that in penta-acyl lipid A species, longer fatty acid chain lengths correlate with greater TLR4 activity. This hypothesis is based on the observation that penta-acyl E. coli LPS with acyl chain lengths of C12 and C14 is a weaker TLR4 agonist in comparison with Porphyromonas gingivalis penta-acyl LPS, which contains acyl chain lengths of C15, C16, and C17 (29).…”

“…Coats et al (29) suggest that in penta-acyl lipid A species, longer fatty acid chain lengths correlate with greater TLR4 activity. This hypothesis is based on the observation that penta-acyl E. coli LPS with acyl chain lengths of C12 and C14 is a weaker TLR4 agonist in comparison with Porphyromonas gingivalis penta-acyl LPS, which contains acyl chain lengths of C15, C16, and C17 (29). In the present study, we have elucidated the genetic reasons for the structural differences between B. pertussis strain BP338 and 18-323 lipid A. lgmA, lgmB, and lgmC are responsible for the GlcN modification present on phosphate groups in BP338, but absent in 18-323, and the single amino acid difference at position 173 of B. pertussis LpxA is responsible for the presence of 14 carbon acyl chains at the C3Ј position in BP338 and only 10 and 12 carbon acyl chains at this position in 18-323.…”

Adjuvant Activity of Naturally Occurring Monophosphoryl Lipopolysaccharide Preparations from Mucosa-Associated Bacteria

“…Therefore, MPLA works well as a safe and effective vaccine adjuvant. Lipid A structural features known to account for the maintenance of adjuvant properties and the loss of toxicity include the number of phosphate groups, as well as the number, type, and location of fatty acid residues (4)(5)(6). Although the most abundant structure in the S. Minnesota MPLA used in these studies is a hexa-acylated structure (Fig.…”

Reconciliation of IL-1ß loss with TRIF-biased TLR4 signaling by monophosphate lipid A.

“…It is interesting to note that bacteria often evade detection by the immune system via modification of their LPS structures [42][43][44][45]. In fact, the actual position of that single phosphate group on the Lipid A head group affects the potency of host immune responses, with a 4' phosphate being less immune-stimulatory than a l' monophosphate structure [39,46]. This increased potency of a l' versus 4' phosphate may be due to the interaction of the l' phosphate with TLR4, possibly inducing better receptor clustering.…”

“…MPLA represents a structural variant of LPS on commensal bacteria MPLA was first discovered as a hydrolytic derivative of LPS that could be generated in vitro, but recent work has shown that various commensal and opportunistic pathogenic bacteria species produce monophosphorylated LPS, including Bacteroides thetaiotamicron and fragilis, Porphormonys gingivalis, and Heliobacter pylori [38][39][40][41]. It is interesting to note that bacteria often evade detection by the immune system via modification of their LPS structures [42][43][44][45].…”