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  • Review Article
  • Published:

Fortifying the barrier: the impact of lipid A remodelling on bacterial pathogenesis

Key Points

  • Lipid A is the bioactive outer-membrane anchor of the major surface molecule, lipopolysaccharide (LPS), of Gram-negative bacteria. Although the synthetic pathway of lipid A is highly conserved, most bacteria encode enzymes that alter the basic structure of this LPS component.

  • Lipid A modifications affect pathogenesis in several ways to allow bacteria to circumvent the host immune system. Some remodelling mechanisms alter the charge of the outer membrane and thereby influence the association of host molecules such as cationic antimicrobial peptides (CAMPs), whereas others decrease binding of the host innate immune receptor complex that is specific for lipid A (Toll-like receptor 4–MD2).

  • A balance between membrane integrity and lipid A modifications is important for survival of a bacterium in the diverse environments that it encounters, and thus many lipid A modification enzymes are regulated transcriptionally and/or post-translationally, by mechanisms such as two-component systems, small RNAs, peptide feedback loops and substrate availability.

  • Gram-negative bacteria have evolved diverse lipid A-remodelling schemes that contribute to adaptation for specific niches. These schemes are exemplified by the complex regulation of lipid A modification in Salmonella enterica subsp. enterica serovar Typhimurium, the extensive evasion of the innate immune system by Helicobacter pylori, temperature-dependent alteration of lipid A in Yersinia pestis and Francisella tularensis, and CAMP resistance in Vibrio cholerae.

  • Host modification mechanisms affect the presence of bioactive lipid A. These range from covalent modifications that remove those segments of the molecule which are necessary for immune responsiveness, to sequestration of lipid A for eventual disposal.

  • Recent work has uncovered links between lipid A modification strategies and other physiological functions in bacteria, such as virulence factor activity, motility and toxin delivery.

Abstract

Gram-negative bacteria decorate their outermost surface structure, lipopolysaccharide, with elaborate chemical moieties, which effectively disguises them from immune surveillance and protects them from the onslaught of host defences. Many of these changes occur on the lipid A moiety of lipopolysaccharide, a component that is crucial for host recognition of Gram-negative infection. In this Review, we describe the regulatory mechanisms controlling lipid A modification and discuss the impact of modifications on pathogenesis, bacterial physiology and bacterial interactions with the host immune system.

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Figure 1: The cell envelope of Gram-negative bacteria.
Figure 2: Transcriptional and post-translational regulation of lipid A modification enzymes.
Figure 3: Toll-like receptor 4–MD2 signalling.
Figure 4: Lipid A modification strategies that promote survival in the host.

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Acknowledgements

This work was supported by the US National Institutes of Health (grants AI064184 and AI76322), by the US Army Research Office (grant 61789-MA-MUR) and by the Cystic Fibrosis Foundation (grant Trent13G0).

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Glossary

Microorganism-associated molecular pattern

(MAMP). A component of a commensal or pathogenic microorganism that is well conserved and universally recognized by the innate immune system. Lipopolysaccharide is a typical MAMP, and other examples include peptidoglycan, lipoproteins and flagella. Previously referred to as PAMPs (pathogen-associated molecular patterns),

Small RNAs

Short, non-coding RNA molecules that can regulate gene expression by interacting with mRNA or can bind protein targets to modify their activity.

Kdo

(3-deoxy-D-manno-octulosonic acid). The sugar residue that constitutes the inner core of lipopolysaccharide. This inner core links the polysaccharide chain to lipid A.

Cationic antimicrobial peptide

A type of positively charged, amphipathic peptide that associates with the negatively charged Gram-negative membrane and is thought to disrupt the membrane, leading to cell lysis and death.

Complement

An innate immune defence mechanism involving many proteins that function in signalling cascades and also form cell-lysing membrane attack complexes.

Opsonization

The tagging of pathogens by molecules such as antibodies. These molecules target the foreign entity for destruction by immune system clearance mechanisms such as phagocytosis and the complement system.

Pattern recognition receptors

Receptors of the innate immune system. These receptors bind microorganism-associated molecular patterns of infecting pathogens and initiate signalling cascades which lead to inflammation, cytokine release and activation of the adaptive immune response.

Cytokine

A signalling protein involved in the recruitment and regulation of cells that participate in the immune response.

Sepsis

The severe and often fatal inflammatory response of the body to the overwhelming presence of infection (usually bacterial), characterized in part by organ failure.

Biotype

A subtype of a bacterial species that can be distinguished from other subtypes by biological characteristics such as motility, resistance to cationic antimicrobial peptides and antibiotics, and the production of virulence factors.

Pandemic

The widespread occurrence of a human infectious disease that is spread over a large geographical region.

Wall teichoic acids

Long anionic glycopolymers that are covalently linked to the peptidoglycan of Gram-positive bacteria and extend beyond the cell wall.

Wall lipoteichoic acids

Teichoic acids that are anchored to the plasma membrane of Gram-positive bacteria and extend into the peptidoglycan layer.

Chylomicrons

Small micelles that are composed of lipids, lipoproteins and proteins, and function to transport lipids.

Flagellar rod

The central, structural component of bacterial flagella that spans the periplasm.

Flagella

Whip- or tail-like appendages that are synthesized by many bacteria and are important for motility.

Outer-membrane vesicles

Small, spherical outer-membrane blebs that are released from Gram-negative bacterial cells and contain membrane and periplasmic components.

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Needham, B., Trent, M. Fortifying the barrier: the impact of lipid A remodelling on bacterial pathogenesis. Nat Rev Microbiol 11, 467–481 (2013). https://doi.org/10.1038/nrmicro3047

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