#FEMSmicroBlog: Bacteria adapting their lipid A coats


To protect themselves from their surrounding, bacteria contain a physical barrier. In Gram-negative bacteria, this outer membrane consists of lipopolysaccharide with its toxic component being lipid A. While generally, lipid A is conserved among diverse bacterial species, it can also vary significantly. The short review “Lipid A heterogeneity and its role in the host interactions with pathogenic and commensal bacteria” published in microLife explores how the heterogeneity of lipid A confers specific benefits to some bacteria. Sukumar Saha explains for the #FEMSmicroBlog how this feature enables these bacteria to modify host responses according to changing host environmental factors. #FascinatingMicrobes


Bacteria contain lipopolysaccharides with lipid A

In some organisms, lipopolysaccharide is not an essential component. Yet, investigations have shown that several strains lacking lipopolysaccharides are less virulent and more susceptible to antibiotics. One crucial component of lipopolysaccharide and responsible for this phenomenon in bacteria is the hexa-acylated lipid A.

This molecule can bind to specific innate immune receptors and induce inflammation. Interestingly, different lipid A structures from distinct bacteria can vary in their immunogenic potential and in their capacity to mediate innate immune receptor signalling.

This is possible because lipid A can differ in the number, position and chain length of the fatty acids. At the same time, the glucosamine disaccharide can be decorated with phosphate, phosphoethanolamine or different amino sugars resulting in this molecule’s high heterogeneity.

All these modifications impact the many physiological processes in bacteria. For example, lipid A can influence the structural integrity and permeability of the outer membrane, its susceptibility to antimicrobial peptides, immune stimulation, formation of outer membrane vesicles and pathogenesis.

General chemical structure of lipid A. The variable R residues gives bacteria their lipid A heterogeneity.
General structure of lipid A. From Saha et al. (2022).

Naturally occurring heterogeneity of lipid A has been particularly well studied in Neisseria meningitides. In this pathogen, the alteration of lipid A plays a major role in virulence and antimicrobial resistance. Specifically, the acylation pattern of lipopolysaccharide modulates the outer membrane permeability and endotoxic activity of this organism.


Using lipid A for biotechnology purposes

The short review Lipid A heterogeneity and its role in the host interactions with pathogenic and commensal bacteria” in microLife not only explains the physiological function of lipid A but also discusses its application in the biotechnology field.

Because lipid A stimulates immune receptors and cells, lipopolysaccharide is a potent adjuvant in vaccines. This is why subunit vaccines often include lipopolysaccharide as a purified component. Also lipopolysaccharide-containing vaccines based on whole bacterial cells or outer membrane vesicles trigger a stronger immune response.

For these purposes, the biological activity of lipopolysaccharide was fine-tuned by utilizing the natural heterogeneity of lipid A. Selecting variants with optimal balances between immunostimulatory and toxic properties resulted in highly effective vaccines.

Yet, researchers are trying to generate novel variants of lipopolysaccharide with improved adjuvant properties. For example, one study used a combinatorial lipid A bioengineering approach based on the great natural variety of lipid A biosynthetic and modifying enzymes. After generating extensive panels of various lipopolysaccharide derivatives in Neisseria meningitides, the work screened for variants with optimal immunostimulation and toxicity.

The study further expressed lipid A biosynthesis enzymes from N. meningitides in Bordetella pertussis. This heterologous expression led to the reduced endotoxic activity of vaccines based on whole cells or outer membrane vesicles.

Another study developed advanced analytical techniques to analyze lipid A structures of bacteria relevant for public health. Such tools together with all the other ones in progress can be used to study the role of the microbiome in health and disease and advance possible therapeutic modifications.


About this blog section

The section #FascinatingMicrobes for the #FEMSmicroBlog explains the science behind a paper and highlights the significance and broader context of a recent finding. One of the main goals is to share the fascinating spectrum of microbes across all fields of microbiology.

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