LPSs are one of the components of the outer membrane of most Gram-negative bacteria and play an important role in protecting the bacteria from stress, the body's ability to generate an immune response, and other processes. LPSs have been better understood over the past few decades, so let's step into LPS today.
 
What is LPS？

LPS is a unique component of Gram-negative bacteria's outer wall and a complex of lipids and polysaccharides. LPS is difficult to detach from the cell wall. It is detached by lysing and destroying the cell when the bacteria die, etc., and it exerts its toxicity by acting on animal cells, etc. Because of its nature, it is not a toxin secreted by bacteria outside the body (exotoxin), but a "toxin that exists inside the bacteria" that is not secreted and is therefore also called an endotoxin.

 

Timeline of LPS research

Structure of LPS

1. Effect of LPS structure on Gram-negative bacteria

The amphiphilic LPS molecule is covalently anchored to the outer membrane (OM) of Gram-negative bacteria by the lipid A region. The OM is a highly structured physiological barrier for Gram-negative bacteria, mainly because of the tight arrangement of LPS on the OM through covalent anchoring and strong electrostatic interactions. Moreover, ionic interactions between neighboring enriched negatively charged phosphates and divalent cations on the surface of the LPS molecule greatly enhance the barrier effect of the OM. Thus, LPS is an important component of the intrinsic immunity of Gram-negative bacteria.

Besides playing an important protective role, the structure of LPS also affects the apparent morphology of Gram-negative bacterial colonies. The type of LPS in bacteria that are usually smooth is predominantly S-type LPS (S-LPS); the type of LPS in bacteria that are usually rough is predominantly R-type LPS (R-LPS).
 

2. Structural analysis of LPS

S-LPS: S-LPS consists of three components: (1) Lipid A ; (2)core OS region; (3) O-antigen .
R-LPS: R-LPS consists only of lipid A with core OS region and lacks the O-antigen portion.  

3. Methods for studying the structure of LPS

Since LPS usually behaves as a complex multimolecular collection in single-strain colonies, extracting from bacteria to analyze the structure of a particular bacterial LPS usually requires isolation and purification, analysis of the structural constituent elements, and speculation about the spatial arrangement of LPS in the bacterial outer membrane. The development of methods to study the structure of LPS requires the intersection of multidisciplinary techniques, which can help researchers understand the connection between the structural composition of LPS and physiological functions.

Composition of LPS
 

1. O-antigen

The monosaccharide nature of the O-antigen region, combined with its glycosidic bond position, stereochemistry, and modifiability, makes it the most variable part of the LPS. The high degree of variability of this region determines the antigenic properties of the bacteria, protecting them from the toxic effects of antibiotics as well as resisting lysis by the complement system. In addition, O-antigens are involved in bacterial-bacterial and bacterial-phage interactions.
 

2. core OS region

The core OS region has less structural variability than the O-antigen and can be further divided into inner and outer core OS. Typically, the inner core OS region is characterized by the monosaccharide Kdop, and the outer core OS region is more variable than the inner core OS region. The core OS chains can also be modified by substitutions of other chemical groups, which are closely related to the divalent cations on the surface of LPS and may also affect the folding and assembly as well as the physiological role of LPS in the bacterial outer membrane.
 

3. Lipid A

As the biologically active center of LPS, lipid A usually consists of two D-GlcpN units: two glucosamine, phosphate, and several fatty acids. The hydrophobic lipid A is linked to the inner core oligosaccharide chain by a ketone glycoside bond, which additionally anchors LPS to the bacterial outer membrane. Although the structure of lipid A is highly conserved, small structural changes will affect the immunostimulatory properties of lipid A. These changes may result from factors such as selective pressures on the bacteria from the environment, bacterial self-adaptation, and external stimuli.

LPS Receptor

Shedding LPSs express their effects through TLR4 present in the cell membrane of the target cell. The TLR family has been implicated in the expression of inflammatory cytokines and plays an important role in natural immunity. To date, 10 molecules belonging to the TLR family are known to be present in the human body. The extracellular structural domains of the TLR family possess structures such as the leucine-rich repeat sequence (LRR). The LRR is composed of a repeating structure between leucine, which is subordinate to one of the amino acids, and a regularly arranged leucine-rich motif (LRM). In addition, the intracellular structural domain known as the Toll/IL-1R homology region (TIR structural domain) is a domain that shares identity with the IL-1 receptor and other molecules belonging to the IL-1 receptor family (IL-18). In recent years, in addition to TLR4, it has been reported that the intracellular protein Nod, which possesses the LRR, is also functioning as a LPS receptor.

The recognition mechanism of LPS in the presence of TLR4 is initiated first in the form of LPS capture by endotoxin-binding proteins, which are then delivered to CD14 molecules. In addition, the LPS-CD14 complex is supposed to bind to TLR4, but the recognition has to be done with the MD-2 molecule.

LPS Signal Transduction

TLR4-mediated signaling pathways.

The intracellular signaling pathway formed through ligand binding is then the same as the IL-1 receptor, as described below.

First, when LPS binds to TLR4, it activates IL-1 Receptor Associating Kinase, IRAK, via Myeloid Differentiation Protein-88 (MyD88). In addition, it exhibits its transcriptional activity by stimulating the activation of NFκB (Nuclear Factor Kappa-B) and the MAP kinase family, among others, which are associated with inflammatory responses, through TNF Receptor-associated Factor-6, which is located downstream of IRAK.
Application of LPS
 

• ● Establishment of disease-related animal models: LPS, as an endotoxin, can activate monocytes to release cytokines and thus initiate a systemic inflammatory response.

• ● Immunological experiments: LPS are immunogens and can be used to prepare antibodies or detect antibodies. Different serotypes of lipopolysaccharide can be used to detect infection or immune status of specific strains of bacteria.

• ● LPS is an important component of bacterial virulence and different serotypes of LPS can be used to assess bacterial virulence.

• ● Drug screening experiment: LPS can stimulate the immune response, and different serotypes of lipopolysaccharide can be used to screen antibacterial drugs or immunomodulators.

• ● Infection modeling experiments: different serotypes of LPS can be used to establish animal infection models to study the pathogenesis of bacterial infections and immune responses.

• ● Vaccine research experiments: LPS is an important component of the vaccine, different serotypes of LPS can be used to study the immunogenicity and protective effect of the vaccine.

In conclusion, different serotypes of LPS have a wide range of applications in immunology, microbiology, and drug research.
 
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