Article

ISSN 0006-2979, Biochemistry (Moscow), 2026, Vol. 91, No. 1, pp. S133-S162 © Pleiades Publishing, Ltd., 2026.

Russian Text © The Author(s), 2026, published in Uspekhi Biologicheskoi Khimii, 2026, Vol. 66, pp. 179-220.

S133

REVIEW

Application of Proteins Binding Components

of Bacterial Cell Wall for Extraction, Concentration,

and Analysis of Biological Samples

Ekaterina Yu. Epova

1,a

*, Elena V. Trubnikova

, Nikita G. Yabbarov

1,b

Elena D. Nikolskaya

, Maksim A. Klimenko

, Margarita V. Chirkina

Mariia R. Mollaeva

, Maria B. Sokol

, and Ilya N. Kurochkin

Emanuel Institute of Biochemical Physics of the Russian Academy of Sciences, 119334 Moscow, Russia

e-mail: cat-epova@mail.ru

e-mail: yabbarovng@gmail.com

Received September 2, 2025

Revised September 19, 2025

Accepted October 27, 2025

Abstract— Proteins that bind components of bacterial cell wall play a key role in innate immunity and in-

teractions between bacteria and host organisms. They participate in the control of peptidoglycan synthesis

and degradation, determine the pathogenic specificity of bacteria, affect their ability to adhere and invade,

and serve as important elements of molecular recognition. The review discusses proteins of diverse origins

and their recombinant analogues, their structure and binding mechanisms, and prospects for application

in the diagnostics of bacterial infections and functionalization of nanomaterials.

DOI: 10.1134/S000629792560406X

Keywords: bacterial cell wall, pathogen-associated molecular patterns, pattern recognition receptors, Toll-like

receptors, lectins, peptidoglycan recognition proteins, scavenger receptors, bacterial infection diagnostics

* To whom correspondence should be addressed.

INTRODUCTION

According to the World Health Organization, in-

fectious diseases are among the top ten causes of

death worldwide [1]. Hundreds of bacterial species

can cause severe infections in humans[2]. The grow-

ing antibiotic resistance has re-established pathogenic

bacteria as a major global health threat. Antibiotic

resistance is closely associated with nosocomial infec-

tions, which frequently lead to disease exacerbation.

Early diagnostics are therefore essential for effective

management of bacterial infections and prevention

of complications, as it enables timely administration

of targeted antimicrobial therapy and helps limit the

spread of drug-resistant pathogens [3, 4].

Currently, the gold standard for diagnosing bac-

terial infections relies on colony counting methods

and biochemical tests for antibiotic resistance [5].

However, conventional microbiological methods are

time-consuming, as they typically require 18-24  h or

longer to yield results, which makes them unsuitable

for clinical scenarios that need immediate interven-

tion [6].

The reproducibility of genomic methods used as

alternatives to conventional culture-based techniques,

such as quantitative PCR, fluorescence in  situ hybrid-

ization (FISH), and 16S rRNA gene sequencing, is of-

ten insufficient to meet the requirements of clinical

diagnostics [7]. Moreover, these approaches generally

fail to provide information on the antibiotic suscep-

tibility, as direct identification of resistance determi-

nants is not feasible in most cases [8].

A variety of methods have been developed for

the rapid phenotypic characterization of bacterial

pathogens, including enzyme-linked immunosorbent

assay (ELISA), impedance measurement, mass spec-

trometry (MS), Raman spectroscopy, image analysis,

and others [4]. However, their performance can be

inconsistent when applied to complex biological sys-

tems [9]. Samples, such as whole blood, stool, saliva,

and sputum, are particularly challenging due to their

multicomponent composition and high viscosity [9-11].

EPOVA et al.S134

BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

In addition, pathogenic bacteria in these samples are

often present at concentrations too low for reliable

analysis [7]. Consequently, successful phenotyping

typically requires preliminary sample preparation,

including selective capture, extraction, and concen-

tration of bacterial cells. For this purpose, function-

alized substrates or particles coated with molecular

recognition agents can be used as sorbents [12-14],

enabling rapid isolation and concentration of in-

tact bacterial cells without sample centrifugation or

chromatographic separation and greatly simplifying

sample processing [15]. The choice of molecules for

functionalization is critical for ensuring the specific-

ity and reliability of the method. Various recognition

systems have been reported in the literature that em-

ploy aptamers, bacteriophages, enzymes, lectins, anti-

bodies, and affinity molecules [16].

This review examines innate immune receptors,

members of the immunoglobulin superfamily (IgSF)

and scavenger receptors (SRs), as well as their appli-

cation as molecular recognition elements in the diag-

nostics of bacterial infections. These receptors show

considerable promise due to their ability to specifical-

ly bind molecular structures exposed on the surfaces

of various groups of bacteria, including pathogenic

species, thereby reducing the risk of false-negative

diagnostic outcomes [16]. Such receptor–bacterium

interactions typically do not have the bactericidal ef-

fects, which is critically important for accurate phe-

notyping of antibiotic resistance. Moreover, many of

these receptors exhibit a modular architecture with

defined ligand-binding domains, which facilitates the

rational design of chimeric proteins.

BACTERIAL CELL WALL COMPONENTS

CRITICAL FOR RECOGNITION

To understand the mechanisms of pattern rec-

ognition receptors (PRRs), it is essential to consider

the nature of their primary ligands. The most import-

ant of these ligands are in the bacterial cell wall, a

structure that plays a fundamental role in maintain-

ing cell morphology and protecting bacteria from

external stresses. The cell wall is an essential com-

ponent of most bacteria, providing the maintenance

of cell shape and protection against mechanical and

osmotic stresses [17,18]. Pathogen-associated molecu-

lar patterns (PAMPs), which are absent from eukary-

otic cells, serve as universal targets recognized by

the innate immune system. Peptidoglycan (PGN, also

known as murein), teichoic acids, lipopolysaccharides

(LPSs), and bacterial lipoproteins are of particular

importance among PAMPs. These components vary in

their chemical composition and organization between

Gram-positive and Gram-negative bacteria.

Peptidoglycans. PGN is a three-dimensional

polymeric matrix composed of alternating residues of

N-acetylglucosamine (GlcNAc) and N-acetylmuramic

acid (MurNAc) linked by β-1,4 glycosidic bonds. Short

peptide fragments (peptide stems) are covalently at-

tached to MurNAc residues, and cross-linking between

these peptides creates a rigid scaffold of the bacterial

cell wall. The interpeptide linkers may include vari-

ous L- and D-amino acids (L- and D-alanine, L-serine,

D-glutamate, L-ornithine, and others), contributing to

the structural diversity of PGNs [19, 20].

Two major types of PGN are distinguished: the

lysine-type and the meso-diaminopimelic acid (meso-

DAP)-type. The lysine-type PGN is characteristic of

Gram-positive cocci, such as Staphylococcus aureus,

where cross-linking occurs via the bridging peptide

connecting L-lysine residues in the peptide stems.

Incontrast, the meso-DAP type is typical of Gram-neg-

ative bacteria and many bacilli (e.g., Escherichia coli

and Bacillus subtilis), in which cross-links are formed

directly through meso-DAP residues in peptide stems

(Fig. 1a) [21].

The degree of PGN cross-linking varies among

bacterial species: in E.  coli, most murein chains re-

main uncross-linked, whereas in S.  aureus, more than

90% of murein is covalently cross-linked[22]. Studies

in E. coli have demonstrated that the composition of

muropeptides depends on the metabolic state of the

cell [23]. Thus, during the transition of a bacterial

culture from the exponential growth to the stationary

phase, the length of PGN chains decreases, the de-

gree of cross-linking increases [24], and the amount

of PGN per cell surface area unit changes[25]. In ad-

dition, PGN undergoes continuous remodeling during

cell growth: hydrolases cleave their fragments, while

newly synthesized units are incorporated into the ma-

trix. The resulting muropeptides exhibit pronounced

immunomodulatory properties [26].

Cell wall of Gram-positive bacteria. In Gram-

positive bacteria, the thick PGN layer is covalently

linked to teichoic and lipoteichoic acids. These poly-

mers, composed of glycerol, mannitol, or ribitol

residues, provide structural rigidity, mediate cation

binding, and contribute to ion homeostasis (Fig.  1b)

[27-29].

The cell wall of Gram-positive bacteria also func-

tions as a scaffold for surface-exposed proteins that

mediate interactions with the environment. These in-

clude covalently anchored M proteins of Streptococ-

cus pyogenes, protein  A of S.  aureus, and non-cova-

lently bound autolysins, lysostaphins, bacteriophage

lytic enzymes, and S-layer proteins [30]. Collectively,

these proteins serve both structural and virulence-re-

lated roles, facilitating immune evasion.

Cell wall of Gram-negative bacteria. In Gram-

negative bacteria, the thin PGN layer resides in the

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Fig.  1. a)  Structures of lysine-type (left) and meso-DAP-type (right) PGNs[21]. b) Cell wall architecture of Gram-positive and

Gram-negative bacteria (top) and PGN organization (bottom).

periplasmic space, which also contains enzymes, trans-

port proteins, and chaperones. Externally, the cell is

enclosed by the outer membrane, whose major struc-

tural components are LPSs. LPS consist of three parts:

lipid  A, core oligosaccharide, and O-specific polysac-

charide (O-antigen). Lipid A is the most conserved

fragment, whereas the core oligosaccharide and O-an-

tigen exhibit structural variability that determines

the serological specificity [29,  31]. The outer mem-

brane is anchored to the PGN layer via lipoproteins,

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BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

whose N-termini are modified with fatty acids [32]

and inserted into the outer membrane, while the

C-termini associate with PGN  [33]. Most bacterial li-

poproteins feature conserved triacylated cysteine

residues at the N-termini [34, 35], whereas mycoplas-

mal lipopeptides contain diacylated cysteines[36]. All

these structures serve as canonical PAMPs recognized

by PRRs. The outer membrane also contains porins

and proteins involved in transport, secretion, and as-

sembly of surface structures (Fig.  1b).

Overall, bacterial cell wall components are key

PAMPs that activate the innate immune system. PGNs,

teichoic acids, LPSs, and lipoproteins are recognized

by PRRs and trigger signaling cascades that lead to

phagocyte activation, production of inflammatory me-

diators, and initiation of adaptive immune responses.

INNATE IMMUNITY

AND PATTERN RECOGNITION RECEPTORS

Innate immunity plays an essential role in the

host’s defense against infection. Since pathogenic mi-

croorganisms pose a constant threat, their prolifer-

ation must be tightly and rapidly regulated by the

host’s immune mechanisms. However, an excessively

strong response aimed at complete pathogen elimina-

tion can cause significant collateral damage to host

tissues. Innate immunity represents an evolutionarily

conserved system that provides the first line of de-

fense against pathogens, maintains homeostasis by

activating effector mechanisms, and induces the ex-

pression of endogenous signals regulating processes

such as inflammation and cell death [37].

In invertebrates, the primary immune cells re-

sponsible for pathogen recognition are hemocytes cir-

culating in the hemolymph [38]. In vertebrates, the

main components of the innate immune system are

leukocytes; they not only detect pathogenic microor-

ganisms but also initiate adaptive immunity respons-

es [39]. While innate immunity lacks the antigen

specificity and immune memory toward individual

antigens, it is characterized by rapid recognition and

activation in response to external stimuli [40].

Pathogens have evolved diverse adaptive strate-

gies to evade or suppress innate immune mechanisms.

These strategies include the disruption of innate sig-

naling pathways via secretion of effector proteins,

modulation of host’s anti-inflammatory responses,

and structural alterations of microbial antigens. For

example, Listeria monocytogenes, Mycobacterium tu-

berculosis, Mycobacterium smegmatis, S.  aureus, and

Neisseria meningitidis have evolved mechanisms to

modify their PGN, preventing its recognition by the

host immune system and facilitating efficient infec-

tion [41].

The concept of pathogen recognition by the in-

nate immunity system has driven the discovery of

numerous PRRs [42,  43]. The competition between

the hosts and pathogens is thought to direct the evo-

lution of innate immunity toward the recognition of

conserved molecular structures shared across broad

groups of pathogens [37]. Indeed, PRRs exhibit broad

specificity and can potentially bind diverse molecules

sharing common structural motifs [44, 45]. As a re-

sult, PRRs can interact not only with pathogenic mi-

croorganisms but also with other microbial compo-

nents [37]. The structures recognized by the immune

system are distinct from host’s antigens, thereby

preventing damage to the host’s own cells and tis-

sues. These pathogen-associated structures include

LPSs of Gram-negative bacteria and teichoic acids of

Gram-positive bacteria, viral double-stranded RNAs,

mannans from yeast cell wall, and others [37].

In animals, PRRs include membrane-bound, in-

tracellular, and secreted receptors with diverse spec-

ificities that enable the detection of a broad range

of molecular signatures from viral, bacterial, fungal,

and multicellular pathogens [41]. Depending on the

receptor type, PRR activation can trigger multiple re-

sponses, including hemolymph coagulation, cell agglu-

tination, release of antimicrobial factors, generation

of reactive oxygen species, cytokine production, ac-

tivation of phenoloxidase, phagocytosis, recruitment

of immune cells, and induction of adaptive immune

responses [46, 47]. PRRs are essential components of

the innate immune system. Unlike adaptive immune

system receptors expressed by lymphocytes (T-cell

receptors, TCRs), PRRs are encoded by genes present

in the inherited genome. They are constitutively ex-

pressed, recognize a wide variety of pathogens, and

provide rapid systemic response to the pathogen in-

vasion. PRRs are predominantly expressed by innate

immune effector cells, including dendritic cells, nat-

ural killer (NK) cells, monocytes/macrophages, and

granulocytes, as well as by endothelial and epithelial

cells that among the first cells to encounter invading

pathogens [37, 48]. This distribution 0f PRRs enables

both immediate activation of innate effector mecha-

nisms within cells and induction of a systemic host’s

response to infectious agents. With the emergence

of adaptive immunity in vertebrates, signals initiat-

ed by innate (nonclonal) receptors have acquired a

central role in regulating the activation and differen-

tiation of lymphocytes bearing clonally specific an-

tigen receptors [49, 50]. Thus, in Drosophila, activa-

tion of the Toll receptor stimulates the synthesis of

antifungal and antibacterial peptides [51, 52], where-

as in mammals, Toll-like receptors (TLRs) induce

the synthesis of cytokines and costimulatory mole-

cules required for the initiation of adaptive immune

response [53].

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BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

PRRs can bind a wide range of molecules that

share common structural motifs [44, 45]. Recognition

of ligands by PRRs activates signaling cascades, such

as nuclear factor κB (NF-κB) and type  I interferon

pathways, and inflammasome assembly. These events

culminate in the production of proinflammatory or

antiviral cytokines and chemokines, enabling the

innate immune system to ensure the host survival

during the early hours of infection [49].

PRRs recognize molecules exposed on the surface

of microorganisms through the catalytically inactive

ligand-binding domain. Ligand binding induces con-

formational changes in this domain and “switches on”

the effector domain, which initiates the downstream

signaling cascades. A defining feature of PRRs is the

functional separation between ligand recognition and

signal transduction that are mediated by different do-

mains. This modular organization allows a relatively

limited number of receptors to respond to a broad

spectrum of ligands and to activate diverse signaling

pathways. As a result, a single microbial component

can be recognized by multiple types of PRRs, ensuring

an appropriate and multifaceted immune response.

Conserved microbial structures recognized by PRRs

are referred to as PAMPs. These include bacterial cell

wall components, such as LPSs of Gram-negative bac-

teria, PGNs, lipoteichoic acids, and lipoproteins [40,  54].

Thus, PRRs recognize conserved microbial molec-

ular structures and trigger essential innate immune

signaling pathways. Their modular organization al-

lows a limited number of receptors to recognize a

broad spectrum of pathogens and to elicit a coordi-

nated host response. These features make PRRs not

only central components of immune defense but also

attractive tools for the development of diagnostic

and biotechnological platforms, as they enable PAMP

binding without compromising bacterial integrity.

Multiple classes of PRRs are involved in the rec-

ognition of bacterial PAMPs. In vertebrates, these in-

clude TLRs, NOD (nucleotide-binding and oligomeri-

zation domain)-like receptors (NLRs), PGN recognition

proteins (PGRPs), and C-type lectin receptors (CLRs)

[40, 55]. Invertebrates possess a more extensive PRR

repertoire, reflecting the absence of adaptive immu-

nity and the inability of invertebrate Toll receptors

to directly bind PAMPs. In addition to the classes

shared with vertebrates, invertebrate PRRs include

lectins, members of the IgSF, β-1,3-glucan recognition

proteins (βGRPs), and lysin motif-containing (LysM)

proteins [40].

LECTINS

Lectins are a diverse group of proteins capable

of specific reversible binding of carbohydrate resi-

dues through the carbohydrate recognition domain

(CRD) without chemically modifying their ligands

[56]. They can be classified according to several cri-

teria, including primary structure, properties of CRD

and associated domains, carbohydrate binding speci-

ficity, and subcellular localization [56-58].

C-type lectin receptors. In animals, PAMP rec-

ognition is mediated by Ca

-dependent lectins of the

CLR family [59,  60]. Compared to other PRRs, CLRs

are more numerous and exhibit greater morpholog-

ical and functional diversity [61]. All Ca

-dependent

lectins contain CRD, which is absent from other types

of animal lectins. The CRD of C-type lectins is a com-

pact globular structure of 110-130 amino acid resi-

dues, characterized by a double loop and two antipar-

allel β-sheets, a unique protein fold distinct from any

other known structure [58, 61]. However, neither the

amino acid sequence nor the three-dimensional struc-

ture of CRD reliably predicts its carbohydrate-binding

specificity, as different lectins may recognize similar

carbohydrate structures [62].

Structural analysis of a typical CRD from the

human mannose-binding C-type lectin revealed con-

served cysteine residues, a characteristic set of hy-

drophobic residues, and invariant glycine and proline

residues. These conserved residues contribute to the

formation of disulfide bonds and hydrophobic core

essential for the establishment of the canonical CRD

fold [63, 64]. Additional residues within the C-termi-

nal domain are involved in the binding of Ca

ion,

which constitutes the central component of the carbo-

hydrate-binding site. Some C-terminal domains bind

multiple Ca

ions; however, in all cases, the carbo-

hydrate-binding activity is invariably associated with

the conserved primary Ca

-binding site [65].

Within the CRD, one of two conserved amino acid

motifs coordinates Ca

and forms hydrogen bonds

with the sugar hydroxyl groups, thereby determining

the primary binding specificity: the Glu-Pro-Asn (EPN)

motif confers specificity for mannose, glucose, fucose,

and GlcNAc, whereas Glu-Pro-Asp (QPD) ensures rec-

ognition of galactose and N-acetylgalactosamine [63,

64, 66].

Animals express two forms of CLRs: soluble and

transmembrane. CLRs lacking the transmembrane do-

mains are found in body fluids, such as mucosal se-

cretions and blood plasma, where they participate in

microbial recognition and activation of host’s defense

mechanisms. Soluble CLRs tend to form extended mul-

timeric structures that enhance their capacity for mi-

crobial capture[40]. Recognition by soluble CLRs pro-

motes opsonization, complement activation, initiation

of phagocytosis, and inhibition of microbial growth.

Soluble CLRs also modulate adaptive immune respons-

es by mediating interactions between antigen-present-

ing cells and microbial surface carbohydrates [65,67].

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BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

Soluble CLRs include ficolins and collectins, such

as mannose-binding lectin (MBL), lung surfactant pro-

teins A and D, and kidney collectin CL-K1 [40, 68].

Collectins. Collectin molecules consists of four

regions: N-terminal leucine-rich repeat (LRR) domain,

collagen-like domain, α-helical domain, and C-ter-

minal CRD. Collectins can assemble into oligomeric

structures. By binding to oligosaccharides and/or lipid

moieties on the surface of microorganisms, collectins

induce microbial aggregation and trigger immune re-

sponses, including modulation of inflammatory and

allergic reactions [69, 70].

A typical representative of the collectin family is

MBL [71]. In rodents, rabbits, and humans, MBL is

synthesized in the liver and then released into the

circulation [72]. Mature MBL consists of three identi-

cal glycosylated subunits of 24  kDa, linked via their

collagen-like domains. These trimers further assemble

into oligomers containing two to six units, forming

a quaternary structure resembling a tulip bouquet

[72-74]. Oligomerization markedly increases the li-

gand-binding affinity of MBL [72]. Within each trim-

er, the ligand-binding sites are spaced approximately

54  Å apart, a distance which readily permits inter-

action with mannose residues of bacterial cell wall

LPSs, but is suboptimal for binding to mannose-con-

taining structures of mammalian origin [71].

MBL recognizes glycans from a wide range of

pathogens, including S.  aureus and group  A hemolyt-

ic streptococci [75,  76]. In the case of the meningo-

coccal pathogen N.  meningitidis, the binding to MBL

depends on the degree of sialylation and is inhibited

for encapsulated isolates [77, 78].

The binding of microorganisms to MBL activates

the lectin pathway of the complement system [71,

72]. In addition, the N-terminal LRR domain of the

MBL bound to a ligand on the microbial cell surface

can interact with collectin receptors on macrophages,

leading to phagocytosis  [79].

Notably, human MBL has been used to generate

functionalized magnetic particles capable of concen-

trating bacterial cells from biological samples [80,

81]. For this purpose, MBL lacking the collagen-like

domain was expressed as a hybrid protein fused to

the Fc fragment of human IgG1 (FcMBL) in CHO-DG44

cells, biotinylated, and immobilized on streptavidin-

coated magnetic particles [80]. FcMBL-coated magnet-

ic particles bound S.  aureus, Candida albicans, and

E.  coli cells, enabling the capture and concentration

of more than 90% bacterial cells from saliva, blood,

and tears.

Ficolins. Ficolins are structurally and function-

ally similar to collectins. At the N-terminus, ficolins

contain the LRR domain, followed by the collagen-like

domain characterized by typical Gly-Xaa-Yaa repeats

of variable length, and the C-terminal fibrinogen

(FBG)-like domain [82-84]. The FBG domain consists

of 220-250 amino acid residues and is found in a

number of proteins other than fibrinogen and ficolins

[85]. Individual ficolin polypeptide chains of approx-

imately 35 kDa assemble into trimers, which further

oligomerize into functional dodecamers [86].

Ficolins bind GlcNAc-containing bacterial glycans

and activate the complement system [87]. L-ficolin

recognizes various encapsulated S.  aureus serotypes,

group  B streptococci, and Streptococcus pneumoniae,

but does not bind nonencapsulated strains [88,  89].

In humans, three types of ficolins have been

identified: M-ficolin, L-ficolin, and H-ficolin. L-ficolin

and H-ficolin circulate in the bloodstream, whereas

M-ficolin is expressed in tissues by activated macro-

phages [82, 90].

Transmembrane CLRs. Transmembrane CLRs

of vertebrates are expressed on the surface of anti-

gen-presenting cells, where they form a high-density

receptor pattern. This organization facilitates strong

interactions with microorganisms over limited con-

tact areas [40]. The binding of microorganisms by

transmembrane CLRs triggers endocytosis, phagocy-

tosis, and antigen presentation to effector cells [91].

Transmembrane CLRs activate diverse intracellular

signaling pathways that directly modulate cellular,

homeostatic, and immune responses [67]. In particu-

lar, CLR activation can induce the release of inflam-

matory mediators [67]. This functional diversity is

enabled by the presence of distinct effector domains

within CLRs.

The cytoplasmic domains of transmembrane

CLRs may contain the immunoreceptor tyrosine-based

activation motif (ITAM), composed of tandem YXXL

repeats, or they may signal through association with

ITAM-bearing adaptor proteins such as the Fc recep-

tor γ-chain (Fig.  2). Other CLRs include the hemi-ITAM

sequence consisting of a single tyrosine-containing

YXXL motif. Some CLRs contain the immunoreceptor

tyrosine-based inhibitory motif (ITIM). Finally, several

CRLs lack both ITAM and ITIM and utilize alternative

signaling pathways [67].

The extracellular domains of many transmem-

brane CLRs, such as the macrophage mannose recep-

tor (MMR), attractin, CD93, or thrombomodulin, can

be shed to perform extracellular functions [92].

Based on their molecular structure, transmem-

brane CLRs are generally classified as either type  I

or type  II receptors[40]. Type  I CLRs feature multiple

CRDs and the N-terminal region exposed on the cell

surface, whereas type  II CLRs have only one extracel-

lular CRD and a cytoplasmic N-terminus. The binding

of type  I CLRs to PAMPs induces endocytosis followed

by antigen presentation [91,  93]. Type  I CLRs include

CD205 and MMR. MMR is expressed on the surface

of tissue macrophages and immature dendritic cells

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BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

Fig.  2. Organization of proteins containing extracellular C-type CRDs and cytoplasmic domains involved in signal trans-

duction. Phosphorylation of tyrosine residues in the ITAMs in the cytoplasmic domain generates binding sites for SH2

domain-containing signaling proteins [65].

and can bind M.  tuberculosis, Mycobacterium kansa-

sii, Klebsiella pneumoniae, S.  pneumoniae, and Fran-

cisella tularensis cells[93]. It primarily interacts with

mannose and fructose, and to a lesser extent with

glucose and GlcNAc. Ligand binding by MMR is me-

diated by several lectin domains [94, 95].

Type II CLRs include Dectin-1, Dectin-2, Mincle,

DC-SIGN (dendritic cell-specific ICAM-3 grabbing

non-integrin), and DNGR-1 (dendritic cell natural kill-

er group receptor-1) [40]. DC-SIGN interacts with a

wide range of bacterial pathogens, including M.  tu-

berculosis, Mycobacterium leprae, Helicobacter pylori,

Lactobacillus reuteri, and Lactobacillus casei [93].

In invertebrates, PRRs of the CLR family are

even more widely distributed than in vertebrates.

Because invertebrates lack adaptive immunity, pro-

tection against pathogens relies entirely on the in-

nate immune system[61]. For example, 34 CLR genes

have been identified in the genome of the tobacco

hornworm (Manduca sexta), encoding proteins with

one, two, or three CRDs [96]; 23  CLR genes in the

silkworm (Bombyx mori) [97]; and 52  CLR genes in

the yellow fever mosquito (Aedes aegypti) [98]. Sin-

gle-CRD CLRs include lectins from the flesh fly Sar-

cophaga peregrina [99] and from the hemolymph of

the American cockroach Periplaneta americana[100].

Immulectins IML-1 and IML-2 from the hemolymph

of M.  sexta larvae, BmLBP from B.  mori, and Hdd15

from the fall webworm (Hyphantria cunea) belong to

a group of humoral PRRs that bind LPSs, contain two

CRDs, are upregulated in response to infection, and

activate the phenoloxidase cascade (a humoral innate

immune pathway in invertebrates) [61].

Galectins. Galectins are S-type lectins that spe-

cifically recognize β-galactosides. They are anchored

to cells via interactions between CRDs and cellular

glycoconjugates. Galectins contain one or several con-

served CRDs and bind ligands irrespectively of the

presence of Ca

ions [101].

Galectins are expressed not only in mammals

but also in birds, fish, nematodes, sponges, and fun-

gi. They play an essential role in immune respons-

es, inflammation, tumor progression, and metastasis

[102-104]. In mammals, galectins are ubiquitously

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BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

expressed in tissues and are found in most cells of

the innate immune system (dendritic cells, macro-

phages, mast cells, NK cells, γδ T cells, and B1 cells)

and adaptive immune system (activated B and T cells)

[105]. Several galectins, in pa1rticular, galectins-1

and -3, have been identified in exosomes derived

from tumor cells and biological samples [106-

109]. Galectin-3 has also been detected in human

sperm-derived exosomes and other sources [110,

111]. Notably, galectin-3 exhibits antimicrobial activ-

ity against bacteria and fungi [112-114]. The pres-

ence of galectin-5 on extracellular vesicles released

by rat reticulocytes is essential for vesicle uptake by

macrophages [115]. Galectin-9 has been identified

on extracellular vesicles derived from nasopharyn-

geal carcinoma cells infected with the Epstein–Barr

virus [116].

Overall, vertebrate galectins are characterized by

diverse ligand specificity. For example, rLhGal-1 from

the redlip mullet (Liza haematocheila) binds both

Gram-positive (Lactococcus garvieae, Streptococcus

iniae, Streptococcus parauberis) and Gram-negative

(E. coli, Edwardsiella tarda, Vibrio anguillarum, Vib-

rio harveyi) bacteria [117]. Human galectin-3 binds

LPSs from K.  pneumoniae, Salmonella enterica, mycol-

ic acids of M.  tuberculosis, the O-antigen of H.  pylori;

it also induces neutrophil recruitment to the sites of

S.  pneumoniae invasion. Moreover, H.  pylori infection

promotes expression of galectin-8 and, to a lesser ex-

tent, galectins-3 and -4 [105]. Mammalian galectins-4

and -8 contain two CRDs located at the at the N- and

C-termini, from which only the N-terminal CRD ex-

hibits bactericidal activity. These CRDs also differ

in ligand specificity, enabling galectins to recognize

both microbial oligosaccharides and endogenous lac-

tosamine-containing glycans. By forming cross-links

between endogenous and exogenous glycans, galec-

tins facilitate opsonization.

Galectins also play important roles in inverte-

brate immunity. For instance, MjGal from the Kuruma

shrimp Marsupenaeus japonicus acts as a typical PRR:

its expression is induced upon infection, and it rec-

ognizes both Gram-positive and Gram-negative bac-

teria. MjGal also binds carbohydrates on the surface

of shrimp hemocytes and potentially mediates their

interactions with pathogens, facilitating phagocyto-

sis and clearance of pathogens from the circulatory

system. Notably, some viruses, bacteria, and proto-

zoan parasites exploit galectins to promote invasion

and evade the host’s immune response [101]. In the

oyster Crassostrea virginica, galectins CvGal1 and

CvGal2 recognize multiple bacterial species, as well

as the protozoan parasite Perkinsus marinus. These

galectins function as opsonins, enhancing pathogen

adhesion and phagocytosis. However, P.  marinus can

survive phagocytosis and replicates within host cells,

leading to systemic infection and high mortality, thus

exemplifying parasite–host coevolution [118].

Interestingly, CvGal contains four non-identical

CRDs, yet minor sequence variations among these

conserved domains do not result in significant dif-

ferences in their binding properties. CvGal can form

cross-links between self and foreign glycans. Remark-

ably, even galectins with a single CRD can mediate

interactions with both pathogen- and host-derived

oligosaccharides. The binding specificity of CRDs is

thought to be regulated by multiple factors, including

local lectin concentration and extent of oligomeriza-

tion, spatial arrangement of multivalent carbohydrate

ligands on the cell surface, CRD solvation, and prop-

erties of the microenvironment in which interactions

occur [119]. Other examples of pathogens exploiting

host galectins for invasion have also been reported

[101, 115, 116].

In addition to the lectin classes discussed above,

other lectins have been identified, including intelec-

tins, which recognize galactose determinants, and

sialic acid-binding lectins (type  I lectins). These pro-

teins largely share the structural and functional fea-

tures of lectins described above.

Therefore, lectins constitute a functionally diverse

group of innate immune molecules, encompassing

transmembrane CLRs, soluble collectins and ficolins,

and calcium-independent galectins. Their capacity to

recognize a broad spectrum of carbohydrates, modu-

lar organization, and diversity of signaling pathways

make lectins key biorecognition molecules and prom-

ising tools in the development of diagnostic and ther-

apeutic applications.

TOLL-LIKE RECEPTORS

TLRs of vertebrates are homologs of Toll recep-

tors first discovered in Drosophila [120]. The Toll

signaling pathway is conserved in many multicellu-

lar organisms [121-123]. In Drosophila, Toll signaling

mediates defense against Gram-positive bacteria and

fungi; its activation induces expression of antimicro-

bial peptides and cellular immune responses [124].

Components of the Toll pathway have been iden-

tified in a broad range of invertebrate species, includ-

ing planarians, mussels, tardigrades, mollusks, crusta-

ceans, and others [125]. In vertebrates, TLRs directly

recognize and bind PAMPs [126, 127]. In contrast, in

insects, PAMP recognition by TLRs is mediated by the

Spätzle protein [128]. Despite these differences, the

cytoplasmic signaling cascades downstream of both

Toll receptors and TLRs are highly conserved. Activa-

tion of either TLRs or Toll receptors leads to the nucle-

ar translocation of NF-κB transcription factors (Dorsal

and Dif in Drosophila and NF-κB p65 in vertebrates),

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BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

Fig.  3. TRL structure.

which in turn activates the expression of antimicro-

bial peptides in insects and cytokines stimulating the

adaptive immune system in vertebrates [122].

TLRs are critical for linking innate and adaptive

immunity, as they regulate the activation of anti-

gen-presenting cells and expression of key cytokines.

TLR signaling directly influences activation, growth,

differentiation, development, and function of T cells

across multiple physiological contexts [53].

To date, 13  TLRs have been identified in mam-

mals. Each recognizes specific ligands and is expressed

in various cell types [129]. TLRs are integrated into

the plasma membrane (TLR1, TLR2, TLR4, TLR5, TLR6,

and TLR10) or can be located in the membranes of

intracellular endosomal compartments, such as endo-

plasmic reticulum, endosomes, lysosomes, and endo-

lysosomes (TLR3, TLR7, TLR8, TLR9, TLR11, TLR12,

and TLR13) [130]. All TLRs undergo N-glycosylation

as a post-translational modification, which is essential

for their normal function, biosynthesis, and secretion

[131].

Structurally, TLRs are type I transmembrane pro-

teins composed of the extracellular, transmembrane,

and cytosolic domains. The ectodomains of TLRs con-

tain 19-25 tandem LRRs, each consisting of 24-29 ami-

no acids and including the XLXXLXLXX motif, along

with other conserved residues. LRRs are composed

of β-strands and α-helices connected by unstructured

regions, forming a horseshoe-shaped structure (Fig.  3)

[132]. The LRR domains are thought to provide rapid

evolutionary adaptation of the ligand-binding speci-

ficity toward recognition of a wide variety of ligands

[131]. More broadly, LRRs are components of domains

involved in specific protein interactions. Approxi-

mately 500 LRR-containing proteins with diverse, of-

ten unknown, functions have been identified in the

human genome [129].

In their inactive state, TLRs exist as monomers in

the membrane. Ligand binding induces receptor di-

merization, resulting in the formation of either homo-

or heterodimers. For example, TLR2 forms heterod-

imers with TLR1 or TLR6 depending on the ligand:

the TLR2–TLR1 complex recognizes triacylated lipo-

peptides, whereas TLR2–TLR6 recognizes diacylated

lipopeptides [35,  129]. The activity of certain TLRs

relies on co-receptors. Thus, effective recognition

of bacterial LPS by TLR4 requires MD-2, CD14, and

LPS-binding protein  [133]. Ligand-induced multim-

erization is considered a critical step in the activation

of multiple TLRs  [35]. Conformational changes in-

duced by ligand binding and/or receptor dimerization

initiate signal transduction to the intracellular Toll/

interleukin-1 receptor (TIR) domain, which in turn

recruits specific adaptor molecules (MyD88, TIRAP,

TRIF, and others), ultimately leading to the activation

of the transcription factor NF-κB and transcription of

proinflammatory cytokine genes [32].

TLRs recognize a broad array of PAMPs from

virtually all known microbial groups. Plasma mem-

brane-associated TLRs primarily detect microbial

surface structures. Several TLR subfamilies can be

distinguished based on recognized PAMPs: the TLR1/

TLR6 subfamily recognizes PGN, TLR2 detects lipo-

proteins and lipopeptides, TLR4 recognizes bacterial

LPS, and TLR5 binds flagellin. In contrast, intracel-

lular TLR3, TLR7, TLR8, and TLR9 recognize nucleic

acids [134-138].

Therefore, TLRs represent a highly conserved

pathogen-recognition system. In invertebrates, Toll

signaling mediates antimicrobial peptide production

via the Toll–Spätzle pathway, whereas mammalian

TLRs directly recognize PAMPs and initiate cascades

leading to the activation of NF-κB and interferon reg-

ulatory factors (IRFs) and production of proinflam-

matory cytokines. By integrating innate and adaptive

immune responses, TLRs play a central role in host

defense and are among the most extensively studied

PRR families.

NOD-LIKE RECEPTORS

NLRs are a family of cytoplasmic PRRs responsible

for the recognition of bacterial cell wall components,

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BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

viral nucleic acids, and endogenous stress signals

[139,  140]. A defining structural feature of these pro-

teins is the presence of the oligomerization-mediating

NACHT domain, C-terminal LRRs involved in ligand

recognition, and N-terminal effector domain (CARD,

PYD, or BIR) providing interactions with adaptor mol-

ecules [141].

Among the best-characterized members of this

family are NOD1 and NOD2. They recognize distinct

PGN fragments: NOD1 binds γ-D-glutamyl-meso-DAP

(iE-DAP) characteristic of Gram-negative bacteria,

while NOD2 binds muramyl dipeptide (MDP), present

in the cell walls of most bacteria. Ligand binding to

NOD1/2 leads to the recruitment of the adaptor RIPK2

protein, activation of NF-κB and MAPK (mitogen-ac-

tivated protein kinase), and subsequent induction of

proinflammatory cytokines and antimicrobial pep-

tides [142].

A distinct subset of NLRs participates in the as-

sembly of inflammasomes, which are multiprotein

complexes responsible for the activation of caspase-1

and processing of IL-1β and IL-18 [143]. The most

extensively studied inflammasome-forming NLR is

NLRP3 activated by a wide range of stimuli, includ-

ing bacterial toxins, uric acid crystals, ATP, and re-

active oxygen species. Other inflammasome-forming

NRLs are NLRP1 and NLRC4, which is activated by

bacterial flagellin.

Collectively, NLRs represent a critical arm of in-

tracellular immune surveillance enabling detection of

bacterial and viral invasion of cytoplasm and endog-

enous stress signals. Their activation provides rapid

production of proinflammatory mediators and initia-

tion of programmed inflammatory responses through

the inflammasome formation.

PEPTIDOGLYCAN RECOGNITION

PROTEINS

PGN recognition proteins (PRPs) are referred to

as PGRPs in invertebrates and PGLYRPs in vertebrates

[144]. Both the PGRP and PGLYRP families play import-

ant roles in pathogen recognition, with different pro-

teins recognizing specific classes of microorganisms

(Fig.  4). In insects, PGRPs constitute the major class

of PRRs. They activate Toll signaling and immune de-

ficiency (Imd) pathways, induce proteolytic cascades

leading to local melanization at infection sites, stim-

ulate the expression of antimicrobial peptides, hydro-

lyze PGN, and trigger phagocytosis [54, 144,145]. The

Imd/Relish pathway specifically contributes to defense

against Gram-negative bacteria, promoting NF-κB-

dependent expression of antimicrobial peptides.

More than a dozen genes encoding PGRPs have

been identified in insects. Alternative splicing of their

transcripts produces short (S) and long (L) splice iso-

forms. For example, in D.  melanogaster, 13 loci gen-

erate 19 splice isoforms, whereas in Anopheles gam-

biae, seven PGRP loci give rise to nine splice isoforms

[149, 150]. Long insect PGRPs are expressed in hemo-

cytes and lack catalytic activity, except for PGRP-LB,

which is expressed in enterocytes and functions as an

N-acetylmuramoyl-L-alanine amidase [144]. PGRP-LC

mediates elimination of primarily of Gram-negative

bacteria and triggers the Imd signaling pathway

[151]. PGRP-LC is the main type  II transmembrane

receptor of the Imd pathway; its activation results in

the processing of Relish, a member of the Rel/NF-κB

family. Activated Relish translocates to the nucleus

where it induces the expression of genes encoding

antibacterial peptides, such as drosomycin, mechniko-

vin, attacin, diptericin (Dpt), and cecropin  A1 (CecA1)

[152-155]. The three PGRP-LC splice isoforms share

identical cytoplasmic and transmembrane domains,

whereas their extracellular domains are only 39%

identical and are activated by different PGNs [155].

PGRP-LCx homodimers recognize polymeric DAP-type

PGN, while PGRP-LCx/PGRP-LCa heterodimers bind

Lys-type PGN [150].

Another form, PGRP-LE, exists as a secreted re-

ceptor, whereas the non-cleaved form functions as

an intracellular receptor [156] that binds DAP-type

PGN [151].

In Drosophila, PGRP-LB binds DAP-type PGN and

is encoded by the gene producing three isoforms:

cytosolic PGRP-LBPA and PGRP-LBPD expressed in

enterocytes and secreted PGRP-LBPC present in the

intestinal lumen [157]. PGRP-LBPC and PGRP-LBPA

represent the same mature protein (PGRP-LBPA/PC),

whereas PGRP-LBPD features an extended N-termi-

nus. PGRP-LB is thought to degrade PGN into non-im-

munogenic fragments, thereby preventing constitutive

systemic immune activation in response to gut micro-

biota [158].

Soluble PGRP-SD binds DAP-type PGN and facili-

tates its representation to PGRP-LC on the cell surface,

thus promoting activation of the Imd pathway [159].

X-ray crystallographic analysis of the PGRP do-

mains of PGRP-LC and PGRP-LE has elucidated the

mechanism of recognition of DAP- and Lys-type PGNs.

In DAP-type PGN recognition, an electrostatic inter-

action occurs between the two negatively charged

carboxyl groups of DAP and an arginine residue in

the PGRPs. In contrast, PGRPs that bind Lys-type PGN

lack this arginine residue [146, 148, 151]. Moreover,

two distinct binding sites were identified in the PGRP

domain: the first binds PGN in an L-shaped groove,

while the second binds a PGN fragment already as-

sociated with the L-shaped groove of another PGRP

domain. This results in the formation of a PGRP ho-

modimer that tightly binds the ligand [146].

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BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

Fig.  4. PGRP complexes with PGN fragments: structure, ligand-induced conformational changes, dimerization, and oligom-

erization. a)  Ribbon diagram of D.  melanogaster PGRP-LE with the C-terminus in complex with a monomeric PGN fragment

of the tracheal cytotoxin (TCT; GlcNAc-1,6-anhydro-MurNAc-L-Ala-D-isoGlu-DAP-D-Ala) [146]. b and  c)  The surface of the

C-terminal domain of human PGLYRP-3 [147] (b) and its complex with N-acetylmuramic acid pentapeptide (MPP)  [147],

which induces conformational changes in the PGRP domain (green), locking the ligand within the PGN-binding groove  (c).

d)  TCT induces dimerization of the extracellular domains of PGRP-LCx (green, space-filling model) and PGRP-LCa (blue

ribbon) through interactions with the PGN-binding groove of PGRP-LCx and second α-helix (α2) of PGRP-LCa [148]. e) Bind-

ing of polymeric PGN to D.  melanogaster PGRP-LCx at the cell surface induces PGRP-LCx oligomerization. Dimerization or

oligomerization of PGRP-LC leads to the activation of the Imd signaling pathway[146].

Short PGRPs of insects recognize Lys-type PGN

and initiate a proteolytic cascade that results in

Spätzle cleavage and release of Toll receptors [160].

An exception is the soluble PGRP-SC1b of Drosophila,

which recognizes DAP-type PGNs. PGRP-SC1b exhib-

its the N-acetylmuramoyl-L-alanine amidase activity,

enabling PGN cleavage and manifestation of bacte-

ricidal properties of PGRP-SC1b [161]. Short PGRPs

are present in the hemolymph, cuticle, and fat bod-

ies, and are sometimes found in intestinal epithelial

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BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

cells and hemocytes [144]. Soluble PGRP-SA, present

in the hemolymph, is required for normal immune

responses to Gram-positive bacteria [162]. PGRP-SA

predominantly recognizes Lys-type PGN [151]. The

binding of Gram-positive PGN by PGRP-SA and GNBP1

(Gram-negative bacteria-binding protein  1) activates a

proteolytic cascade that produces the mature Toll li-

gand [150, 163-165]. Activation of Toll receptors pro-

motes the nuclear translocation of Dif and Dorsal

(members of the Rel/NF-κB family), which induce ex-

pression of the antimicrobial peptide drosomycin [166].

Four PGLYRP genes have been identified in

mammals. PGLYRP-1 encodes the short form PGRP-S

(19-25  kDa); PGLYRP-2 encodes the long form PGRP-L

(up to 90  kDa), while PGLYRP-3 and PGLYRP-4 en-

code the intermediate forms PGRP-Iα and PGRP-Iβ

(40-45  kDa) [167]. All four human PGLYRPs bind PGN,

as well as Gram-positive and Gram-negative bacteria

[168, 169].

PGLYRP-2 is constitutively expressed in the liver

and secreted into the bloodstream. It is also found

in intestinal epithelial cells and is induced in kera-

tinocytes and other epithelial cells in response to

bacteria and cytokines [169]. PGLYRP-2 is the only

N-acetylmuramoyl-L-alanine amidase that hydrolyzes

PGN and reduces its pro-inflammatory activity [144,

170]. It preferentially binds soluble PGNs [171] and

induces inflammatory responses, with its immuno-

modulatory effects occurring independently on the

amidase activity [167].

PGLYRP-1, PGLYRP-3, and PGLYRP-4 are soluble

proteins that exist as homo- and heterodimers linked

by disulfide bonds  [144]. All three proteins exhib-

it direct bactericidal activity against a wide range

of Gram-positive and Gram-negative bacteria  [172].

In addition, PGLYRP-3 stimulates phagocytosis and

modulates immune responses in a context-dependent

manner  [167]. PGLYRP-1 primarily localizes to the

granules of polymorphonuclear leukocytes, whereas

PGLYRP-3 and PGLYRP-4 are expressed in the skin,

eyes, salivary glands, tongue, throat, esophagus, stom-

ach, and intestine  [172]. In mammals, PGLYRP-3 and

PGLYRP-4 contain two non-identical PGRP domains

[160]. The bactericidal activity of these proteins is

mediated through their interaction with PGN. During

bacterial cell division, the PGRP domain binds an

exposed region of PGN and activates the CssR–CssS

two-component system, which detects misfolded se-

creted proteins. The bound PGRP domain is recog-

nized by bacterial cells as a defect in protein secre-

tion, triggering a cascade that results in membrane

depolarization, production of hydroxyl radicals in the

cytoplasm, and, ultimately, bacterial death [170, 172].

Thus, PGRPs/PGLYRPs constitute a family of PRRs

that provide defense in both invertebrates and mam-

mals. In insects, PGRPs participate in humoral and

cellular defense through the Toll, Imd, and phenolox-

idase pathways. In mammals, PGLYRPs combine di-

rect bactericidal activity with enzymatic inactivation

of PGN and immunomodulatory functions. Such func-

tional versatility makes this family one of the most

unique components of innate immunity crucial for

maintaining the balance between inflammation and

tolerance to the microbiota. In addition to PGRP/

PGLYRP, invertebrates possess abundant βGRPs and

GNBPs, which interact with PGRPs and jointly acti-

vate the Toll pathway and the phenoloxidase system.

β-1,3-GLUCAN RECOGNITION

PROTEINS AND GRAM-NEGATIVE

BACTERIA-BINDING PROTEINS

βGRPs are found in most invertebrates, including

insects, crustaceans, and mollusks [173]. βGRPs/GNBPs

are structurally and functionally related to PGRPs:

they act as invertebrate PRRs in the hemolymph and

initiate similar signaling cascades. However, βGRPs/

GNBPs primarily recognize β-1,3-glucans and LPSs,

hereby expanding the spectrum of detectable patho-

gens [173]. GNBPs and βGRPs belong to the same PRR

family that recognizes β-1,3-glucans [174, 175].

The first βGRP was described in the silkworm

B.  mori as a protein capable of binding to the cell

wall of Gram-negative bacteria. The B.  mori GNBP

(BmGNBP) shares sequence similarity with CD14, a

co-receptor of vertebrate TLRs, and specifically binds

anti-CD14 antibodies [176]. Drosophila GNBP1 exhib-

its structural resemblance to CD14 due to its glyco-

sylphosphatidylinositol (GPI)-mediated membrane an-

choring [126].

In insects, βGRPs are expressed in the fat body

and are constitutively present in the hemolymph.

Upon binding to microbial cells, βGRPs activate

the Toll pathway and initiate prophenoloxidase cas-

cades, leading to melanization at the site of tissue

damage [175, 177, 178].

Full-length recombinant βGRPs bind whole bac-

terial cells [175, 177, 179, 180] through the cyste-

ine-rich (CR) domain recognizing β-1,3-glucan, LPSs,

or lipoteichoic acid [178,  181]. Most βGRPs contain

the glucanase-like domain that is susceptible to pro-

teolytic cleavage and generally exhibits lower affin-

ity for polysaccharides than the CR domain [178].

Ligand binding promotes interaction of βGRPs with

an initiating serine protease which undergoes auto-

activation and triggers a series of reactions result-

ing in the proteolytic activation of phenoloxidases,

Spätzle, and other cytokines [182]. However, in βGRP

from the Indianmeal moth Plodia interpunctella, both

CR and glucanase-like domains bind laminarin (solu-

ble β-1,3-glucan). This protein is used for diagnosing

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fungal infections [179, 183]. The glucanase-like do-

main of B.  mori GNBP3 lacks the glucanase activi-

ty and affinity for β-1,3-glucan [173]. Similarly, this

domain is enzymatically inactive in Drosophila and

P.  interpunctella βGRPs, whereas genomes of A.  gam-

biae and Daphnia pulex encode proteins with and

without predicted catalytic sites [178]. Although the

glucanase-like domain had been initially proposed to

have evolved for glucan binding [179], subsequent

evidence indicates that its primary function in cata-

lytically inactive βGRPs is to recruit adaptor proteins

required for the initiation of the serine protease

cascade [175].

Some βGRPs interact with PGRP-family recep-

tors that recognize Lys-type PGN [165]. For example,

Drosophila GNBP1 and GNBP2 participate in the Toll

pathway activation in response to Gram-positive bac-

terial infection [173]. GNBP1 is thought to hydrolyze

Gram-positive PGN with the generation of muropep-

tides that are subsequently recognized by PGRP-SA;

GNBP1 and PGRP-SA physically interact [160, 184].

Target recognition initiates a proteolytic cascade lead-

ing to the activation of Spätzle, the ligand of the Toll

receptor on the surface of immune cells [185].

Three distinct GNBPs have been identified in

D.  melanogaster (DmGNBP1–3). DmGNBP1 exhibits

high affinity for both β-1,3-glucan and LPS and ex-

ists in both soluble and membrane-anchored forms,

the latter being covalently linked to the membrane

via a GPI anchor. DmGNBP3 plays a key role in the

defense against fungal infections and represents an

ortholog of βGRP family proteins from B.  mori and

A.  gambiae [173, 180].

In mosquitoes of the Anopheles genus, GNBPB4 is

of particular importance due to its broad specificity.

In addition to the antibacterial defense, it contributes

to protection against Plasmodium parasites by inter-

acting with Plasmodium berghei ookinetes in the mid-

gut epithelium [185].

Related proteins with similar sequences and

functions have been described in insects from other

orders. For instance, in M.  sexta, recombinant GNBP

induced prophenoloxidase activation in the hemo-

lymph, enhanced antimicrobial peptide expression,

and acted synergistically with PGRP, indicating close

cooperation among different PRRs [186].

Comparative analysis of amino acid sequences

reveals a high degree of conservation among GNBPs

across diverse insect species. Notably, most GNBPs

lack the catalytic residues required for the gluca-

nase hydrolytic activity, indicating that the primary

function of βGRPs/GNBPs is ligand binding and signal

transmission rather than ligand degradation [47, 174,

176, 186-190].

Together with PGRPs, βGRPs/GNBPs form a major

PRR family in invertebrates. While PGRPs primarily

recognize PGN, βGRPs/GNBPs expand the immune

recognition repertoire to include fungal β-1,3-glu-

cans and LPSs from Gram-negative bacteria. Through

their interactions with protease cascades and PGRPs,

βGRPs/GNBPs provide integrate multiple signals and

coordinate activation of the Toll and phenoloxidase

pathways, emphasizing the highly cooperative nature

of invertebrate innate immune system.

IMMUNOGLOBULIN

SUPERFAMILY RECEPTORS

PRRs of the IgSF are characterized by the pres-

ence of one or more Ig-like domains, each forming

a sandwich-like structure composed of two β-sheets.

The IgSF represents one of the largest and diverse

protein families, unified by the presence of these

conserved structural domains. Members of this su-

perfamily play essential roles in cell–cell interactions,

adhesion, and recognition of foreign molecules. Many

IgSF receptors participate in both innate and adap-

tive immune responses, thereby forming a functional

“bridge” between different branches of the immune

system [191].

In invertebrates, IgSF members play a significant

role in immune defense and, similar to mammalian

immunoglobulins, exhibit substantial diversity, which

is critical for their functional activity [192,  193].

A particularly well-studied example is DSCAM (down

syndrome cell adhesion molecule) found in insects

and crustaceans. Through extensive alternative splic-

ing, DSCAM forms tens of thousands of isoforms, each

with unique ligand specificity. This hypervariability

functionally parallels DSCAM with components of the

vertebrate adaptive immune system, enabling recog-

nition of a broad spectrum of pathogens and provid-

ing phenotype-level immune memory in invertebrates

[192,  194].

Another important class is fibrinogen-related

proteins (FREPs), which have been most extensive-

ly studied in the gastropod Biomphalaria glabrata.

FREPs contain variable Ig domains at the N-terminus

and a conserved fibrinogen-like domain of approxi-

mately 200 amino acids at the C-terminus, which is

homologous to the β- and γ-chains of vertebrate fi-

brinogen [195, 196]. Through somatic mutations and

exon loss, FREPs exhibit pronounced polymorphism,

enabling selective binding of a broad range of patho-

gens [192]. For example, FREP3 interacts with bacte-

ria and fungi, whereas FREP2 predominantly binds

sporocysts of pathogenic trematodes [196]. FREP3

has been shown to bind monosaccharides, with the

highest affinity toward α-D-galactose [197,198]. Some

FREPs form multimers, which presumably enhances

their antigen-binding efficiency [199-201].

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FREP analogues have also been described in oth-

er invertebrates, including the Mediterranean mussel

Mytilus galloprovincialis, the mud crab Scylla para-

mamosain, the bay scallop Argopecten irradians, the

signal crayfish Pacifastacus leniusculus, the Chinese

razor clam Sinonovacula constricta, and the Pacific

oyster Crassostrea gigas [198, 202, 203]. The latter

contains the IgSF family member CgIgIT2 composed

of four Ig domains, one fibronectin type III domain,

a transmembrane region, and a cytoplasmic effector

domain. Recombinant CgIgIT2 binds LPSs, PGN, and

mannose, with the highest affinity for LPSs, and effi-

ciently interacts with Gram-negative bacteria (Vibrio

splendidus, V.  anguillarum, E.  coli), Gram-positive

bacteria (S.  aureus, B.  subtilis), and the yeast Pichia

pastoris [204].

Hemolin is a characteristic IgSF receptor in in-

sects, which was first isolated from pupae of Cecro-

pia moth (Hyalophora cecropia) infected with bacte-

ria (Fig.  5) [205]. Hemolin contains four Ig domains

[206, 207]; it is secreted into the hemolymph and also

exists in a membrane-bound form associated with

hemocytes [208].

Hemolin binds LPSs of Gram-negative bacteria

and lipoteichoic acids of Gram-positive bacteria, re-

sulting in microbial agglutination. It does not exhibit

direct bactericidal activity but functions as an agglu-

tinin that restricts pathogen dissemination [206, 210,

211].

Recombinant hemolin expressed in E.  coli cells

induced agglutination of E.  coli cells in the presence

of calcium, thereby confirming its role as a biorecogni-

tion molecule (Fig.  5) [209]. Interestingly, hemolin-like

proteins, which had previously been thought to be

specific to Lepidoptera, have also been identified in

the whiteleg shrimp Litopenaeus vannamei [212].

Thus, IgSF receptors in invertebrates are repre-

sented by a number of specialized molecules (DSCAM,

FREPs, hemolin, CgIgIT2, and others). Their distin-

guishing features are hypervariability and capacity

for multimerization, which substantially broaden the

spectrum of foreign structures they can recognize.

In contrast to PGRPs or βGRPs/GNBPs, IgSF receptors

do not exhibit direct bactericidal activity; instead,

they play a key role in pathogen agglutination, ac-

tivation of signaling cascades, and integration of in-

nate immune responses with more complex adaptive

mechanisms.

PROTEINS CONTAINING THE LysM DOMAIN

LysM is a highly conserved carbohydrate-bind-

ing module of approximately 40 amino acids, that

is widely distributed among proteins in most living

organisms except archaea [213]. LysM binds a vari-

ety of ligands containing GlcNAc [214]. Despite the

variability of their amino acid sequences, LysM do-

mains adopt a highly conserved fold consisting of

two α-helices adjacent to two antiparallel β-strands

[215]. Conserved residues include Ile/Leu at positions

23 and 30 and Asn at position 27. Most LysM-con-

taining proteins contain multiple LysM repeats, which

enhances their ligand-binding affinity [213].

The name LysM originates from the first iden-

tification of these motifs in lysins of Bacillus phage

θ29, which degrade bacterial cell wall [216]. Since

then, LysM domains have been found in numerous

proteins involved in diverse biological processes:

1. In bacteria, LysM sequences are present in PGN

hydrolases, adhesins, and virulence factors[217];

2. In fungi, LysM-containing effector proteins, such

as Ecp6 in Cladosporium fulvum and Slp1 in

Magnaporthe oryzae, block chitin recognition by

plant PRRs [218];

3. In plants, LysM receptor-like proteins (LysM-RLPs)

and receptor-like kinases (LysM-RLKs) recognize

chitin and PGN and initiate immune responses

[79, 215];

Fig.  5. Structure of hemolin (UniProt P25033) (top panel).

Agglutination of E.  coli cells by recombinant hemolin (bot-

tom panel): E.  coli cell in PBS  (a), in PBS with BSA  (b), and

in PBS containing recombinant hemolin  (c) [209].

PROTEINS BINDING COMPONENTS OF BACTERIAL CELL WALLS S147

BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

4. In vertebrates, LysM proteins are represented by

the highly conserved subfamilies LysMD and OXR

[219-221]. Interestingly, expression of these pro-

teins was not induced by bacterial pathogens in

either zebrafish (Danio rerio) or mice (Mus mus-

culus) [220, 222, 223]. The physiological functions

of LysM proteins in vertebrates remain largely

unknown [221].

In contrast to vertebrates, LysM-containing pro-

teins play a more prominent role in the immune de-

fense in invertebrates. They are expressed in hemo-

cytes, gills, and the intestine. These proteins bind

components of bacterial cell wall and can induce the

expression of antimicrobial peptides [222, 224, 225]:

1. In the red swamp crayfish Procambarus clarkii,

PcLysM is strongly upregulated following infec-

tion with V. anguillarum and S. aureus and par-

ticipates in antibacterial defense [222];

2. In the mud crab S.  paramamosain, SpLysMD3 ex-

pression increases upon bacterial invasion. The

knockout of this protein reduces antimicrobial

peptide levels. SpLysMD3 binds Gram-negative

(Vibrio spp., E. coli) and Gram-positive (S.  au-

reus, Bacillus spp.) bacteria and the yeast C.  al-

bicans, confirming its role as a PRR [224];

3. In the Kuruma shrimp M.  japonicus, a LysM pro-

tein regulates the transcription of immune genes

and promotes elimination of V.  anguillarum

in  vivo [226];

4. In the Hong Kong oyster Crassostrea hongkon-

gensis, ChLysM is expressed mainly in hemo-

cytes and gills. It binds PGN and LPSs and exhib-

its direct bactericidal activity against S.  aureus,

B.  subtilis, E.  coli, and Vibrio alginolyticus [227];

5. In the whiteleg shrimp L.  vannamei, LvLysM2

regulates antimicrobial peptide expression and

binds various bacterial polysaccharides [228].

LysM domains are found across virtually all

kingdoms of living organisms. In plants and fungi,

LysM proteins play a key role in the immune recogni-

tion of PAMPs. In vertebrates, their functions remain

poorly characterized. In invertebrates, LysM proteins

function as bona fide PRRs: they bind PGN and LPS,

stimulate the expression of antimicrobial peptides,

and exhibit intrinsic bactericidal activity.

SCAVENGER RECEPTORS

Scavenger receptors (SRs) constitute a function-

ally defined, rather than structurally homologous,

family of innate immune receptors. They are united

by their ability to bind a wide range of endogenous

and exogenous ligands, from modified lipoproteins

and apoptotic cells to bacterial cell wall components.

The SR family includes more than 30 members

grouped into several classes (A-J), which differ in the

architecture of extracellular domains but share over-

lapping functional properties [37, 178].

SRs can interact with LPS, PGN, lipoteichoic ac-

ids, fungal surface polysaccharides, as well as ox-

idized lipids and nucleic acids. Thus, by combining

the properties of PRRs and scavengers, they remove

both pathogenic microbial components and products

of cellular degradation from the organism [229].

In D.  melanogaster, SR-CI has been identified as a

PRR that binds bacteria and mediates their phagocy-

tosis. Mutations in its gene reduce the phagocytic ac-

tivity of hemocytes [229]. Other Drosophila SRs, such

as Croquemort (SCRBQ2), are involved in the clear-

ance of apoptotic cells and can also bind bacterial

components [151]. These findings indicate that insect

SRs perform a dual function, contributing to both the

antibacterial immunity and the maintenance of tissue

homeostasis.

In vertebrates, SRs are represented by multiple

subfamilies [230]:

1. Class  A (SR-A, MARCO). Macrophage receptors

that bind LPS, lipoteichoic acid, and PGN. MARCO

is expressed on macrophages and dendritic cells

and plays a key role in bacterial uptake.

2. Class  B (CD36, SR-BI) participates in lipid metab-

olism and bind bacterial cell components.

3. Class  E (LOX-1) binds oxidized lipoproteins and

bacterial antigens, contributing to endothelial in-

flammatory responses.

4. Class  F (SREC-I) is involved in bacterial phagocy-

tosis and antigen presentation.

Overall, SRs contribute to immunity through mul-

tiple mechanisms including phagocytosis of bacteria

and apoptotic cells, recognition of bacterial cell wall

components (LPS, PGN, lipoteichoic acids), innate im-

mune signal transduction (NF-κB activation, cytokine

production), regulation of inflammation (both pro-

and anti-inflammatory processes), and participation

in autophagy.

Thus, SRs represent a broad and functionally

heterogeneous family of PRRs united by their ability

to bind a wide range of foreign and modified self

molecules. In insects, SRs mediate bacterial phago-

cytosis and clearance of apoptotic cells, whereas in

vertebrates, they play a crucial role in the clearance

of pathogens and endogenous ligands, integrating

immune recognition with the maintenance of tissue

homeostasis.

APPLICATION OF PRRS

AS BIOSENSING MOLECULES

Natural PRRs are molecules with a high selectiv-

ity for conserved PAMPs, which makes them highly

EPOVA et al.S148

BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

Fig. 6. Applications of PRRs: microfluidic devices for binding microbial cell wall components (top); adsorption of microor-

ganisms on particles for concentrating microbial cells from clinical samples prior to analysis (left); investigation of inter-

actions between microorganisms or their cell wall fragments and surfaces, for example, using surface plasmon resonance

(SPR) analysis (right).

attractive as biorecognition modules in diagnostic

and biosensor systems. Unlike antibodies or aptam-

ers, PRRs are directed toward fundamentally con-

served structures of microbial cells, such as PGNs,

LPSs, β-glucans, and mannose-containing oligosac-

charides, ensuring broad applicability and versa-

tility.

Among the most extensively studied PRR-based

sensing platforms are those utilizing TLRs, primari-

ly TLR4, which recognizes LPSs from Gram-negative

bacteria. Immobilized TLR4/MD-2/CD14 complexes

have been employed on SPR and electrochemical

chips for LPS detection and for investigating phago-

cytosis in cell-based models (Fig.  6). These platforms

have demonstrated high sensitivity and compatibility

with clinical matrices [231-233].

PRRs are also used for pathogen concentration

from complex samples. Magnetic carriers functional-

ized with PRRs have proven effective for pre-analyt-

ical enrichment from both purified and clinical sam-

ples. For example, the FcMBL construct consisting of

the IgG Fc fragment fused to MBL can be immobilized

on magnetic particles and used for capturing a broad

spectrum of bacteria, fungi, and viruses, including

antibiotic-lysed cells and free PAMPs (Fig.  6). After

immobilization, such particles can be readily concen-

trated, and the bound components can be identified

using ELISA, sequencing, or mass spectrometry. Such

a platform was developed for rapid diagnostics of

sepsis and has demonstrated effective performance

with clinically relevant blood samples [234].

Proteins of the PGRP family and their recombi-

nant analogues are also recognized as universal ele-

ments of biosensors for detecting PGN. Based on these

platforms, magnetic nanoparticles and nanostruc-

tured substrates have been developed that can selec-

tively catch bacteria for subsequent identification us-

ing surface-enhanced Raman spectroscopy (SERS) or

impedancemetry (Fig. 6). These systems enable rapid

and highly sensitive analysis of both Gram-positive

and Gram-negative microorganisms [235, 236]. For

example, magnetic nanoparticles functionalized with

a PGN-recognizing protein provided selective binding

of S.  aureus from blood for subsequent identification

and analysis of antibiotic resistance, which reduced

the overall assay time and increased the number of

target cells at the detection stage. The enriched cellu-

lar fraction (or a fraction of cell wall fragments) can

then be assessed by SERS on substrates or using me-

tallic particles, impedancemetry, or electrochemical

methods, effectively combining the high specificity of

PRRs with the sensitivity of physicochemical analyti-

cal methods [237].

CLRs, particularly Dectin-1, have been employed

for the detection of fungal β-(1→3)-glucans. For ex-

ample, sensors incorporating immobilized Dectin-1

PROTEINS BINDING COMPONENTS OF BACTERIAL CELL WALLS S149

BIOCHEMISTRY (Moscow) Vol. 91 Suppl. 1 2026

CRD domain have demonstrated high specificity in

amperometric analysis [238]. Other lectin-type PRRs,

e.g., MBL and DC-SIGN, have been used for recogniz-

ing mannose- and fucose-containing bacterial glycans.

Such biosensors enable detection of both bacterial

pathogens and fungal infections [239, 240].

LysM domains, which exhibit high affinity for

GlcNAc, serve as universal modules for designing sen-

sors that bind PGN and chitin. Due to their compact

size and modular architecture, LysM domains are

particularly suitable for integration into nanomate-

rials and construction of multivalent platforms [217,

241, 242].

SRs, including SR-A, MARCO, CD36, LOX-1, and

SREC-I, have also been explored as biorecognition

elements. They bind a broad range of microbial pat-

terns, such as LPS, lipoteichoic acid, and PGN, and

have been employed in studies investigating patho-

gen-binding kinetics using SPR and quartz crystal mi-

crobalance (QCM) methods [243-246].

Thus, PRRs represent promising candidates for

the development of biorecognition platforms. Their

high selectivity toward PAMPs and structural diversi-

ty across families (TLRs, PGRPs, lectin receptors, LysM

domains, SRs) enable the adaptation of sensors to dif-

ferent types of pathogens. Recent studies indicate that

PRR-modified systems may become effective tools for

both the therapy and diagnostics of infectious diseases.

CONCLUSION

PRRs are evolutionary conserved molecules that

serve as the first line of the host’s defense by selec-

tively recognizing bacterial cell wall components. In

this review, we examined the major PRR classes, in-

cluding TLRs, NLRs, PGRPs, βGRPs/GNBPs, lectin re-

ceptors, IgSF members, LysM-containing proteins, and

SRs. Each family possesses unique structural features

and functional specialization, enabling recognition of

a broad range of PAMPs.

PRRs not only initiate innate signaling cascades

but also form the basis for the activation of adaptive

immune response, acting as a link between different

immune system levels. Another key area of research

is understanding how PRRs regulate tolerance toward

commensal microorganisms.

Recent studies highlight a significant potential

of PRRs in biotechnology and medicine, as biorecog-

nition molecules in diagnostic platforms and biosen-

sors. The use of PRRs enables the development of

highly specific detection systems for PGN, LPS, β-glu-

cans, and other microbial PAMPs, opening prospects

for creating advanced diagnostic systems.

Overall, PRRs are both fundamental components

of the innate immunity and promising tools for ap-

plied biotechnology and design of next-generation di-

agnostic platforms.

Abbreviations

βGRP β-1,3-glucan recognition protein

CLRs C-type lectin receptor

IgSF immunoglobulin superfamily

LPS lipopolysaccharide

LysM lysine-binding domain, lysin motif

MBL mannan-binding lectin

NLR NOD (nucleotide-binding oligomeriza-

tion domain)-like receptor

NOD nucleotide binding and oligomeriza-

tion domain

PAMP pathogen-associated molecular pattern

PGN peptidoglycan

PGRP/

PGLYRP

peptidoglycan recognition protein

PRR pattern recognition receptor

SR scavenger receptor

TLR Toll-like receptor

Contributions

E.D.N. and I.N.K. supervised the study; E.Yu.E., E.V.T.,

N.G.Ya., E.D.N., and I.N.K. developed the study con-

cept; E.Yu.E., E.V.T., N.G.Ya., and M.B.S. wrote the text

of the article; M.A.K., M.B.Ch., and M.R.M. prepared

the figures; N.G.Ya. and E.D.N. edited the manuscript.

Funding

This work was supported by the Ministry of Science

and Higher Education of the Russian Federation

(FFZR–2024–0005, agreement No.  075-00422-24-02 dat-

ed May 28, 2024).

Ethics approval and consent to participate

This work does not contain any studies involving hu-

man or animal subjects.

Conflict of interest

The authors of this work declare that they have no

conflicts of interest.

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