Ficolins are innate pattern recognition receptors (PRR) and play integral roles within the innate immune response to numerous pathogens throughout the circulation, as well as within organs. Pathogens are primarily removed by direct opsonisation following the recognition of cell surface carbohydrates and other immunostimulatory molecules or via the activation of the lectin complement pathway, which results in the deposition of C3b and the recruitment of phagocytes. In recent years, there have been a number of studies implicating ficolins in the recognition and removal of numerous bacterial, viral, fungal, and parasitic pathogens. Moreover, there has been expanding evidence highlighting that mutations within these key immune proteins, or the possession of particular haplotypes, enhance susceptibility to colonization by pathogens and dysfunctional immune responses. This review will therefore encompass previous knowledge on the role of ficolins in the recognition of bacterial and viral pathogens, while acknowledging the recent advances in the immune response to fungal and parasitic infections. Additionally, we will explore the various genetic susceptibility factors that predispose individuals to infection.
Ficolins are innate pattern recognition receptors (PRRs) similar to the collectin, the mannose-binding lectin (MBL), and the surfactant proteins (SP). Like the collectins, ficolins consist of an N-terminal rich in cysteine residues, a collagen-like domain composed of glycine-X-Y repeats, and a neck region. However, in the ficolins, the carbohydrate-recognition domain (CRD) of the collectins is replaced by a C-terminal fibrinogen-like domain (FBG; Figure
Ficolin structure and the lectin complement pathway. (a) MBL is composed of a cysteine-rich region, a MASP-interacting collagenous region, and a pathogen-binding carbohydrate recognition domain. Ficolins have structural similarity to MBL, albeit the carbohydrate recognition domain is replaced by a fibrinogen-like domain. (b) There are three main pathways of complement activation: the classical, lectin, and alternative pathways. Ficolins interact with MASPs to cleave C4 and C2 to form the C3 convertase C4bC2a. This results in the cleavage of C3 into C3a and C3b. C3b then functions as an opsonin or enters the alternative pathway forming an amplification loop. Each pathway can also result in the formation of the membrane attack complex following the cleavage of C5 by the C5 convertases C4bC2aC3b or C3BbC3b and subsequent association with C6, C7, C8, and C9.
Ficolins function within innate immunity via the recognition of pathogen-associated molecular patterns (PAMPs) on microbial pathogens. Binding to acetylated polysaccharides on microbial pathogens, in particular
To date, all of the human and rodent ficolins have been observed to activate the lectin-complement pathway (Figures
In this review, we describe updates on the opsonic activity of human and rodent ficolins and explore their role within innate immune responses against pathogens. Moreover, we briefly discuss the effects of single nucleotide polymorphisms on pathogen susceptibility.
The FBG of ficolins is composed of a number of different binding sites that can work synergistically or alone in a complex interaction that allow ficolins to distinguish nonself structures from self. This allows ficolins to play an integral role in the opsonisation of various pathogens whereby they can recognise a vast number of ligands on the microbial cell-surface.
In recent years, it has been discovered that the binding range of M-ficolin is a lot broader than was first anticipated, and the tethering of M-ficolin to the leukocyte surface is due to the recognition of sialic acid by the FBG, in particular 9-
L-ficolin is the best characterised of all of the ficolins and binds to a wide range of antigens, thus allowing L-ficolin to recognise an array of microorganisms. L-ficolin shares a common binding specificity to GlcNAc and GalNAc but also binds to a wider range of structures such as lipoteichoic acid (LTA), 1,3-
H-ficolin shares common binding specificities with the other ficolins, namely, the recognition of the acetylated polysaccharides GlcNAc and GalNAc, but, additionally D-fucose and galactose [
As a consequence of its recognition spectrum (Table
Expression, sugar specificity, and target pathogens of human and rodent ficolins.
Tissues of origin | Gene localization | Sugars | PAMPs | Endogenous/artificial ligands | Pathogen interactions | |
---|---|---|---|---|---|---|
M-ficolin | Cell surface, serum | 9q34 | GlcNAc, GalNAc, LacNAc, SiaLacNAc, CysNAc, sialic acid, gangliosides | Ebola virus glycoprotein, chitin, |
Acetylated human albumin CD43 | |
L-ficolin | Serum | 9q34 | GlcNAc, GalNAc, ManNAc, CysNAc, GlyNAc, NeuNAc, acetylcholine, elastin | Acetylcholine, elastin, corticosteroids | ||
H-ficolin | Serum, bronchus, alveolus, bile | 1p36.11 | GlcNAc, GalNAc, fucose, glucose, acetylsalicylic acid, sialic acid, D-mannose, GlyNAc, CysNAc | LPS, PSA, Ag85 | — | |
Ficolin-A | Serum | 2A3 | GlcNAc, GalNAc | LPS | Fibrinogen | |
Ficolin-B | Peritoneal MØ | 2A3 | GlcNAc, GalNAc, LacNAc, SiaLacNAc, LDL, NeuNAc | — | LDL, fetuin | Nk |
BM, bone marrow; GlcNAc,
Bartlomiejczyk and colleagues also demonstrated M-ficolin binding to
Verma et al. [
Until recently, there had been no reports of M-ficolin binding to
There has been a paucity of information regarding the role of ficolins in immunity to parasites, but due to its recognition spectrum, it would seem likely that M-ficolin would interact with parasites and is an area that needs to be explored.
L-ficolin is undoubtedly the most widely investigated ficolin, and studies have identified important roles within infection and immunity. L-ficolin was first observed to enhance the opsonophagocytosis of
Group B streptococci (GBS), in particular capsular polysaccharide (CPS) from serotypes Ib, III, V, VI, and VIII, is also avidly recognised by L-ficolin, leading to a significant increase in opsonophagocytosis and C3b deposition via the lectin pathway working synergistically with the alternative complement pathway [
L-ficolin has arisen as an important defence molecule within the liver in particular, whereby lower L-ficolin levels are correlated with an increased incidence of bacterial infections and disease severity during sepsis [
Additionally, L-ficolin has been observed to bind to mycobacteria. L-ficolin recognises
A role for L-ficolin in viral defence is now also starting to emerge. Liu et al. [
L-ficolin has been observed to bind to the pathogenic fungus,
Parasitic binding is also a characteristic of L-ficolin. L-ficolin has been observed to bind to glycosylated proteins on the cell surface of
Early work from Sugimoto et al. [
Observations regarding the role of H-ficolin in the defence against viruses are encouraging. Recent studies have exhibited the ability of recombinant H-ficolin, H-ficolin from human serum, and from bronchoalveolar lavage to bind to IAV, the mouse-adapted PR-8H1N1 and a pandemic H1N1 strain [
Similar to L-ficolin, H-ficolin has been implicated in the recognition of
As for L-ficolin, H-ficolin has also recently been observed to bind to the parasites
Until recently, the recognition spectrum of ficolin-A with microorganisms was relatively unknown. However, there has been much progress in characterising the interaction of ficolin-A with pathogens. Hummelshøj et al. [
Ficolin-A has been observed to partake in the activation of the lectin-complement pathway via the association with MASPs. Further interactions with fibrinogen and thrombin have been observed to potentiate the activation of complement on
To date, there have been very few studies implicating ficolin-A or -B in viral recognition. Pan et al. [
We have further characterised the interactions of ficolin-A with
We also recently elucidated a role of the lectin pathway of complement in the defence against
Ficolin-A has also exhibited both pro- and anti-inflammatory potential. Recent evidence suggests that ficolin-A may be capable of binding to LPS- and inhibiting TLR-4-mediated inflammation on mast cells [
Akin to its human orthologue, ficolin-A is also important in the defence against parasites. In an
The current knowledge on the role of ficolin-B in the recognition and defence against pathogens is largely unkown, but Endo et al. [
Single nucleotide polymorphisms (SNPs) can have significant effects on the susceptibility to various infections by altering the function or concentration of ficolins found within serum or organs. Early research in the Garred laboratory indicated that there were large ethnic differences in the distribution of SNPs [
Single nucleotide polymorphisms in ficolin genes contributing to pathophysiology and colonization.
Ficolin gene | rs number | Position | Gene region | Amino acid change | Reference |
---|---|---|---|---|---|
M-ficolin ( |
rs2989727 | -1981G>A | Promoter | — | [ |
rs10120023 | -542G>A | Promoter | — | [ | |
rs10117466 | -144C>A | Promoter | — | [ | |
rs148669884 | +6658G>A | Exon 8 | Ala218Thr | [ | |
rs150625869 | +7895T>C | Exon 9 | Ser268Pro | [ | |
rs1071583 | +7918G>A | Exon 9 | Gln275Gln | [ | |
rs138055828 | +7959A>G | Exon 9 | Asn289Ser | [ | |
L-ficolin ( |
rs3124952 | -986G>A | Promoter | — | [ |
rs3124953 | -602G>A | Promoter | — | [ | |
rs3811140 | -557A>G | Promoter | — | [ | |
rs28969369 | -64A>C | Promoter | — | [ | |
rs175141136 | -4A>G | Promoter | — | [ | |
rs17549193 | +6359C>T | Exon 8 | Thr236Met | [ | |
rs7851696 | +6424G>T | Exon 8 | Ala258Met | [ | |
H-ficolin ( |
rs28357092 | +1637CdC | Exon 5 | Leu117fs | [ |
rs4494157 | +4473C>A | Intron 7 | — | [ |
To date, there have been very few polymorphisms identified in the
Polymorphisms in
Cystic fibrosis patients heterozygous or homozygous for mutant alleles for two SNPs in
Boldt and colleagues [
L-ficolin polymorphisms have been the most widely reported, with polymorphisms in the
Cedzynski and colleagues initially reported four polymorphisms that were linked to extremes in L-ficolin concentrations in a cohort of Polish children suffering from recurrent respiratory infections [
The
The +6359C>T SNP was also reported as a significant risk factor in patients on continuous ambulatory peritoneal dialysis with a history of staphylococcal peritonitis [
B acute lymphoblastic leukemia patients were observed to be at a greater risk of bacterial infections and present prolonged episodes of febrile neutropenia if they possessed a medium-/high-risk haplotype for
Following genotyping of 219 severely injured patients admitted to a level 1 trauma centre over a period of 3 years, a
Although the vast majority of SNPs are associated with a negative output, three SNPs within
SNPs in
Elevated levels of L-ficolin observed in leishmaniasis were reported to be due to the +6359C>T structural variant [
Malaria patients were tested for polymorphisms known to be associated with varying L-ficolin plasma levels, and, although concentrations varied between mild and severe cases of malaria, there was no significant association for any of the haplotypes with disease severity [
Ouf et al., [
SNPs in
As aforementioned,
The first incidence of H-ficolin deficiency was highlighted by Munthe-Fog et al. in 2009 [
Recently, there has also been a link to leprosy. Although there was no direct link observed between polymorphisms in
There has been ever increasing evidence that ficolins play an integral role in a plethora of infectious diseases, additionally mutations within these proteins generally results in enhanced susceptibility to infection. In recent years, there has been a lot of interest in the role of ficolins within fungal disease, with each of the human ficolins and rodent ficolin-A proving beneficial to antifungal immunity. Furthermore, the recognition spectra of both M- and H-ficolin are increasing, but compared to L-ficolin, are still relatively limited. Future research could therefore focus on further exploration of the role of M-ficolin within antifungal immunity and enhancing our knowledge on the roles of M- and H-ficolin within innate immunity.
The authors declare that there is no conflict of interest regarding the publication of this article.
This work was supported by the Faculty of Health, University of East Anglia, UK PhD studentship (FMH 04.4.66 C4).